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Sample records for cisplatin-induced heat hyperalgesia

  1. Transient Receptor Potential Vanilloid 1 is essential for cisplatin-induced heat hyperalgesia in mice

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    Carlton Susan M

    2010-03-01

    Full Text Available Abstract Background Cisplatin is primarily used for treatment of ovarian and testicular cancer. Oxaliplatin is the only effective treatment for metastatic colorectal cancer. Both are known to cause dose related, cumulative toxic effects on the peripheral nervous system and thirty to forty percent of cancer patients receiving these agents experience painful peripheral neuropathy. The mechanisms underlying painful platinum-induced neuropathy remain poorly understood. Previous studies have demonstrated important roles for TRPV1, TRPM8, and TRPA1 in inflammation and nerve injury induced pain. Results In this study, using real-time, reverse transcriptase, polymerase chain reaction (RT-PCR, we analyzed the expression of TRPV1, TRPM8, and TRPA1 induced by cisplatin or oxaliplatin in vitro and in vivo. For in vitro studies, cultured E15 rat dorsal root ganglion (DRG neurons were treated for up to 48 hours with cisplatin or oxaliplatin. For in vivo studies, trigeminal ganglia (TG were isolated from mice treated with platinum drugs for three weeks. We show that cisplatin and oxaliplatin-treated DRG neurons had significantly increased in TRPV1, TRPA1, and TRPM8 mRNA expression. TG neurons from cisplatin treated mice had significant increases in TRPV1 and TRPA1 mRNA expression while oxaliplatin strongly induced only TRPA1. Furthermore, compared to the cisplatin-treated wild-type mice, cisplatin-treated TRPV1-null mice developed mechanical allodynia but did not exhibit enhancement of noxious heat- evoked pain responses. Immunohistochemistry studies showed that cisplatin-treated mice had no change in the proportion of the TRPV1 immunopositive TG neurons. Conclusion These results indicate that TRPV1 and TRPA1 could contribute to the development of thermal hyperalgesia and mechanical allodynia following cisplatin-induced painful neuropathy but that TRPV1 has a crucial role in cisplatin-induced thermal hyperalgesia in vivo.

  2. Secondary hyperalgesia to heat stimuli after burn injury in man

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    Pedersen, J L; Kehlet, H

    1998-01-01

    was not significantly different between the two zones of hyperalgesia. In conclusion, secondary hyperalgesia in man is not restricted to mechanical stimuli, as significant hyperalgesia to heat developed within the zone of secondary hyperalgesia to punctate mechanical stimuli. The data, combined with other evidence......The aim of the study was to examine the presence of hyperalgesia to heat stimuli within the zone of secondary hyperalgesia to punctate mechanical stimuli. A burn was produced on the medial part of the non-dominant crus in 15 healthy volunteers with a 50 x 25 mm thermode (47 degrees C, 7 min......), and assessments were made 70 min and 40 min before, and 0, 1, and 2 h after the burn injury. Hyperalgesia to mechanical and heat stimuli were examined by von Frey hairs and contact thermodes (3.75 and 12.5 cm2), and pain responses were rated with a visual analog scale (0-100). The area of secondary hyperalgesia...

  3. Secondary hyperalgesia to heat stimuli after burn injury in man

    DEFF Research Database (Denmark)

    Pedersen, J L; Kehlet, H

    1998-01-01

    area). The burns decreased pain thresholds and increased pain responses to both thermal and mechanical stimuli within the burn (P hyperalgesia (mean 89 cm2) to punctate mechanical stimuli (P ...The aim of the study was to examine the presence of hyperalgesia to heat stimuli within the zone of secondary hyperalgesia to punctate mechanical stimuli. A burn was produced on the medial part of the non-dominant crus in 15 healthy volunteers with a 50 x 25 mm thermode (47 degrees C, 7 min......), and assessments were made 70 min and 40 min before, and 0, 1, and 2 h after the burn injury. Hyperalgesia to mechanical and heat stimuli were examined by von Frey hairs and contact thermodes (3.75 and 12.5 cm2), and pain responses were rated with a visual analog scale (0-100). The area of secondary hyperalgesia...

  4. Cisplatin Induced Nephrotoxicity

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    Seyed Seifollah Beladi Mousavi

    2014-02-01

    The standard approach to prevent cisplatin-induced nephrotoxicity is the administration of lower doses of cisplatin in combination with the administration of full intravenous isotonic saline before and after cisplatin administration. Although a number of pharmacologic agents including sodium thiosulfate, N-acetylcysteine, theophylline and glycine have been evaluated for prevention of nephrotoxicity, none have proved to have an established role, thus, additional clinical studies will be required to confirm their probable effects.

  5. Hyperalgesia and temporal summation of pain after heat injury in man

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    Pedersen, J L; Andersen, O K; Arendt-Nielsen, L

    1998-01-01

    , in three areas: primary and secondary mechanical hyperalgesia induced by the heat injury, and in a mirror image of the injury on the opposite leg. Temporal summation of pain was induced by repeated electrical stimuli (five stimuli at 2 Hz) and assessed by visual analog scale (VAS). Primary hyperalgesia...... and pain intensity during the induction of heat injury. We conclude that the development of primary and secondary mechanical hyperalgesia after heat injury in man was not associated with changes in temporal summation of painful electrical stimuli....

  6. Is heat pain detection threshold associated with the area of secondary hyperalgesia following brief thermal sensitization?

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    Hansen, Morten Sejer; Wetterslev, Jørn; Pipper, Christian Bressen

    2016-01-01

    if HPDT, a known quantitative sensory test, is associated with areas of secondary hyperalgesia following brief thermal sensitization TRIAL REGISTRATION: Clinicaltrials.gov (Identifier: NCT02527395 ). Danish Research Ethics Committee (Identifier: H-8-2014-012). Danish Data Protection Agency (Identifier: 30-1436)....... investigates different aspects of the human pain response. Brief thermal sensitization induces a mild burn injury, resulting in development of primary hyperalgesia at the site of stimulation, and secondary hyperalgesia surrounding the site of stimulation. Central sensitization is believed to play an important...... role in the development of secondary hyperalgesia; however, a possible association of secondary hyperalgesia following brief thermal sensitization and other heat pain models remains unknown. Our aim with this study is to investigate how close the heat pain detection threshold is associated...

  7. Gender differences in pain and secondary hyperalgesia after heat/capsaicin sensitization in healthy volunteers

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    Jensen, Magnus Thorsten; Petersen, Karin Lottrup

    2006-01-01

    In most published studies women are more sensitive to experimental pain than men. Enhanced central pain processing in women has been suggested, but psychosocial factors might also have affected the findings. Data from five completed healthy volunteer studies were analyzed to investigate gender...... differences in development of secondary hyperalgesia. Cutaneous hyperalgesia was induced with the heat/capsaicin sensitization model. Outcome measures were areas of secondary hyperalgesia to brush and von Frey hair stimulation after heat and capsaicin sensitization, rating of pain during heat....../capsaicin sensitization, and heat pain detection thresholds. There was a trend toward smaller areas of secondary hyperalgesia in women. After adjusting for estimated gender differences in forearm surface area, areas to brush but not von Frey hair stimulation after capsaicin sensitization were larger in women. Peak pain...

  8. Cisplatin-Induced Eosinophilic Pneumonia

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    Hideharu Ideguchi

    2014-01-01

    Full Text Available A 67-year-old man suffering from esophageal cancer was admitted to our hospital complaining of dyspnea and hypoxemia. He had been treated with cisplatin, docetaxel, and fluorouracil combined with radiotherapy. Chest computed tomography revealed bilateral ground-glass opacity, and bronchoalveolar lavage fluid showed increased eosinophils. Two episodes of transient eosinophilia in peripheral blood were observed after serial administration of anticancer drugs before the admission, and drug-induced lymphocyte stimulation test to cisplatin was positive. Thus cisplatin-induced eosinophilic pneumonia was suspected, and corticosteroid was effectively administered. To our knowledge, this is the first reported case of cisplatin-induced eosinophilic pneumonia.

  9. The Area of Secondary Hyperalgesia following Heat Stimulation in Healthy Male Volunteers

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    Hansen, Morten Sejer; Wetterslev, Jørn; Pipper, Christian Bressen;

    2016-01-01

    -individual variation in secondary hyperalgesia elicited by brief thermal sensitization (45°C for 3 min) in healthy volunteers. MATERIAL AND METHODS: Fifty healthy volunteers were included. Areas of secondary hyperalgesia following brief thermal sensitization were investigated by 2 observers on 4 experimental days......, with a minimum interval of 7 days. Additionally, heat pain detection threshold and pain during thermal stimulation (45°C for 1 min.), and the psychological tests Pain Catastrophizing Scale and Hospital Anxiety and Depression Score were applied. RESULTS: For areas of secondary hyperalgesia, an intra...... and above the 3rd quartile considering all included participants. Heat pain detection threshold predicted area of secondary hyperalgesia with an adjusted R2 of 0.20 (P = 0.0006). CONCLUSIONS: We have demonstrated a low intra-individual, and a high inter-individual variation in thermally induced secondary...

  10. Evaluation of heat hyperalgesia and anxiety like-behaviors in a rat model of orofacial cancer.

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    Gambeta, Eder; Kopruszinski, Caroline Machado; Dos Reis, Renata Cristiane; Zanoveli, Janaina Menezes; Chichorro, Juliana Geremias

    2016-04-21

    Pain and anxiety are commonly experienced by cancer patients and both significantly impair their quality of life. Some authors claim that there is a relationship between pain and anxiety, while others suggest that there is not a direct association. In any case, there is indeed a consensus that anxiety impairs the pain condition beyond be under diagnosed and undertreated in cancer pain patients. Herein we investigated if rats presenting heat hyperalgesia induced by orofacial cancer cell inoculation would display anxiety-like behaviors. In addition, we evaluated if pain blockade would result in alleviation of anxiety behaviors, as well as, if blockade of anxiety would result in pain relief. Orofacial cancer was induced in male Wistar rats by inoculation of Walker-256 cells into the right vibrissal pad. Heat facial hyperalgesia was assessed on day 6 after the inoculation, and on this time point rats were submitted to the elevated plus maze and the light-dark transition tests. The influence of lidocaine and midazolam on heat hyperalgesia and anxiety-like behaviors was assessed. The peak of facial heat hyperalgesia was detected 6 days after cancer cells inoculation, and at this time point, rats exhibited increased anxiety-like behaviors. Local treatment with lidocaine (2%/50μL) caused a marked reduction of heat hyperalgesia, but failed to affect the anxiety-like behaviors, while midazolam (0.5mg/kg, i.p.) treatment failed to change the heat threshold, but induced an anxiolytic-like effect. Altogether, our data demonstrated that rats with orofacial cancer present pain- and anxiety-like behaviors, but brief heat hyperalgesia relief does not affect the anxiety-like behaviors, and vice-versa, in our experimental conditions.

  11. Aberrant TRPV1 Expression in Heat Hyperalgesia Associated with Trigeminal Neuropathic Pain

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    Hiroko Urano, Toshiaki Ara, Yoshiaki Fujinami, B. Yukihiro Hiraoka

    2012-01-01

    Full Text Available Trigeminal neuropathic pain is a facial pain syndrome associated with trigeminal nerve injury. However, the mechanism of trigeminal neuropathic pain is poorly understood. This study aimed to determine the role of transient receptor potential vanilloid 1 (TRPV1 in heat hyperalgesia in a trigeminal neuropathic pain model. We evaluated nociceptive responses to mechanical and heat stimuli using a partial infraorbital nerve ligation (pIONL model. Withdrawal responses to mechanical and heat stimuli to vibrissal pads (VP were assessed using von Frey filaments and a thermal stimulator equipped with a heat probe, respectively. Changes in withdrawal responses were measured after subcutaneous injection of the TRP channel antagonist capsazepine. In addition, the expression of TRPV1 in the trigeminal ganglia was examined. Mechanical allodynia and heat hyperalgesia were observed in VP by pIONL. Capsazepine suppressed heat hyperalgesia but not mechanical allodynia. The number of TRPV1-positive neurons in the trigeminal ganglia was significantly increased in the large-diameter-cell group. These results suggest that TRPV1 plays an important role in the heat hyperalgesia observed in the pIONL model.

  12. Bilateral hand/wrist heat and cold hyperalgesia, but not hypoesthesia, in unilateral carpal tunnel syndrome.

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    de la Llave-Rincón, Ana Isabel; Fernández-de-las-Peñas, César; Fernández-Carnero, Josué; Padua, Luca; Arendt-Nielsen, Lars; Pareja, Juan A

    2009-10-01

    The aim of the current study was to evaluate bilaterally warm/cold detection and heat/cold pain thresholds over the hand/wrist in patients with carpal tunnel syndrome (CTS). A total of 25 women with strictly unilateral CTS (mean 42 +/- 10 years), and 20 healthy matched women (mean 41 +/- 8 years) were recruited. Warm/cold detection and heat/cold pain thresholds were assessed bilaterally over the carpal tunnel and the thenar eminence in a blinded design. Self-reported measures included both clinical pain history (intensity, location and area) and Boston Carpal Tunnel Questionnaire. No significant differences between groups for both warm and cold detection thresholds in either carpal tunnel or thenar eminence (P > 0.5) were found. Further, significant differences between groups, but not between sides, for both heat and cold pain thresholds in both the carpal tunnel and thenar eminence were found (all P < 0.001). Heat pain thresholds (P < 0.01) were negatively correlated, whereas cold pain thresholds (P < 0.001) were positively correlated with hand pain intensity and duration of symptoms. Our findings revealed bilateral thermal hyperalgesia (lower heat pain and reduced cold pain thresholds) but not hypoesthesia (normal warm/cold detection thresholds) in patients with strictly unilateral CTS when compared to controls. We suggest that bilateral heat and cold hyperalgesia may reflect impairments in central nociceptive processing in patients with unilateral CTS. The bilateral thermal hyperalgesia associated with pain intensity and duration of pain history supports a role of generalized sensitization mechanisms in the initiation, maintenance and spread of pain in CTS.

  13. Time course of primary and secondary hyperalgesia after heat injury to the skin

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    Møiniche, S; Dahl, J B; Kehlet, H

    1993-01-01

    We have examined the time course of, and relationship between, primary and secondary hyperalgesia after thermal injury to the skin in humans. Burn injuries (15 x 25 mm rectangular thermode, 49 degrees C, 5 min) were produced in eight healthy, unmedicated male volunteers, on the medial side...... of the right calf, on two occasions at least 8 days apart. Heat pain detection thresholds (HPDT), heat pain tolerance (HPT), mechanical pain detection threshold (MPDT) and the intensity of burn-injury induced erythema (skin erythema index, SEI) were assessed inside the burn injury. HPT was assessed only in one...

  14. The Area of Secondary Hyperalgesia following Heat Stimulation in Healthy Male Volunteers: Inter- and Intra-Individual Variance and Reproducibility.

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    Morten Sejer Hansen

    Full Text Available Clinical pain models can be applied when investigating basic physiologic pain responses in healthy volunteers. Several pain models exist; however, only few have been adequately validated. Our primary aim with this prospective study was to investigate the intra- and inter-individual variation in secondary hyperalgesia elicited by brief thermal sensitization (45°C for 3 min in healthy volunteers.Fifty healthy volunteers were included. Areas of secondary hyperalgesia following brief thermal sensitization were investigated by 2 observers on 4 experimental days, with a minimum interval of 7 days. Additionally, heat pain detection threshold and pain during thermal stimulation (45°C for 1 min., and the psychological tests Pain Catastrophizing Scale and Hospital Anxiety and Depression Score were applied.For areas of secondary hyperalgesia, an intra-observer intra-person correlation of 0.85, 95% CI [0.78, 0.90], an intra-observer inter-person correlation of 0.03, 95% CI [0.00, 0.16], and a coefficient of variation of 0.17, 95% CI [0.14, 0.21] was demonstrated. Four percent of the study population had areas of secondary hyperalgesia both below the 1st and above the 3rd quartile considering all included participants. Heat pain detection threshold predicted area of secondary hyperalgesia with an adjusted R2 of 0.20 (P = 0.0006.We have demonstrated a low intra-individual, and a high inter-individual variation in thermally induced secondary hyperalgesia. We conclude that brief thermal sensitization produce secondary hyperalgesia with a high level of reproducibility, which can be applied to investigate different phenotypes related to secondary hyperalgesia in healthy volunteers.clinicaltrials.gov NCT02166164.

  15. The BDNF/TrkB signaling pathway is involved in heat hyperalgesia mediated by Cdk5 in rats.

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    Hong-Hai Zhang

    Full Text Available BACKGROUND: Cyclin-dependent kinase 5 (Cdk5 has been shown to play an important role in mediating inflammation-induced heat hyperalgesia. However, the underlying mechanism remains unclear. The aim of this study was to determine whether roscovitine, an inhibitor of Cdk5, could reverse the heat hyperalgesia induced by peripheral injection of complete Freund's adjuvant (CFA via the brain-derived neurotrophic factor (BDNF-tyrosine kinase B (TrkB signaling pathway in the dorsal horn of the spinal cord in rats. RESULTS: Heat hyperalgesia induced by peripheral injection of CFA was significantly reversed by roscovitine, TrkB-IgG, and the TrkB inhibitor K252a, respectively. Furthermore, BDNF was significantly increased from 0.5 h to 24 h after CFA injection in the spinal cord dorsal horn. Intrathecal adminstration of the Cdk5 inhibitor roscovitine had no obvious effects on BDNF levels. Increased TrkB protein level was significantly reversed by roscovitine between 0.5 h and 6 h after CFA injection. Cdk5 and TrkB co-immunoprecipitation results suggested Cdk5 mediates the heat hyperalgesia induced by CFA injection by binding with TrkB, and the binding between Cdk5 and TrkB was markedly blocked by intrathecal adminstration of roscovitine. CONCLUSION: Our data suggested that the BDNF-TrkB signaling pathway was involved in CFA-induced heat hyperalgesia mediated by Cdk5. Roscovitine reversed the heat hyperalgesia induced by peripheral injection of CFA by blocking BDNF/TrkB signaling pathway, suggesting that severing the close crosstalk between Cdk5 and the BDNF/TrkB signaling cascade may present a potential target for anti-inflammatory pain.

  16. Heat pain detection threshold is associated with the area of secondary hyperalgesia following brief thermal sensitization: a study of healthy male volunteers

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    Hansen, Morten Sejer; Wetterslev, Jørn; Pipper, Christian Bressen; Asghar, Mohammad Sohail; Dahl, Jørgen Berg

    2017-01-01

    Introduction The area of secondary hyperalgesia following brief thermal sensitization (BTS) of the skin and heat pain detection thresholds (HPDT) may both have predictive abilities in regards to pain sensitivity and clinical pain states. The association between HPDT and secondary hyperalgesia, however, remains unsettled, and the dissimilarities in physiologic properties suggest that they may represent 2 distinctively different pain entities. The aim of this study was to investigate the association between HPDT and BTS-induced secondary hyperalgesia. Methods A sample of 121 healthy male participants was included and tested on 2 separate study days with BTS (45°C, 3 minutes), HPDT, and pain during thermal stimulation (45°C, 1 minute). Areas of secondary hyperalgesia were quantified after monofilament pinprick stimulation. The pain catastrophizing scale (PCS) and hospital anxiety and depression scale (HADS) were also applied. Results A significant association between HPDT and the size of the area of secondary hyperalgesia (p<0.0001) was found. The expected change in area of secondary hyperalgesia due to a 1-degree increase in HPDT was estimated to be −27.38 cm2, 95% confidence interval (CI) of −37.77 to −16.98 cm2, with an R2 of 0.19. Likewise, a significant association between HADS-depression subscore and area of secondary hyperalgesia (p=0.046) was found, with an estimated expected change in secondary hyperalgesia to a 1-point increase in HADS-depression subscore of 11 cm2, 95% CI (0.19–21.82), and with R2 of 0.03. We found no significant associations between secondary hyperalgesia area and PCS score or pain during thermal stimulation. Conclusion HPDT and the area of secondary hyperalgesia after BTS are significantly associated; however, with an R2 of only 19%, HPDT only offers a modest explanation of the inter-participant variation in the size of the secondary hyperalgesia area elicited by BTS. PMID:28184167

  17. Cisplatin-induced anorexia and ghrelin.

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    Hattori, Tomohisa; Yakabi, Koji; Takeda, Hiroshi

    2013-01-01

    Cisplatin, a formidable anticancer treatment, is used for several varieties of cancer. There are, however, many cases in which treatment must be abandoned due to a decrease in the patient's quality of life from loss of appetite associated with vomiting and nausea. There is a moderate degree of improvement in prevention of cisplatin-induced nausea and vomiting when serotonin (5-HT) 3 receptor antagonists, neurokinin 1 receptor antagonists, and steroids-either alone or in combination-are administered. The mechanism of action for anorexia, which continues during or after treatment, is, however, still unclear. This anorexia is, similar to the onset of vomiting and nausea, caused by the action of large amounts of 5-HT released as a result of cisplatin administration on tissue 5-HT receptors. Among the 5-HT receptors, the activation of 5-HT2b and 5-HT2c receptors, in particular, seems to play a major role in cisplatin-induced anorexia. Following activation of these two receptors, there is reduced gastric and hypothalamic secretion of the appetite-stimulating hormone ghrelin. There is ample evidence of the usefulness of exogenous ghrelin, synthetic ghrelin agonists, and the endogenous ghrelin signal-enhancer rikkunshito, which are expected to play significant roles in the clinical treatment and prevention of anorexia in future.

  18. Cellular Responses to Cisplatin-Induced DNA Damage

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    Alakananda Basu

    2010-01-01

    Full Text Available Cisplatin is one of the most effective anticancer agents widely used in the treatment of solid tumors. It is generally considered as a cytotoxic drug which kills cancer cells by damaging DNA and inhibiting DNA synthesis. How cells respond to cisplatin-induced DNA damage plays a critical role in deciding cisplatin sensitivity. Cisplatin-induced DNA damage activates various signaling pathways to prevent or promote cell death. This paper summarizes our current understandings regarding the mechanisms by which cisplatin induces cell death and the bases of cisplatin resistance. We have discussed various steps, including the entry of cisplatin inside cells, DNA repair, drug detoxification, DNA damage response, and regulation of cisplatin-induced apoptosis by protein kinases. An understanding of how various signaling pathways regulate cisplatin-induced cell death should aid in the development of more effective therapeutic strategies for the treatment of cancer.

  19. Serum thymic factor, FTS, attenuates cisplatin nephrotoxicity by suppressing cisplatin-induced ERK activation.

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    Kohda, Yuka; Kawai, Yoshiko; Iwamoto, Noriaki; Matsunaga, Yoshiko; Aiga, Hiromi; Awaya, Akira; Gemba, Munekazu

    2005-11-01

    Serum thymic factor (FTS), a thymic peptide hormone, has been reported to attenuate the bleomycin-induced pulmonary injury and also experimental pancreatitis and diabetes. In the present study, we investigated the effect of FTS on cis-diamminedichloroplatinum II (cisplatin)-induced nephrotoxicity. We have already demonstrated that cephaloridine, a nephrotoxic antibiotic, leads to extracellular signal-regulated protein kinase (ERK) activation in the rat kidney, which probably contributes to cephaloridine-induced renal dysfunction. The aim of this study was to examine the effect of cisplatin on ERK activation in the rat kidney and also the effect of FTS on cisplatin-induced nephrotoxicity in rats. In vitro treatment of LLC-PK1 cells with FTS significantly ameliorated cisplatin-induced cell injury. Treatment of rats with intravenous cisplatin for 3 days markedly induced renal dysfunction and increased platinum contents in the kidney cortex. An increase in pERK was detected in the nuclear fraction prepared from the rat kidney cortex from days 1 to 3 after injection of cisplatin. FTS suppressed cisplatin-induced renal dysfunction and ERK activation in the kidney. FTS did not influence any Pt contents in the kidney after cisplatin administration. FTS has been shown to enhance the in vivo expression of heat shock protein (HSP) 70 in the kidney cortex. The beneficial role of FTS against cisplatin nephrotoxicity may be mediated in part by HSP70, as suggested by its up-regulation in the kidney cortex treated with FTS alone. Our results suggest that FTS participates in protection from cisplatin-induced nephrotoxicity by suppressing ERK activation caused by cisplatin.

  20. Differential effects of lidocaine on nerve growth factor (NGF)-evoked heat- and mechanical hyperalgesia in humans.

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    Weinkauf, B; Obreja, O; Schmelz, M; Rukwied, R

    2012-04-01

    We investigated the effects of a non-specific sodium channel blocker (lidocaine) on heat pain thresholds and mechanical impact pain at day 7 and 21 after intradermal injection of 1 μg NGF. Measurements were performed in 12 healthy male subjects prior to and 5 min after intradermal injection of 150 μl lidocaine administered at concentrations of 0.01% (∼0.4 mM) and 0.1% (∼4 mM) to both NGF and control skin sites. NGF caused a maximum reduction of heat pain thresholds at day 7 (NGF 42.6 ± 0.6 vs. 49.4 ± 0.3 °C in control skin). Lidocaine sensitized normal skin for heat pain, but reduced heat hyperalgesia after NGF at day 7 (44.3 ± 0.8 °C, lidocaine 0.1%; p Lidocaine dose-dependently attenuated mechanically-induced pain at both control and NGF-treated sites. Maximum lidocaine effects on mechanical hyperalgesia were recorded at day 21 in NGF skin (pain reduction to VAS 37 ± 4, p lidocaine 0.1%. Lidocaine differentially affects NGF-induced mechanical hyperalgesia (analgesic effect) and heat sensitivity of nociceptors (sensitizing effect). These opposing responses may be attributed to block of sodium channels vs. sensitization of TRPV1. NGF-evoked extreme mechanical impact pain indicates high action potential discharge frequencies, which might be more susceptible to lidocaine block.

  1. Amelioration of cisplatin-induced nephrotoxicity by statins

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    Rajesh A Maheshwari

    2013-01-01

    Conclusions: This finding suggests that simvastatin and rosuvastatin may have a protective effect against cisplatin-induced kidney damage via amelioration of lipid peroxidation as well as due to improvement of renal function, and lipid-lowering effects.

  2. Protective Effect of Tempol against Cisplatin-Induced Ototoxicity.

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    Youn, Cha Kyung; Kim, Jun; Jo, Eu-Ri; Oh, Jeonghyun; Do, Nam Yong; Cho, Sung Il

    2016-11-18

    One of the major adverse effects of cisplatin chemotherapy is hearing loss. Cisplatin-induced ototoxicity hampers treatment because it often necessitates dose reduction, which decreases cisplatin efficacy. This study was performed to investigate the effect of Tempol on cisplatin-induced ototoxicity in an auditory cell line, House Ear Institute-Organ of Corti 1 (HEI-OC1). Cultured HEI-OC1 cells were exposed to 30 μM cisplatin for 24 h with or without a 2 h pre-treatment with Tempol. Cell viability was determined using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and apoptotic cells were identified using terminal deoxynucleotidyl transferase dUTP nick end labeling of nuclei (TUNEL) assay and flow cytometry. The effects of Tempol on cisplatin-induced cleaved poly(ADP-ribose) polymerase, cleaved caspase, and mitochondrial inducible nitric oxide synthase expression were evaluated using western blot analysis. Levels of intracellular reactive oxygen species (ROS) were measured to assess the effects of Tempol on cisplatin-induced ROS accumulation. Mitochondria were evaluated by confocal microscopy, and the mitochondrial membrane potential was measured to investigate whether Tempol protected against cisplatin-induced mitochondrial dysfunction. Cisplatin treatment decreased cell viability, and increased apoptotic features and markers, ROS accumulation, and mitochondrial dysfunction. Tempol pre-treatment before cisplatin exposure significantly inhibited all these cisplatin-induced effects. These results demonstrate that Tempol inhibits cisplatin-induced cytotoxicity in HEI-OC1, and could play a preventive role against cisplatin-induced ototoxicity.

  3. Protective Effect of Tempol against Cisplatin-Induced Ototoxicity

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    Cha Kyung Youn

    2016-11-01

    Full Text Available One of the major adverse effects of cisplatin chemotherapy is hearing loss. Cisplatin-induced ototoxicity hampers treatment because it often necessitates dose reduction, which decreases cisplatin efficacy. This study was performed to investigate the effect of Tempol on cisplatin-induced ototoxicity in an auditory cell line, House Ear Institute-Organ of Corti 1 (HEI-OC1. Cultured HEI-OC1 cells were exposed to 30 μM cisplatin for 24 h with or without a 2 h pre-treatment with Tempol. Cell viability was determined using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT assay and apoptotic cells were identified using terminal deoxynucleotidyl transferase dUTP nick end labeling of nuclei (TUNEL assay and flow cytometry. The effects of Tempol on cisplatin-induced cleaved poly(ADP-ribose polymerase, cleaved caspase, and mitochondrial inducible nitric oxide synthase expression were evaluated using western blot analysis. Levels of intracellular reactive oxygen species (ROS were measured to assess the effects of Tempol on cisplatin-induced ROS accumulation. Mitochondria were evaluated by confocal microscopy, and the mitochondrial membrane potential was measured to investigate whether Tempol protected against cisplatin-induced mitochondrial dysfunction. Cisplatin treatment decreased cell viability, and increased apoptotic features and markers, ROS accumulation, and mitochondrial dysfunction. Tempol pre-treatment before cisplatin exposure significantly inhibited all these cisplatin-induced effects. These results demonstrate that Tempol inhibits cisplatin-induced cytotoxicity in HEI-OC1, and could play a preventive role against cisplatin-induced ototoxicity.

  4. Suramin protects from cisplatin-induced acute kidney injury.

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    Dupre, Tess V; Doll, Mark A; Shah, Parag P; Sharp, Cierra N; Kiefer, Alex; Scherzer, Michael T; Saurabh, Kumar; Saforo, Doug; Siow, Deanna; Casson, Lavona; Arteel, Gavin E; Jenson, Alfred Bennett; Megyesi, Judit; Schnellmann, Rick G; Beverly, Levi J; Siskind, Leah J

    2016-02-01

    Cisplatin, a commonly used cancer chemotherapeutic, has a dose-limiting side effect of nephrotoxicity. Approximately 30% of patients administered cisplatin suffer from kidney injury, and there are limited treatment options for the treatment of cisplatin-induced kidney injury. Suramin, which is Federal Drug Administration-approved for the treatment of trypanosomiasis, improves kidney function after various forms of kidney injury in rodent models. We hypothesized that suramin would attenuate cisplatin-induced kidney injury. Suramin treatment before cisplatin administration reduced cisplatin-induced decreases in kidney function and injury. Furthermore, suramin attenuated cisplatin-induced expression of inflammatory cytokines and chemokines, endoplasmic reticulum stress, and apoptosis in the kidney cortex. Treatment of mice with suramin 24 h after cisplatin also improved kidney function, suggesting that the mechanism of protection is not by inhibition of tubular cisplatin uptake or its metabolism to nephrotoxic species. If suramin is to be used in the context of cancer, then it cannot prevent cisplatin-induced cytotoxicity of cancer cells. Suramin did not alter the dose-response curve of cisplatin in lung adenocarcinoma cells in vitro. In addition, suramin pretreatment of mice harboring lung adenocarcinomas did not alter the initial cytotoxic effects of cisplatin (DNA damage and apoptosis) on tumor cells. These results provide evidence that suramin has potential as a renoprotective agent for the treatment/prevention of cisplatin-induced acute kidney injury and justify future long-term preclinical studies using cotreatment of suramin and cisplatin in mouse models of cancer.

  5. Heat hyperalgesia and mechanical hypersensitivity induced by calcitonin gene-related peptide in a mouse model of neurofibromatosis.

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    Stephanie White

    Full Text Available This study examined whether mice with a deficiency of neurofibromin, a Ras GTPase activating protein, exhibit a nociceptive phenotype and probed a possible contribution by calcitonin gene-related peptide. In the absence of inflammation, Nf1+/- mice (B6.129S6 Nf1/J and wild type littermates responded comparably to heat or mechanical stimuli, except for a subtle enhanced mechanical sensitivity in female Nf1+/- mice. Nociceptive phenotype was also examined after inflammation induced by capsaicin and formalin, which release endogenous calcitonin gene-related peptide. Intraplantar injection of capsaicin evoked comparable heat hyperalgesia and mechanical hypersensitivity in Nf1+/- and wild type mice of both genders. Formalin injection caused a similar duration of licking in male Nf1+/- and wild type mice. Female Nf1+/- mice licked less than wild type mice, but displayed other nociceptive behaviors. In contrast, intraplantar injection of CGRP caused greater heat hyperalgesia in Nf1+/- mice of both genders compared to wild type mice. Male Nf1+/- mice also exhibited greater mechanical hypersensitivity; however, female Nf1+/- mice exhibited less mechanical hypersensitivity than their wild type littermates. Transcripts for calcitonin gene-related peptide were similar in the dorsal root ganglia of both genotypes and genders. Transcripts for receptor activity-modifying protein-1, which is rate-limiting for the calcitonin gene-related peptide receptor, in the spinal cord were comparable for both genotypes and genders. The increased responsiveness to intraplantar calcitonin gene-related peptide suggests that the peripheral actions of calcitonin gene-related peptide are enhanced as a result of the neurofibromin deficit. The analgesic efficacy of calcitonin gene-related peptide receptor antagonists may therefore merit investigation in neurofibromatosis patients.

  6. Mechanisms of cisplatin-induced muscle atrophy

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    Sakai, Hiroyasu, E-mail: sakai@hoshi.ac.jp [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Sagara, Atsunobu; Arakawa, Kazuhiko; Sugiyama, Ryoto; Hirosaki, Akiko; Takase, Kazuhide; Jo, Ara [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Sato, Ken [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Chiba, Yoshihiko [Department of Biology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Yamazaki, Mitsuaki [Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 9300194 (Japan); Matoba, Motohiro [Department of Palliative Medicine and Psychooncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 1040045 (Japan); Narita, Minoru, E-mail: narita@hoshi.ac.jp [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan)

    2014-07-15

    Fatigue is the most common side effect of chemotherapy. However, the mechanisms of “muscle fatigue” induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3 mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only the muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggest that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue. - Highlights: • Cisplatin decreased mass and myofiber diameter in quadriceps muscle. • The mRNA of MAFbx, MuRF1 and FOXO3 were increased by the cisplatin. • The mRNA of myostatin and p21 were upregulated by cisplatin. • The phosphorylation of Akt and FOXO3a was decreased by cisplatin.

  7. Protective effect of metalloporphyrins against cisplatin-induced kidney injury in mice.

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    Hao Pan

    Full Text Available Oxidative and nitrative stress is a well-known phenomenon in cisplatin-induced nephrotoxicity. The purpose of this work is to study the role of two metalloporphyrins (FeTMPyP and MnTBAP, water soluble complexes, in cisplatin-induced renal damage and their ability to scavenge peroxynitrite. In cisplatin-induced nephropathy study in mice, renal nitrative stress was evident by the increase in protein nitration. Cisplatin-induced nephrotoxicity was also evident by the histological damage from the loss of the proximal tubular brush border, blebbing of apical membranes, tubular epithelial cell detachment from the basement membrane, or intra-luminal aggregation of cells and proteins and by the increase in blood urea nitrogen and serum creatinine. Cisplatin-induced apoptosis and cell death as shown by Caspase 3 assessments, TUNEL staining and DNA fragmentation Cisplatin-induced nitrative stress, apoptosis and nephrotoxicity were attenuated by both metalloporphyrins. Heme oxygenase (HO-1 also plays a critical role in metalloporphyrin-mediated protection of cisplatin-induced nephrotoxicity. It is evident that nitrative stress plays a critical role in cisplatin-induced nephrotoxicity in mice. Our data suggest that peroxynitrite is involved, at least in part, in cisplatin-induced nephrotoxicity and protein nitration and cisplatin-induced nephrotoxicity can be prevented with the use of metalloporphyrins.

  8. Cutaneous C-polymodal fibers lacking TRPV1 are sensitized to heat following inflammation, but fail to drive heat hyperalgesia in the absence of TPV1 containing C-heat fibers

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    Koerber H Richard

    2010-09-01

    Full Text Available Abstract Background Previous studies have shown that the TRPV1 ion channel plays a critical role in the development of heat hyperalgesia after inflammation, as inflamed TRPV1-/- mice develop mechanical allodynia but fail to develop thermal hyperalgesia. In order to further investigate the role of TRPV1, we have used an ex vivo skin/nerve/DRG preparation to examine the effects of CFA-induced-inflammation on the response properties of TRPV1-positive and TRPV1-negative cutaneous nociceptors. Results In wildtype mice we found that polymodal C-fibers (CPMs lacking TRPV1 were sensitized to heat within a day after CFA injection. This sensitization included both a drop in average heat threshold and an increase in firing rate to a heat ramp applied to the skin. No changes were observed in the mechanical response properties of these cells. Conversely, TRPV1-positive mechanically insensitive, heat sensitive fibers (CHs were not sensitized following inflammation. However, results suggested that some of these fibers may have gained mechanical sensitivity and that some previous silent fibers gained heat sensitivity. In mice lacking TRPV1, inflammation only decreased heat threshold of CPMs but did not sensitize their responses to the heat ramp. No CH-fibers could be identified in naïve nor inflamed TRPV1-/- mice. Conclusions Results obtained here suggest that increased heat sensitivity in TRPV1-negative CPM fibers alone following inflammation is insufficient for the induction of heat hyperalgesia. On the other hand, TRPV1-positive CH fibers appear to play an essential role in this process that may include both afferent and efferent functions.

  9. Pathophysiology of Cisplatin-Induced Acute Kidney Injury

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    Abdullah Ozkok

    2014-01-01

    Full Text Available Cisplatin and other platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors. A known complication of cisplatin administration is acute kidney injury (AKI. The nephrotoxic effect of cisplatin is cumulative and dose-dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI may result in chronic kidney disease. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, oxidative stress, inflammation, and vascular injury in the kidney. There is predominantly acute tubular necrosis and also apoptosis in the proximal tubules. There is activation of multiple proinflammatory cytokines and infiltration of inflammatory cells in the kidney. Inhibition of the proinflammatory cytokines TNF-α or IL-33 or depletion of CD4+ T cells or mast cells protects against cisplatin-induced AKI. Cisplatin also causes endothelial cell injury. An understanding of the pathogenesis of cisplatin-induced AKI is important for the development of adjunctive therapies to prevent AKI, to lessen the need for dose decrease or drug withdrawal, and to lessen patient morbidity and mortality.

  10. Renoprotective mechanisms of morin in cisplatin-induced kidney injury.

    Science.gov (United States)

    Wei, Zhengkai; He, Xuexiu; Kou, Jinhua; Wang, Jingjing; Chen, Libin; Yao, Minjun; Zhou, Ershun; Fu, Yunhe; Guo, Changming; Yang, Zhengtao

    2015-09-01

    In this study, we investigated the renoprotective effects of morin on cisplatin-induced kidney injury in mice. Serum creatinine and blood urea nitrogen (BUN) levels, glutathione peroxidase (GSH-PX) and superoxide dismutase (SOD) activities were determined according to the corresponding kits. The mRNA levels of TNF-α and IL-1β in kidney tissues were measured by quantitative real-time PCR (qRT-PCR). The activities of cytochrome P450 2E1 (CYP2E1), nuclear factor kappa B (NF-κB) p65, P38 mitogen-activated protein kinase (MAPK), Bax, p53 and cleaved caspase 3 were evaluated by western blotting. The results showed that the model of cisplatin-induced kidney injury was successfully replicated, and morin significantly attenuated histopathological changes and decreased the levels of TNF-α and IL-1β in the kidneys. In addition, morin attenuated the activation of CYP2E1, phospho-NF-κB p65, phospho-P38 MAPK, Bax, phospho-p53 and cleaved caspase 3 in CP-induced kidney injury. In conclusion, these results indicated that the renoprotective mechanisms of morin may be attributed to the suppression of oxidative stress, inflammation and apoptosis in CP-induced kidney injury.

  11. The effect of Thespesia populnea on cisplatin induced nephrotoxicity

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    Denish Mika

    2013-01-01

    Full Text Available Aim of the Study: To study the effect of Thespesia populnea on Cisplatin induced Nephrotoxicity. Materials and Methods: Experiments were conducted on Male Sprague Dawley Rats (4-6 weeks old weighing 100-120g B.Wt. The drug under study was cisplatin, which is an anticancer drug. Thespesia populnea extract was used to test its ability to alleviate the harmful effects of cisplatin. The animals were divided into three groups: Group I was considered as normal, Group II was given a single dose of cisplatin (6 mg/kg/b.wt., i.p and they constituted the control animals and Group III was treated with cisplatin along with Thespesia populnea (5 mg/kg/b.wt., i.p for 10 consecutive days. Results: Administration of cisplatin resulted in significant (P < 0.05 increase in the levels of serum urea (137 ± 1.6, creatinine (1.69 ± 0.14, ALT (96.18 ± 3.44, AST (80.84 ± 3.34 and bilirubin (4.57 ± 0.08 as compared to normal animals. On the other hand, introduction of Thespesia populnea extract caused a significant (P < 0.05 reduction in the levels of serum markers namely urea (112 ± 2.16, creatinine (0.54 ± 0.004, ALT (76.4 ± 1.45, AST (58.80 ± 1.6 and bilirubin (3.96 ± 0.85. Discussion: Increase in the levels of urea and creatinine in serum as well as ALT, AST and bilirubin is suggestive of both kidney and liver damage. Thespesia populnea extract ameliorated cisplatin induced kidney and liver damage as indicated by reduction in the levels of serum urea, creatinine, AST, ALT and bilirubin. Reduction in the levels of these biochemical markers is an indication of regeneration process. Thus it is concluded that the extract might contain nephroprotective compounds such as flavonoids, alkaloids, etc. which are responsible for alleviating cisplatin induced toxicity.

  12. Efficacy of safranal to cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Karafakıoğlu, Yasemin Sunucu; Bozkurt, Mehmet Fatih; Hazman, Ömer; Fıdan, A Fatih

    2017-03-20

    The aim of the present study was to investigate the effects of safranal on cisplatin-induced nephrotoxicity and oxidative stress in rats. Adult male Sprague-Dawley rats were randomly divided into five groups. The control group received physiological saline; animals in Group 2 received only safranal and in Group 3 received only cisplatin; 5 days of safranal treatment was performed following administration of cisplatin for the animals in Group 4; 5 days of safranal pretreatment was applied to the animals in Group 5 before administration of cisplatin. Cisplatin (7 mg/kg) was intraperitoneally injected as a single dose and safranal (200 mg/kg) was administered by gavage. Biochemical and histopathological methods were utilized for evaluation of the nephrotoxicity. The concentrations of creatinine and urea in plasma and levels of malondialdehyde (MDA) and glutathione (GSH) as well as total antioxidant status (TAS) and total oxidant status (TOS) were determined in kidney tissue. Administration of cisplatin to rats induced a marked renal failure, characterized with a significant increase in plasma creatinine and urea concentrations. MDA and TOS levels of rats that received cisplatin alone were not significantly different compared with those of the control group, but GSH and TAS levels in the only cisplatin-administered group were significantly decreased. Safranal administration produced amelioration in biochemical indices of nephrotoxicity in both plasma and kidney tissues when compared with the only cisplatin-administered group, pretreatment with safranal being more effective. As a result, safranal treatment might have a protective effect against cisplatin-induced nephrotoxicity and oxidative stress in rat.

  13. Cisplatin-induced cardiotoxicity: Mechanisms and cardioprotective strategies.

    Science.gov (United States)

    El-Awady, El-Sayed E; Moustafa, Yasser M; Abo-Elmatty, Dina M; Radwan, Asmaa

    2011-01-10

    Increased oxidative stress and apoptosis have been implicated in the cardiotoxicity that limits the clinical use of cisplatin as an anti-tumoral drug. Our study was conducted to evaluate the protective potential of acetyl-l-carnitine, DL-α-lipoic acid and silymarin against cisplatin-induced myocardial injury. Eighty male albino rats were divided into eight groups. The first four groups were treated with normal saline, acetyl-l-carnitine (500mg/kg, i.p.), DL-α-lipoic acid (100mg/kg, p.o.) and silymarin (100mg/kg, p.o.) respectively, for 10 successive days. The remaining groups were treated with the same doses of normal saline, acetyl-l-carnitine, DL-α-lipoic acid and silymarin, respectively, for 5 successive days before and after a single dose of cisplatin (10mg/kg, i.p.). Serum activities of lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme MB (CK-MB) and plasma cardiac troponin I (cTnI) concentration were estimated. Malondialdehyde (MDA), reduced glutathione (GSH) contents, superoxide dismutase activity (SOD) and protein content in cardiac tissues were measured. Moreover, integrity of both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) was also examined. Cisplatin-treated rats experienced a significant elevation of serum activities of LDH, CK, CK-MB and cTnI plasma concentration. These effects were accompanied by a significant increase in MDA level. On the other hand, a significant decrease in GSH content, SOD activity and total protein content was observed. In addition, both mtDNA and nDNA were heavily damaged. However, acetyl-l-carnitine, DL-α-lipoic acid and silymarin significantly attenuated the cisplatin-evoked disturbances in the above-mentioned parameters. In conclusion, the former drugs were proven to be potential candidates to ameliorate cisplatin-induced cardiotoxicity.

  14. Tropisetron attenuates cisplatin-induced nephrotoxicity in mice.

    Science.gov (United States)

    Zirak, Mohammad Reza; Rahimian, Reza; Ghazi-Khansari, Mahmoud; Abbasi, Ata; Razmi, Ali; Mehr, Shahram Ejtemaei; Mousavizadeh, Kazem; Dehpour, Ahmad Reza

    2014-09-05

    Nephrotoxicity is one of the most important complications of cisplatin, a potent chemotherapeutic agent used in the treatment of various malignancies. 5-HT3 antagonists are widely used to counteract chemotherapy-induced emesis and new studies reveal that they poses notable anti-inflammatory properties. In current study, we investigated the effects of 5-HT3 antagonists on cisplatin induced nephrotoxicity in mice. To identify the underlying mechanism of renal protection by tropisetron, we investigated the probable involvement of alpha7 nicotinic acetylcholine receptor (α7nAChR). A single injection of cisplatin (20mg/kg; i.p) induced nephrotoxicity, 5-HT3 antagonists (tropisetron, granisetron and ondansetron,) were given twice daily for 3 day (3mg/kg; i.p). Finally animals were euthanized and blood sample was collected to measure urea and creatinin level. Also kidneys were removed for histopathological examination and biochemical measurements including glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) activity, inducible nitric oxide synthase (iNOS) expression and inflammatory cytokines. Tropisetron decreased the expression of inflammatory molecules including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and iNOS and improved histopathological damage and renal dysfunction. However other 5-HT3 antagonists, granisetron or ondansetron do not have any elicit effects on biochemical markers and histological damages. Since methyllycaconitine, antagonist of α7nAChR, was unable to reverse the beneficial effect of tropisetron, we concluded that this effect of tropisetron is not mediated by α7nAChR.Our results showed that tropisetron treatment markedly ameliorated the experimental cisplatin induced-nephrotoxicity and this effect might be 5-HT3 receptor and α7nAChR independent.

  15. Protection against cisplatin-induced nephrotoxicity by recombinant human erythropoietin.

    Science.gov (United States)

    Yalcin, Suayib; Müftüoğlu, Sevda; Cetin, Eren; Sarer, Banu; Yildirim, Berna Akkuş; Zeybek, Dilara; Orhan, Bülent

    2003-01-01

    Cisplatin (CDDP) is a potent nephrotoxin, and nephrotoxicity is its most important dose-limiting toxicity. In this study, we aimed to investigate the role of recombinant human erythropoietin (rhEPO) in the protection of cisplatin-induced nephrotoxicity and compare its efficacy with the cell-protective agent amifostine. All experiments were conducted on female Wistar albino rats. Animals were randomly assigned to four groups, each including six rats. Group A received only CDDP, group B received CDDP plus rhEPO, group C received CDDP plus amifostine, and group D received only rhEPO. At the end of 7 wk, hemoglobin (Hgb), hematocrite (Htc), blood urea nitrogen (BUN), and creatinine (Cr) levels were determined and kidneys of the rats were removed. The weights of the kidneys were measured and sent for histopathological examination. Proximal tubules from four areas of the kidney (outer cortex, inner cortex, the medullary ray, and outer stripe of outer medulla [OSOM]) were evaluated. There were statistically significant differences among the groups in terms of tubular scores, including overall renal tubular score, cortex, inner cortex, OSOM, and medullary ray tubular scores, and Htc levels. Group A rats had the worse tubular scores in all categories when compared to group D rats. When the results of groups B and C were compared, there were no differences in terms of BUN, Cr levels, and tubular scores, but the Htc level was significantly higher in group B. Group B rats had better overall and OSOM tubular scores when compared to group A. Group C also had better overall and OSOM tubular scores compared to group A. The present study showed for the first time that rhEPO plays an important role in the prevention of cisplatin-induced nephrotoxicity and it is as effective as amifostine.

  16. Disparity in actions of rosiglitazone against cisplatin-induced nephrotoxicity in female Sprague-Dawley rats.

    Science.gov (United States)

    Kumar, Parveen; Prashanth, Krishna Shastrula; Gaikwad, Anil Bhanudas; Vij, Mohit; Barua, Chandana C; Bezbaruah, Babul

    2013-11-01

    Cisplatin is one of the most common chemotherapeutic drugs used against various solid, tumours. Despite of its therapeutic benefits, its use in clinical practice is often limited because of dose, related toxicity. The nephrotoxic potential of cisplatin has been ascribed to its accumulation in the, renal tubular cells generating reactive oxygen species (ROS), activation of Bax, increased secretion of, TNFα and activation of certain inflammatory mediators like cytokines. The present investigation was, undertaken with an objective to study the effect of rosiglitazone against cisplatin induced, nephrotoxicity. Pretreatment of rosiglitazone prevents cisplatin induced nephrotoxicity which was, clearly evident from the renal biochemical parameters like reduced BUN, creatinine and TNFα levels, and increased albumin levels, which was also supported by histopathological studies of the kidneys. In contrast, posttreatment of rosiglitazone was not able to protect the renal damage in cisplatin induced, renal toxicity. These results showed the variation of pre & posttreatment effects of rosiglitazone, against the cisplatin induced nephrotoxicity.

  17. Novel synthetic protective compound, KR-22335, against cisplatin-induced auditory cell death.

    Science.gov (United States)

    Shin, Yoo Seob; Song, Suk Jin; Kang, Sungun; Hwang, Hye Sook; Jung, Young-Sik; Kim, Chul-Ho

    2014-02-01

    Cisplatin [cis-diammine-dichloroplatinum (II)] is a widely used chemotherapeutic agent, and one of its most severe side effects is ototoxicity. In the course of developing a new protective agent against cisplatin-induced ototoxicity, we have been interested in a novel synthetic compound, 3-Amino-3-(4-fluoro-phenyl)-1H-quinoline-2,4-dione (KR-22335). We evaluated the effectiveness of KR-22335 as an otoprotective agent against cisplatin-induced toxicity. The otoprotective effect of KR-22335 against cisplatin was tested in vitro in cochlear organs of Corti-derived cell lines, HEI-OC1, and in vivo in a zebrafish (Danio rerio) model. Cisplatin-induced apoptosis, cell cycle arrest and an increase in intracellular reactive oxygen species (ROS) generation were demonstrated in HEI-OC1 cells. KR-22335 inhibited cisplatin-induced apoptosis and mitochondrial injury in HEI-OC1 cells. KR-22335 inhibited cisplatin-induced activation of JNK, p-38, caspase-3 and PARP in HEI-OC1 cells. Scanning and transmission electron micrographs showed that KR-22335 prevented cisplatin-induced destruction of kinocilium and stereocilia in zebrafish neuromasts. Tissue TUNEL of neuromasts in zebrafish demonstrated that KR-22335 blocked cisplatin-induced TUNEL positive hair cells in neuromasts. The results of this study suggest that KR-22335 may prevent ototoxicity caused by the administration of cisplatin through the inhibition of mitochondrial dysfunction and suppression of ROS generation. KR-22335 may be considered as a potential candidate for protective agents against cisplatin-induced ototoxicity.

  18. Calpain mediated cisplatin-induced ototoxicity in mice*

    Institute of Scientific and Technical Information of China (English)

    Liang Chang; Aimei Wang

    2013-01-01

    Ototoxic drug-induced apoptosis of inner ear cel s has been shown to be associated with calpain expression. Cisplatin has severe ototoxicity, and can induce cochlear cel apoptosis. This study assumed that cisplatin activated calpain expression in apoptotic cochlear cel s. A mouse model of cisplatin-induced ototoxicity was established by intraperitoneal injection with cisplatin (2.5, 3.5, 4.5, 5.5 mg/kg). Immunofluorescence staining, image analysis and western blotting were used to detect the expression of calpain 1 and calpain 2 in the mouse cochlea. At the same time, the auditory brainstem response was measured to observe the change in hearing. Results revealed that after intraperitoneal injection with cisplatin for 5 days, the auditory brainstem response threshold shifts increased in mice. Calpain 1 and calpain 2 expression significantly increased in outer hair cel s, the spiral ganglion and stria vascularis. Calpain 2 protein expression markedly increased with an in-creased dose of cisplatin. Results suggested that calpain 1 and calpain 2 mediated cispla-tin-induced ototoxicity in BALB/c mice. During this process, calpain 2 plays a leading role.

  19. Targeted amelioration of cisplatin-induced ototoxicity in guinea pigs.

    Science.gov (United States)

    Mohan, Shaulnie; Smyth, Brendan J; Namin, Arya; Phillips, Grady; Gratton, Michael Anne

    2014-11-01

    This pilot study compared otoprotection provided by trans-tympanic formulations and systemic intraperitoneal administration of L-N-acetylcysteine from cisplatin-induced cochlear oxidative stress. Protection was assessed by measures of hearing loss and cochlear glutathione levels. All groups received an equivalent single dose of L-N-acetylcysteine followed by cisplatin. Cisplatin was administered subcutaneously for 3 days (5.5 mg/kg/day). Two hours prior to day 1 cisplatin, L-N-acetylcysteine was administered either intraperitoneally (250 mg/kg), trans-tympanic as 2% L-N-acetylcysteine in gel, or trans-tympanic as L-N-acetylcysteine-loaded nanocapsules in gel. Hearing was assessed prior to and 3 days after cisplatin followed by microdissection of cochlear tissue. The levels of reduced (GSH) and oxidized (GSSG) glutathione in homogenized tissue supernatants were determined via luminometry. Intraperitoneal L-N-acetylcysteine administration preceding cisplatin resulted in less hearing loss and a higher GSH/GSSG ratio than either trans-tympanic formulation. This suggests that for equivalent doses of L-N-acetylcysteine, systemic rather than targeted cochlear delivery provides increased otoprotection from cisplatin ototoxicity.

  20. Supraspinal contributions to hyperalgesia

    OpenAIRE

    Urban, M. O.; Gebhart, G. F.

    1999-01-01

    Tissue injury is associated with sensitization of nociceptors and subsequent changes in the excitability of central (spinal) neurons, termed central sensitization. Nociceptor sensitization and central sensitization are considered to underlie, respectively, development of primary hyperalgesia and secondary hyperalgesia. Because central sensitization is considered to reflect plasticity at spinal synapses, the spinal cord has been the principal focus of studies of mechani...

  1. Excitatory Hindbrain-Forebrain Communication Is Required for Cisplatin-Induced Anorexia and Weight Loss.

    Science.gov (United States)

    Alhadeff, Amber L; Holland, Ruby A; Zheng, Huiyuan; Rinaman, Linda; Grill, Harvey J; De Jonghe, Bart C

    2017-01-11

    Cisplatin chemotherapy is commonly used to treat cancer despite severe energy balance side effects. In rats, cisplatin activates nucleus tractus solitarius (NTS) projections to the lateral parabrachial nucleus (lPBN) and calcitonin-gene related peptide (CGRP) projections from the lPBN to the central nucleus of the amygdala (CeA). We demonstrated previously that CeA glutamate receptor signaling mediates cisplatin-induced anorexia and body weight loss. Here, we used neuroanatomical tracing, immunofluorescence, and confocal imaging to demonstrate that virtually all NTS→lPBN and lPBN→CeA CGRP projections coexpress vesicular glutamate transporter 2 (VGLUT2), providing evidence that excitatory projections mediate cisplatin-induced energy balance dysregulation. To test whether lPBN→CeA projection neurons are required for cisplatin-induced anorexia and weight loss, we inhibited these neurons chemogenetically using a retrograde Cre-recombinase-expressing canine adenovirus-2 in combination with Cre-dependent inhibitory Designer Receptors Exclusive Activated by Designer Drugs (DREADDs) before cisplatin treatment. Inhibition of lPBN→CeA neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Using a similar approach, we additionally demonstrated that inhibition of NTS→lPBN neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Together, our data support the view that excitatory hindbrain-forebrain projections are necessary for cisplatin's untoward effects on energy intake, elucidating a key neuroanatomical circuit driving pathological anorexia and weight loss that accompanies chemotherapy treatment.

  2. An Extract of Rhodobacter sphaeroides Reduces Cisplatin-Induced Nephrotoxicity in Mice

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    Wen-Wei Chang

    2013-11-01

    Full Text Available Cisplatin is used as a treatment for various types of solid tumors. Renal injury severely limits the use of cisplatin. Renal cell apoptosis, oxidative stress, and inflammation contribute to cisplatin-induced nephrotoxicity. Previously, we found that an extract of Rhodobacter sphaeroides (Lycogen™ inhibited proinflammatory cytokines and the production of nitric oxide in activated macrophages in a dextran sodium sulfate (DSS-induced colitis model. Here, we evaluated the effect of Lycogen™, a potent anti-inflammatory agent, in mice with cisplatin-induced renal injury. We found that attenuated renal injury correlated with decreased apoptosis due to a reduction in caspase-3 expression in renal cells. Oral administration of Lycogen™ significantly reduced the expression of tumor necrosis factor-α and interleukin-1β in mice with renal injury. Lycogen™ reduces renal dysfunction in mice with cisplatin-induced renal injury. The protective effects of the treatment included blockage of the cisplatin-induced elevation in serum urea nitrogen and creatinine. Meanwhile, Lycogen™ attenuated body weight loss and significantly prolonged the survival of mice with renal injury. We propose that Lycogen™ exerts anti-inflammatory activities that represent a promising strategy for the treatment of cisplatin-induced renal injury.

  3. Tangeretin Alleviates Cisplatin-Induced Acute Hepatic Injury in Rats: Targeting MAPKs and Apoptosis.

    Science.gov (United States)

    Omar, Hany A; Mohamed, Wafaa R; Arab, Hany H; Arafa, El-Shaimaa A

    2016-01-01

    Despite its broad applications, cisplatin affords considerable nephro- and hepatotoxicity through triggering inflammatory and oxidative stress cascades. The aim of the current investigation was to study the possible protective effects of tangeretin on cisplatin-induced hepatotoxicity. The impact of tangeretin on cisplatin-evoked hepatic dysfunction and histopathologic changes along with oxidative stress, inflammatory and apoptotic biomarkers were investigated compared to silymarin. Tangeretin pre-treatment significantly improved liver function tests (ALT and AST), inhibited cisplatin-induced lipid profile aberrations (total cholesterol and triglycerides) and diminished histopathologic structural damage in liver tissues. Tangeretin also attenuated cisplatin-induced hepatic inflammatory events as indicated by suppression of tumor necrosis factor-α (TNF-α) and enhancement of interleukin-10 (IL-10). Meanwhile, it lowered malondialdehyde (MDA), nitric oxide (NO) and nuclear factor erythroid 2-related factor 2 (NRF-2) levels with restoration of glutathione (GSH), and glutathione peroxidase (GPx). Regarding mitogen-activated protein kinase (MAPK) pathway, tangeretin attenuated cisplatin-induced increase in phospho-p38, phospho-c-Jun N-terminal kinase (p-JNK) and phospho-extracellular signal-regulated kinase (p-ERK1/2) in liver tissues. In addition, tangeretin downregulated Bax expression with augmentation of Bcl-2 promoting liver cell survival. Our results highlight the protective effects of tangeretin against cisplatin-induced acute hepatic injury via the concerted modulation of inflammation, oxidative stress, MAPKs and apoptotic pathways.

  4. Tangeretin Alleviates Cisplatin-Induced Acute Hepatic Injury in Rats: Targeting MAPKs and Apoptosis.

    Directory of Open Access Journals (Sweden)

    Hany A Omar

    Full Text Available Despite its broad applications, cisplatin affords considerable nephro- and hepatotoxicity through triggering inflammatory and oxidative stress cascades. The aim of the current investigation was to study the possible protective effects of tangeretin on cisplatin-induced hepatotoxicity. The impact of tangeretin on cisplatin-evoked hepatic dysfunction and histopathologic changes along with oxidative stress, inflammatory and apoptotic biomarkers were investigated compared to silymarin. Tangeretin pre-treatment significantly improved liver function tests (ALT and AST, inhibited cisplatin-induced lipid profile aberrations (total cholesterol and triglycerides and diminished histopathologic structural damage in liver tissues. Tangeretin also attenuated cisplatin-induced hepatic inflammatory events as indicated by suppression of tumor necrosis factor-α (TNF-α and enhancement of interleukin-10 (IL-10. Meanwhile, it lowered malondialdehyde (MDA, nitric oxide (NO and nuclear factor erythroid 2-related factor 2 (NRF-2 levels with restoration of glutathione (GSH, and glutathione peroxidase (GPx. Regarding mitogen-activated protein kinase (MAPK pathway, tangeretin attenuated cisplatin-induced increase in phospho-p38, phospho-c-Jun N-terminal kinase (p-JNK and phospho-extracellular signal-regulated kinase (p-ERK1/2 in liver tissues. In addition, tangeretin downregulated Bax expression with augmentation of Bcl-2 promoting liver cell survival. Our results highlight the protective effects of tangeretin against cisplatin-induced acute hepatic injury via the concerted modulation of inflammation, oxidative stress, MAPKs and apoptotic pathways.

  5. A model for prediction of cisplatin induced nephrotoxicity by kidney weight in experimental rats

    Directory of Open Access Journals (Sweden)

    Mehdi Nematbakhsh

    2013-01-01

    Full Text Available Background: Cisplatin (cis-diamminedichloroplatinum II; CP is used widely as an antitumor drug in clinics, but is accompanied with renal toxicity. Cisplatin induced nephrotoxicity consists of change in kidney weight, histological changes in kidney and increase in serum creatinine (Cr and blood urea nitrogen (BUN. This study was designed to find out a model for prediction of cisplatin induced nephrotoxicity. Materials and Methods: Pathological damage score, kidney weight, BUN, and Cr of 227 rats that were involved in different projects were determined. A total of 187 rats were treated with 7 mg/kg cisplatin and sacrificed 1 week later. Results: There was a good significant correlation between normalized kidney weight and logarithmic scale of BUN and Cr. Relationship between BUN, Cr or normalized kidney weight and pathology damage score was significant. Conclusion: Normalized kidney weight and pathology damage score is a good predictor of renal function in cisplatin induced nephrotoxicity in experimental rats.

  6. Preventive Effect of Dihydromyricetin against Cisplatin-Induced Nephrotoxicity In Vitro and In Vivo

    Directory of Open Access Journals (Sweden)

    Fei Wu

    2016-01-01

    Full Text Available Nephrotoxicity is a frequent severe side effect of cisplatin chemotherapy, limiting its clinical use despite being one of the most potent chemotherapy drugs. Dihydromyricetin is a highly abundant compound purified from the leaves of Ampelopsis grossedentata. Previous studies have demonstrated the anti-inflammatory and antioxidative effects of Dihydromyricetin both in vitro and in vivo, but little is known about the effects of Dihydromyricetin on cisplatin-induced nephrotoxicity and its underlying mechanisms. In the present study, we investigated its potential renoprotective effect and found that Dihydromyricetin ameliorated the renal functional impairment and structural damage caused by cisplatin. Moreover, Dihydromyricetin markedly attenuated cisplatin-induced oxidative stress, as well as protecting against cisplatin-induced inflammation and apoptotic cell death in mouse kidney tissues. These results collectively highlight the potential of DMY as a rational renoprotective agent against cisplatin.

  7. Carnosic acid attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Sahu, Bidya Dhar; Rentam, Kiran Kumar Reddy; Putcha, Uday Kumar; Kuncha, Madhusudana; Vegi, Ganga Modi Naidu; Sistla, Ramakrishna

    2011-12-01

    Nephrotoxicity is one of the serious dose limiting side effects of cisplatin when used in the treatment of various malignant conditions. Accumulating evidence suggests that oxidative stress caused by free radicals and apoptosis of renal cells contributes to the pathogenesis of cisplatin-induced nephrotoxicity. Present study was aimed to explore the effect of carnosic acid, a potent antioxidant, against cisplatin induced oxidative stress and nephrotoxicity in rats. A single dose of cisplatin (7.5mg/kg) caused marked renal damage, characterized by a significant (PGSH (reduced glutathione) levels and lowered tissue nitrite, SOD (superoxide dismutase), CAT (catalase), GSH-Px (glutathione peroxidase), GR (glutathione reductase) and GST (glutathione S-transferase) levels compared to normal control. Carnosic acid treatment significantly (PGSH-Px, GR and GST compared to cisplatin control. The present study demonstrates that carnosic acid has a protective effect on cisplatin induced experimental nephrotoxicity and is attributed to its potent antioxidant and antiapoptotic properties.

  8. Central Diabetes Insipidus and Cisplatin-Induced Renal Salt Wasting Syndrome: A Challenging Combination.

    Science.gov (United States)

    Cortina, Gerard; Hansford, Jordan R; Duke, Trevor

    2016-05-01

    We describe a 2-year-old female with a suprasellar primitive neuroectodermal tumor and central diabetes insipidus (DI) who developed polyuria with natriuresis and subsequent hyponatremia 36 hr after cisplatin administration. The marked urinary losses of sodium in combination with a negative sodium balance led to the diagnosis of cisplatin-induced renal salt wasting syndrome (RSWS). The subsequent clinical management is very challenging. Four weeks later she was discharged from ICU without neurological sequela. The combination of cisplatin-induced RSWS with DI can be confusing and needs careful clinical assessment as inaccurate diagnosis and management can result in increased neurological injury.

  9. Protective effects of pine bark extract against cisplatin-induced hepatotoxicity and oxidative stress in rats

    OpenAIRE

    Ko, Je-Won; Lee,In-Chul; Park, Sung-Hyuk; Moon, Changjong; Kang, Seong-Soo; Kim, Sung-Ho; Kim, Jong-Choon

    2014-01-01

    We investigated the protective effects of pine bark extract (pycnogenol®, PYC) against cisplatin-induced hepatotoxicity and oxidative stress in rats. Twenty-four male rats were divided into the following four groups: (1) vehicle control, (2) cisplatin (7.5 mg/kg), (3) cisplatin & PYC 10 (10 mg/kg/day), and (4) cisplatin & PYC 20 (20 mg/kg/day). A single intraperitoneal injection of cisplatin induced hepatotoxicity, as evidenced by an increase in serum aminotransferase and histopathological al...

  10. Antiemetic role of thalidomide in a rat model of cisplatin-induced emesis.

    Science.gov (United States)

    Han, Zheng-xiang; Xu, Jie; Wang, Hong-mei; Ma, Jan; Sun, Xuan; Du, Xiu-ping

    2014-09-01

    The efficacy of thalidomide to attenuate cisplatin-induced emesis was evaluated in a rat model. Four groups were utilized: control group (peritoneal injection and gastric lavage with normal saline), cisplatin group (peritoneal injection of cisplatin at 10 mg/kg and gastric lavage with normal saline), thalidomide group (cisplatin as above and gastric lavage with thalidomide at 10 mg/kg), and granisetron group (positive control for antiemetic effects; cisplatin given as above and gastric lavage done with granisetron at 0.5 mg/kg). The cisplatin-induced kaolin consumption (pica behavior) was used as a model of emesis in patients. The animals' kaolin and food intakes were measured. Further, medulla and gastric tissues were obtained 5 and 33 h after peritoneal injections to quantify the levels of Substance P and Neurokinin-1 receptor (NK-1R). The cisplatin-induced kaolin consumption was significantly (p thalidomide 72 h after the injection. The levels of Substance P in the medulla and gastric tissue were increased 5 h after the injection in both cisplatin and thalidomide groups, however, returned faster to normal levels in the thalidomide group (p thalidomide, and granisetron group were significantly increased at both 5 and 33 h (p thalidomide attenuates animal equivalent of cisplatin-induced emesis, and this beneficial effect is associated with decreased levels of Substance P levels in the medulla and gastric tissue.

  11. Hydrogen sulfide: A novel nephroprotectant against cisplatin-induced renal toxicity.

    Science.gov (United States)

    Dugbartey, George J; Bouma, Hjalmar R; Lobb, Ian; Sener, Alp

    2016-07-01

    Cisplatin is a potent chemotherapeutic agent for the treatment of various solid-organ cancers. However, a plethora of evidence indicates that nephrotoxicity is a major side effect of cisplatin therapy. While the antineoplastic action of cisplatin is due to formation of cisplatin-DNA cross-links, which damage rapidly dividing cancer cells upon binding to DNA, its nephrotoxic effect results from metabolic conversion of cisplatin into a nephrotoxin and production of reactive oxygen species, causing oxidative stress leading to renal tissue injury and potentially, kidney failure. Despite therapeutic targets in several pre-clinical and clinical studies, there is still incomplete protection against cisplatin-induced nephrotoxicity. Hydrogen sulfide (H2S), the third discovered gasotransmitter next to nitric oxide and carbon monoxide, has recently been identified in several in vitro and in vivo studies to possess specific antioxidant, anti-inflammatory and anti-apoptotic properties that modulate several pathogenic pathways involved in cisplatin-induced nephrotoxicity. The current article reviews the molecular mechanisms underlying cisplatin-induced nephrotoxicity and displays recent findings in the H2S field that could disrupt such mechanisms to ameliorate cisplatin-induced renal injury.

  12. Depletion of Mitofusin-2 Causes Mitochondrial Damage in Cisplatin-Induced Neuropathy.

    Science.gov (United States)

    Bobylev, Ilja; Joshi, Abhijeet R; Barham, Mohammed; Neiss, Wolfram F; Lehmann, Helmar C

    2017-01-21

    Sensory neuropathy is a relevant side effect of the antineoplastic agent cisplatin. Mitochondrial damage is assumed to play a critical role in cisplatin-induced peripheral neuropathy, but the pathomechanisms underlying cisplatin-induced mitotoxicity and neurodegeneration are incompletely understood. In an animal model of cisplatin-induced neuropathy, we determined in detail the extent and spatial distribution of mitochondrial damage during cisplatin treatment. Changes in the total number of axonal mitochondria during cisplatin treatment were assessed in intercostal nerves from transgenic mice that express cyan fluorescent protein. Further, we explored the impact of cisplatin on the expression of nuclear encoded molecules of mitochondrial fusion and fission, including mitofusin-2 (MFN2), optic atrophy 1 (OPA1), and dynamin-related protein 1 (DRP1). Cisplatin treatment resulted in a loss of total mitochondrial mass in axons and in an abnormal mitochondrial morphology including atypical enlargement, increased vacuolization, and loss of cristae. These changes were observed in distal and proximal nerve segments and were more prominent in axons than in Schwann cells. Transcripts of fusion and fission proteins were reduced in distal nerve segments. Significant reduced expression levels of the fusion protein MFN2 was detected in nerves of cisplatin-exposed animals. In summary, we provide for the first time an evidence that cisplatin alters mitochondrial dynamics in peripheral nerves. Loss of MFN2, previously implicated in the pathogenesis of other neurodegenerative diseases, also contributes to the pathogenesis in cisplatin-induced neuropathy.

  13. Protective Activity of Dendropanax Morbifera Against Cisplatin-Induced Acute Kidney Injury

    Directory of Open Access Journals (Sweden)

    Eun-Sun Kim

    2015-01-01

    Full Text Available Background/Aims: Drug-induced acute kidney injury (AKI has been a severe threat to hospitalized patients, raising the urgent needs to develop strategies to reduce AKI. We investigated the protective activity of Dendropanax morbifera (DP, a medicinal plant which has been widely used to treat infectious and pain diseases, on acute kidney injury (AKI using cisplatin-induced nephropathic models. Methods: Both in vitro renal tubular cells (NRK-52E and in vivo rat models were used to demonstrate the nephroprotective effect of DP. Results: Methanolic extract from DP significantly reduced cisplatin-induced toxicity in renal tubular cells. Through successive liquid extraction, the extract of DP was separated into n-hexane, CHCl3, EtOAc, n-BuOH, and H2O fractions. Among these, the CHCl3 fraction (DPCF was found to be most potent. The protective activity of DPCF was found to be mediated through anti-oxidant, mitochondrial protective, and anti-apoptotic activities. In in vivo rat models of AKI, treatment with DPCF significantly reversed the cisplatin-induced increase in blood urea nitrogen and serum creatinine and histopathologic damage, recovered the level of anti-oxidant enzymes, and inhibited renal apoptosis. Conclusion: We demonstrated that DP extracts decreased cisplatin-induced renal toxicity, indicating its potential to ameliorate drug-associated acute kidney damage.

  14. Role of ellagic acid against cisplatin-induced nephrotoxicity and oxidative stress in rats.

    Science.gov (United States)

    Ateşşahín, Ahmet; Ceríbaşi, Ali Osman; Yuce, Abdurrauf; Bulmus, Ozgür; Cikim, Gürkan

    2007-02-01

    The aim of this study was to investigate the possible protective role of antioxidant treatment with ellagic acid on cisplatin-induced nephrotoxicity using biochemical and histopatological approaches. Adult male Sprague-Dawley rats were randomly divided into four groups. The control group received 0.9% saline; animals in the ellagic acid group received only ellagic acid (10 mg/kg); animals in the cisplatin group received only cisplatin (7 mg/kg); animals in the cisplatin + ellagic acid group received ellagic acid for 10 days after cisplatin. The effects of ellagic acid on cisplatin-induced nephrotoxicity were evaluated by plasma creatinine, urea, sodium and calcium concentrations; kidney tissue malondialdehyde, reduced glutathione (GSH), glutathione peroxidase (GSH peroxidase) and catalase activities and histopatological examinations. Administration of cisplatin to rats induced a marked renal failure, characterized by significant increases in plasma creatinine, urea and calcium concentrations. Cisplatin also induced oxidative stress, as indicated by increased kidney tissue concentrations of malondialdehyde, and reduced activities of GSH peroxidase and catalase. Furthermore, treatment with cisplatin caused a marked tubular necrosis, degeneration and desquamation, luminal cast formation, karyomegaly, tubular dilatation, interstitial mononuclear cell infiltration and inter-tubular haemorrhagia. Ellagic acid markedly reduced elevated plasma creatinine, urea and calcium levels and counteracted the deleterious effects of cisplatin on oxidative stress markers. In the same way, ellagic acid ameliorated cisplatin-induced pathological changes including tubular necrosis, degeneration, karyomegaly, tubular dilatation when compared to the cisplatin alone group. These results indicate that the antioxidant ellagic acid might have a protective effect against cisplatin-induced nephrotoxicity and oxidative stress in rat, but not enough to inhibit cisplatin-induced renal dysfunction.

  15. Nephroprotective effect of gelsemine against cisplatin-induced toxicity is mediated via attenuation of oxidative stress.

    Science.gov (United States)

    Lin, Lin; Zheng, Jing; Zhu, Weiping; Jia, Ning

    2015-03-01

    Cisplatin-induced generation of reactive oxygen species leads to acute nephrotoxicity limiting its use in the treatment of various cancers. Gelsemine, an alkaloid isolated from Gelsemium elegans, is known to possess anti-inflammatory and anti-cancer activities. This study was aimed to investigate as to whether gelsemine can serve as a protective agent against cisplatin-induced nephrotoxicity. Male Wistar rats were divided into 6 groups, each with 6 rats. Group 1 served as control and received the vehicles (peanut oil for 14 days and 0.9 % saline on day 14 for gelsemine and cisplatin respectively). Group 2 received a single intraperitoneal injection of cisplatin on day 14. Group 3 and 4 were pretreated with two different doses of gelsemine in addition to cisplatin, and group 5 and 6 received only gelsemine. The effects of gelsemine on cisplatin-induced nephrotoxicity were examined by measuring anti-oxidant enzymes activities, lipid peroxidation, and DNA damage in the kidneys, a well-established model of oxidative damage. Pretreatment of rats with gelsemine caused a significant attenuation of cisplatin-induced DNA and oxidative damages. The blockade of lipid peroxidation and xanthine oxidase activity was accompanied by increased production and/or activity of anti-oxidants, both enzymatic (catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase) and non-enzymatic (GSH). The biomarkers of kidney malfunctioning, creatinine, and blood urea nitrogen were ameliorated. The results of the present study suggest that gelsemine effectively suppressed cisplatin-induced renal injury by improving redox status.

  16. Protective effects of 6-hydroxy-1-methylindole-3-acetonitrile on cisplatin-induced oxidative nephrotoxicity via Nrf2 inactivation.

    Science.gov (United States)

    Moon, Ji Hee; Shin, Ji-Sun; Kim, Jong-Bin; Baek, Nam-In; Cho, Young-Wuk; Lee, Yong Sup; Kay, Hee Yeon; Kim, Soo-dong; Lee, Kyung-Tae

    2013-12-01

    We previously demonstrated the ethanol extract of the roots of Brassica rapa protects against cisplatin-induced nephrotoxicity by attenuating oxidative stress. Here, we investigated the nephroprotective effects of 6-hydroxy-1-methylindole-3-acetonitrile (6-HMA), which was isolated from the roots of B. rapa, on cisplatin-induced toxicity in renal epithelial LLC-PK1 cells and in rats with acute renal injury. Pretreatment of LLC-PK1 cells with 6-HMA ameliorated cisplatin-induced cytotoxicity caused by oxidative stress, as was demonstrated by reductions in the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and increased levels of glutathione (GSH). In addition, 6-HMA inhibited cisplatin-induced heme oxygenase-1 (HO-1) expression, possibly due to the suppression of the nuclear translocation and binding activity of NF-E2-related factor 2 (Nrf2). Furthermore, 6-HMA administered rats showed lower levels of blood urea nitrogen (BUN), creatinine, and urinary lactate dehydrogenase (LDH) than cisplatin alone-treated rats in cisplatin-induced renal injury model. Moreover, 6-HMA inhibited the cisplatin-induced formation of MDA and GSH depletion and increased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GR). Taken together, these findings indicate 6-HMA is a major active constituent from the roots of B. rapa to have a protective effect against cisplatin-induced nephrotoxicity by attenuating oxidative stress.

  17. The effect of pre- versus postinjury infiltration with lidocaine on thermal and mechanical hyperalgesia after heat injury to the skin

    DEFF Research Database (Denmark)

    Dahl, J B; Brennum, J; Arendt-Nielsen, L

    1993-01-01

    The aim of the study was to evaluate the effects of pre- and postinjury infiltration with lidocaine on alterations in mechanical and thermal sensitivity after heat injury to the skin. In the first part of the study, burn injuries (15 x 25 mm rectangular thermode, 50 degrees C, 7 min) were produced...... twice in each subject on the medial side of the left and right calves at least 24 h apart in 8 healthy, unmedicated male volunteers, in order to investigate the effects of the injury on sensitivity in untreated skin. In the second part of the study, burn injuries (15 x 25 mm rectangular thermode, 50...... degrees C, 6 min) were produced twice in each subject on the medial side of the left and right calves at least 24 h apart (n = 10). This was preceded by subcutaneous (s.c.) infiltration with 5-6 ml of 1% plain lidocaine (pre-injury block) on one day, and the same block was performed 35 min after injury...

  18. Pinpointing differences in cisplatin-induced apoptosis in adherent and non-adherent cancer cells

    DEFF Research Database (Denmark)

    Tastesen, Hanne Sørup; Holm, Jacob Bak; Poulsen, Kristian Arild

    2010-01-01

    Platinum compounds are used in the treatment of cancer. We demonstrate that cisplatin-induced (10 µM) apoptosis (caspase-3 activity) is pronounced within 18 hours in non-adherent Ehrlich ascites tumour cells (EATC), whereas there is no increase in caspase-3 activity in the adherent Ehrlich Lettré...... ascites tumour cells (ELA). Loss of KCl and cell shrinkage are hallmarks in apoptosis and has been shown in EATC. However, we find no reduction in cell volume and only a minor loss of K(+) which is accompanied by net uptake of Na(+) following 18 hours cisplatin exposure in ELA. Glutathione and taurine...... have previously been demonstrated to protect cells from apoptosis. We find, however, that increase or decrease in the cellular content of glutathione and taurine has no effect on cisplatin-induced cell death in EATC and ELA. Nevertheless, knock-down of the taurine transporter TauT leads...

  19. Decursin Mediated Protection on Cisplatin-induced Nephrotoxicity in SD Rats and BDF1 Mice

    Institute of Scientific and Technical Information of China (English)

    Jiang Cheng-zhe; Han Ilhyun; Choung Seyoung

    2012-01-01

    Tisplatin is one of the valuable icancer agents against several types of neoplasm. However, nephrotoxicity is the major adverse effect representing in cisplatin therapy. In this study, the animal tests detecting protective effects of a natural compound, Decursin, on cisplatin-induced nephrotoxicity were examined by using in vivo model. Pretreatment Decursin 10, 20 and 40 mg · kg^-1 at 48, 24 and 6 h, and administration of a single dose of Cisplatin 5.2 mg · kg^-1. Nephrotoxicity was evaluated by serum BUN and creatinine examination. There was significant difference in body weights, serum BUN and creatinine levels of the normal group. Based on the new understanding of the protective mechanisms of cisplatin-induced nephrotocivity, new strategies can be developed to prevent renal injury or to enhance recovery after cisplatin treatment.

  20. Oral erdosteine administration attenuates cisplatin-induced renal tubular damage in rats.

    Science.gov (United States)

    Yildirim, Zeki; Sogut, Sadik; Odaci, Ersan; Iraz, Mustafa; Ozyurt, Huseyin; Kotuk, Mahir; Akyol, Omer

    2003-02-01

    The effect of oral erdosteine on tissue malondialdehyde (MDA) and nitric oxide (NO) levels, and catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities are investigated in the cisplatin model of acute renal failure in rats. A single dose of cisplatin caused kidney damage manifested by kidney histology as well as increases in plasma creatinine and blood urea nitrogen (BUN) levels. Treatment with free radical scavenger erdosteine attenuated increases in plasma creatinine and BUN, and tissue MDA and NO levels, and provided a histologically-proven protection against cisplatin-induced acute renal failure. Erdosteine also reduced depletion in the tissue CAT, GSH-Px, and SOD activities. These results show that erdosteine may be a promising drug for protection against cisplatin-induced nephrotoxicity. However, further studies with different doses of erdosteine are warranted for clarifying the issue.

  1. Nephroprotective effect of Bauhinia variegata (Linn.) whole stem extract against cisplatin-induced nephropathy in rats.

    Science.gov (United States)

    Pani, Saumya R; Mishra, Satyaranjan; Sahoo, Sabuj; Panda, Prasana K

    2011-04-01

    The nephroprotective activity of the ethanolic extract of Bauhinia variegata (Linn.) whole stem against cisplatin-induced nephropathy was investigated by an in vivo method in rats. Acute nephrotoxicity was induced by i.p. injection of cisplatin (7 mg/kg of body weight (b.w.)). Administration of ethanol extract at dose levels of 400 and 200 mg/kg (b.w.) to cisplatin-intoxicated rats for 14 days attenuated the biochemical and histological signs of nephrotoxicity of cisplatin in a dose-dependent fashion. Ethanol extract at 400 mg/kg decreased the serum level of creatinine (0.65 ± 0.09; Pvariegata at 400 mg/kg (b.w.) exhibited significant and comparable nephroprotective potential to that of the standard polyherbal drug cystone. The statistically (one-way-ANOVA followed by Tukey-Kramer multiple comparison) processed results suggested the protective action of B. variegate whole stem against cisplatin-induced nephropathy.

  2. Neuropeptide Y protects kidney against cisplatin-induced nephrotoxicity by regulating p53-dependent apoptosis pathway.

    Science.gov (United States)

    Kim, Namoh; Min, Woo-Kie; Park, Min Hee; Lee, Jong Kil; Jin, Hee Kyung; Bae, Jae-Sung

    2016-05-01

    Cisplatin is a platinum-based chemotherapeutic drug for treating various types of cancers. However, the use of cisplatin is limited by its negative effect on normal tissues, particularly nephrotoxicity. Various mechanisms such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and apoptosis are involved in the adverse effect induced by cisplatin treatment. Several studies have suggested that neuropeptide Y (NPY) is involved in neuroprotection as well as restoration of bone marrow dysfunction from chemotherapy induced nerve injury. However, the role of NPY in chemotherapy- induced nephrotoxicity has not been studied. Here, we show that NPY rescues renal dysfunction by reducing the expression of pro-apoptotic proteins in cisplatin induced nephrotoxicity through Y1 receptor, suggesting that NPY can protect kidney against cisplatin nephrotoxicity as a possible useful agent to prevent and treat cisplatin-induced nephrotoxicity. [BMB Reports 2016; 49(5): 288-292].

  3. Neuropeptide Y protects kidney against cisplatin-induced nephrotoxicity by regulating p53-dependent apoptosis pathway

    Science.gov (United States)

    Kim, Namoh; Min, Woo-Kie; Park, Min Hee; Lee, Jong Kil; Jin, Hee Kyung; Bae, Jae-sung

    2016-01-01

    Cisplatin is a platinum-based chemotherapeutic drug for treating various types of cancers. However, the use of cisplatin is limited by its negative effect on normal tissues, particularly nephrotoxicity. Various mechanisms such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and apoptosis are involved in the adverse effect induced by cisplatin treatment. Several studies have suggested that neuropeptide Y (NPY) is involved in neuroprotection as well as restoration of bone marrow dysfunction from chemotherapy induced nerve injury. However, the role of NPY in chemotherapy-induced nephrotoxicity has not been studied. Here, we show that NPY rescues renal dysfunction by reducing the expression of pro-apoptotic proteins in cisplatin induced nephrotoxicity through Y1 receptor, suggesting that NPY can protect kidney against cisplatin nephrotoxicity as a possible useful agent to prevent and treat cisplatin-induced nephrotoxicity. [BMB Reports 2016; 49(5): 288-292] PMID:26728272

  4. Thalidomide ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in an experimental model.

    Science.gov (United States)

    Amirshahrokhi, Keyvan; Khalili, Ali-Reza

    2015-04-01

    Cisplatin is a platinum-based chemotherapy drug. However, its chemotherapeutic use is restricted by serious side effects, especially nephrotoxicity. Inflammatory mechanisms have a significant role in the pathogenesis of cisplatin-induced nephrotoxicity. Thalidomide is an immunomodulatory and anti-inflammatory agent and is used for the treatment of various inflammatory diseases. The purpose of this study was to investigate the potential nephroprotective effect of thalidomide in a mouse model of cisplatin-induced nephrotoxicity. Nephrotoxicity was induced in mice by a single injection of cisplatin (15 mg/kg, i.p.) and treated with thalidomide (50 and 100 mg/kg/day, orally) for 4 days, beginning 24 h prior to the cisplatin injection. Renal toxicity induced by cisplatin was demonstrated by increasing plasma levels of creatinine and blood urea nitrogen (BUN). Cisplatin increased the renal production of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and transforming growth factor (TGF)-β1. In addition, kidney levels of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) were increased by cisplatin. Biochemical results showed that thalidomide reduced cisplatin-induced increase in plasma creatinine and BUN. Thalidomide treatment also significantly reduced tissue levels of the proinflammatory cytokines, MDA, MPO, and NO and increased anti-inflammatory cytokine IL-10. Furthermore, histological examination indicated that thalidomide ameliorated renal damage caused by cisplatin. These data suggest that thalidomide attenuates cisplatin-induced nephrotoxicity possibly by inhibition of inflammatory reactions. Taken together, our findings indicate that thalidomide might be a valuable candidate for the prevention of nephrotoxicity in patients receiving cisplatin.

  5. MutS homologue hMSH5: role in cisplatin-induced DNA damage response

    OpenAIRE

    Tompkins Joshua D; Wu Xiling; Her Chengtao

    2012-01-01

    Abstract Background Cisplatin (cis-diamminedichloroplatinum (II), CDDP) and its analogues constitute an important class of anticancer drugs in the treatment of various malignancies; however, its effectiveness is frequently affected by mutations in genes involved in the repair and signaling of cisplatin-induced DNA damage. These observations necessitate a need for a better understanding of the molecular events governing cellular sensitivity to cisplatin. Results Here, we show that hMSH5 mediat...

  6. Beneficial Effects of Hesperidin against Cisplatin-Induced Nephrotoxicity and Oxidative Stress in Rats

    OpenAIRE

    Wafaa R Mohamed; Arafa, El-Shaimaa A.; Basim A. Shehata; Gamal A. El Sherbiny; Abdel Nasser A.M. Elgendy

    2015-01-01

    Cisplatin has been frequently used for treatment of wide variety of tumors. The use of cisplatin is associated with severe cytotoxicity such as nephrotoxicity, hepatotoxicity and spermiotoxicity which radically limits its clinical use. The present study aimed to investigate the possible protective effects of multiple doses of hesperidin against cisplatin-induced nephrotoxicity induced by single i.p injection of cisplatin (7.5 mg/kg). Hesperidin was given to rats at two different doses (100 an...

  7. The mechanism of mesna in protection from cisplatin-induced ovarian damage in female rats

    OpenAIRE

    Li, Xiaohuan; Yang, Shu; Lv,Xiangyang; Sun, Haimei; Weng, Jing; Liang, Yuanjing; Zhou, Deshan

    2013-01-01

    Objective Cisplatin is a widely used chemotherapeutic agent in the treatment of cancers in clinic; but it often induces adverse effects on ovarian functions such as reduced fertility and premature menopause. Mesna could attenuate the cisplatin-induced ovarian damages; however, the underlying mechanism is still unknown. This study aimed to figure out the underlying mechanism of the protection of mesna for ovaries against cisplatin therapy in cancers. Methods We performed female adult Sprague-D...

  8. The renoprotective activity of hesperetin in cisplatin induced nephrotoxicity in rats: Molecular and biochemical evidence.

    Science.gov (United States)

    Kumar, Mukesh; Dahiya, Vicky; Kasala, Eshvendar Reddy; Bodduluru, Lakshmi Narendra; Lahkar, Mangala

    2017-03-14

    Nephrotoxicity remain a major life-threatening complication in cancer patients on cisplatin chemotherapy. In this study, we investigated the protective effect and possible cellular mechanism of the hesperetin, a naturally-occurring bioflavonoid against cisplatin-induced renal injury in rats. Hesperetin was administered at a dose of 50mg/kg and 100mg/kg orally for 10days and cisplatin (7.5mg/kg, ip) was administered on the 5th day of experiment. Cisplatin induced nephrotoxicity was evidenced by alteration in the level of markers such as blood urea nitrogen, creatinine, serum albumin and severe histopathological changes in kidney. Cisplatin administration also resulted in significant increase in the tissue oxidative stress and inflammatory cytokines. The level of antioxidants enzymes were decreased significantly in the cisplatin administered rats. Hesperetin treatment (50mg/kg and 100mg/kg) normalized the renal function by attenuation of the cisplatin-induced oxidative stress, lipid peroxidation, and inflammatory cytokines and histopathological alterations. On the basis of these experimental findings our present study postulate that co-administration of hesperetin with cisplatin chemotherapy may be promising preventive approach to limit the major mortal side effect of cisplatin.

  9. Changes in the Mucus Barrier during Cisplatin-Induced Intestinal Mucositis in Rats

    Directory of Open Access Journals (Sweden)

    Hajime Yamamoto

    2013-01-01

    Full Text Available Aim. Gastrointestinal mucositis is a frequent complication of antineoplastic chemotherapy, but the effects of chemotherapy on mucosal defense mechanisms remain poorly understood. We studied the effects of cisplatin on mucin, one of the principal defense factors of the gastrointestinal mucosa, and evaluated the efficacy of two different types of H2-receptor antagonists against cisplatin-induced mucositis. Methods. Cisplatin (6 mg/kg was administered intravenously to rats (day 0. The rats were sacrificed 1, 3, 7, and 11 days after treatment, and their stomach, jejunum, ileum, and colon were removed. Immunoreactivity of the mucosa was compared with the use of anti-mucin monoclonal antibody. To evaluate the efficacy of H2-receptor antagonists, either famotidine (3 mg/kg or lafutidine (30 mg/kg was given orally once daily on days 0, 1, and 2. Histological and biochemical findings were compared among the groups to assess effects on cisplatin-induced injury. Results. Cisplatin significantly altered the immunoreactivity and content of mucin in the small intestinal mucosa, especially in the ileum. Lafutidine protected against cisplatin-induced mucosal injury and attenuated decreased mucin accumulation. Conclusion. Cisplatin appears to alter the mucus barrier function in the intestinal mucosa. Lafutidine might effectively prevent chemotherapy-induced mucositis by activating intestinal mucus cells.

  10. Effect of Camel's Milk on Cisplatin-Induced Nephrotoxicity in Swiss Albino Mice

    Directory of Open Access Journals (Sweden)

    Mohamed M.E. Afifi

    2010-01-01

    Full Text Available Problem statement: Nephrotoxicity is a major complication and a dose limiting factor for cisplatin therapy. Cisplatin mediated nephrotoxicity is remarkably documented by reactive oxygen species. Camel's milk has good nutritive value, antigenotoxic and anticytotoxic effects. The aim of the present study was to assess the protective effect of camel's milk against Cisplatin-induced renal oxidative stress in mice. Approach: Forty mal Swiss albino mice were randomly divided into four groups (n = 10. Group I, control group. Group II was received cisplatin (12 mg kg-1 for 5 alternate days. Group III was received camel's milk (33 mL kg-1 for consecutive 30 days. Group IV was received camel's milk (33 mL kg-1 for consecutive 30 days before administration of Cisplatin. Results: Cisplatin-induced oxidative stress was indicated by increased level of tissue Malondialdehyde (MDA, serum creatinine and urea, decreased the concentration of reduced Glutathione (GSH, Vitamin C (Vit. C and Vitamin E (Vit. E and decreased both activities and gene expression of Superoxid Dismutase (SOD, Catalase (CAT, Glutathione Raductase (GR and Glutathione Peroxidase (GPx. Camel's milk reduced these biochemical changes and counteracted the deleterious effects of cisplatin Conclusion: The present study demonstrated the renoprotective potential of camel's milk against cisplatin-induced oxidative stress and renal dysfunction in mice. Hence, camel's milk has a potential to be used as therapeutic adjuvant in cisplatin nephrotoxicity.

  11. Antiemetic and Myeloprotective Effects of Rhus verniciflua Stoke in a Cisplatin-Induced Rat Model

    Science.gov (United States)

    Kim, Hyo-Seon; Kim, Hyeong-Geug; Im, Hwi-Jin; Lee, Jin-Seok; Lee, Sung-Bae; Kim, Won-Yong; Lee, Hye-Won; Lee, Sam-Keun; Byun, Chang Kyu

    2017-01-01

    Rhus verniciflua Stoke has been commonly used in traditional medicine to treat gastrointestinal (GI) dysfunction diseases. In order to investigate pharmacological properties of Rhus verniciflua Stoke water extract (RVX) on cisplatin-induced amnesia, RVX (0, 25, 50, or 100 mg/kg) was orally administrated for five consecutive days after a single intraperitoneal injection of cisplatin (6 mg/kg) to SD rat. Cisplatin injection significantly increased the kaolin intake (emesis) but reduced the normal diet intake (anorexia) whereas the RVX treatment significantly improved these abnormal diet behaviors at both the acute and delayed phase. The serotonin concentration and the related gene expressions (5-HT3 receptors and SERT) in small intestine tissue were abnormally altered by cisplatin injection, which were significantly attenuated by the RVX treatment. Histological findings of gastrointestinal tracts, as well as the proteins level of proinflammatory cytokines (TNF-α, IL-6, and IL-1β), revealed the beneficial effect of RVX on cisplatin-induced gastrointestinal inflammation. In addition, RVX significantly improved cisplatin-induced myelosuppression, as evidenced by the observation of leukopenia and by histological examinations in bone marrow. Our findings collectively indicated Rhus verniciflua Stoke improved the resistance of rats to chemotherapy-related adverse effects in the gastrointestinal track and bone marrow.

  12. Protective effects of pine bark extract against cisplatin-induced hepatotoxicity and oxidative stress in rats.

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    Ko, Je-Won; Lee, In-Chul; Park, Sung-Hyuk; Moon, Changjong; Kang, Seong-Soo; Kim, Sung-Ho; Kim, Jong-Choon

    2014-12-01

    We investigated the protective effects of pine bark extract (pycnogenol®, PYC) against cisplatin-induced hepatotoxicity and oxidative stress in rats. Twenty-four male rats were divided into the following four groups: (1) vehicle control, (2) cisplatin (7.5 mg/kg), (3) cisplatin & PYC 10 (10 mg/kg/day), and (4) cisplatin & PYC 20 (20 mg/kg/day). A single intraperitoneal injection of cisplatin induced hepatotoxicity, as evidenced by an increase in serum aminotransferase and histopathological alterations, including degeneration/necrosis of hepatocytes, vacuolation, and sinusoidal dilation. In addition, an increase in the malondialdehyde (MDA) concentration and a decrease in the reduced glutathione (GSH) content and catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST) activities were observed in the cisplatin-treated rat hepatic tissues. In contrast, PYC treatment effectively prevented cisplatin-induced hepatotoxicity, including the elevation of aminotransferase and histopathological lesions, in a dosedependent manner. Moreover, PYC treatment also induced antioxidant activity by decreasing MDA level and increasing GSH content and SOD and GST activities in liver tissues. These results indicate that PYC has a protective effect against acute hepatotoxicity induced by cisplatin in rats, and that the protective effects of PYC may be due to inhibiting lipid peroxidation and increasing antioxidant activity.

  13. Protective effects of sildenafil citrate administration on cisplatin-induced ovarian damage in rats.

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    Taskin, Mine Islimye; Yay, Arzu; Adali, Ertan; Balcioglu, Esra; Inceboz, Umit

    2015-04-01

    The aim of this study is to evaluate the effects of sildenafil citrate on cisplatin-induced ovarian toxicity. Thirty-two female rats were divided into four groups. Group 1: saline control; group 2: cisplatin; group 3: sildenafil citrate; and group 4: cisplatin plus sildenafil citrate group. In groups 2 and 4, the rats were injected with 5 mg/kg cisplatin intraperitoneally (i.p.). In groups 3 and 4, the rats were injected with 1.4 mg/kg sildenafil citrate i.p. The ovaries were removed two weeks later in all groups. Histopathologic examination, follicle counting and classification were performed. The expression of anti-Müllerian hormone (AMH) was detected immunohistochemically in the ovarian tissues. Sildenafil alleviated cisplatin-induced histopathological changes in the ovarian tissue. Primordial, secondary and tertiary follicles were diminished in group 2 compared with group 1 (p sildenafil citrate preserved primordial follicle count in group 4 compared with group 2, and the difference was statistically significant (p sildenafil citrate is beneficial for protecting the ovaries from cisplatin-induced damage. Sildenafil citrate can be a choice for fertility preservation.

  14. Metformin Protects Against Cisplatin-Induced Tubular Cell Apoptosis and Acute Kidney Injury via AMPKα-regulated Autophagy Induction.

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    Li, Jianzhong; Gui, Yuan; Ren, Jiafa; Liu, Xin; Feng, Ye; Zeng, Zhifeng; He, Weichun; Yang, Junwei; Dai, Chunsun

    2016-04-07

    Metformin, one of the most common prescriptions for patients with type 2 diabetes, is reported to protect the kidney from gentamicin-induced nephrotoxicity. However, the role and mechanisms for metformin in preventing cisplatin-induced nephrotoxicity remains largely unknown. In this study, a single intraperitoneal injection of cisplatin was employed to induce acute kidney injury (AKI) in CD1 mice. The mice exhibited severe kidney dysfunction and histological damage at day 2 after cisplatin injection. Pretreatment of metformin could markedly attenuate cisplatin-induced acute kidney injury, tubular cell apoptosis and inflammatory cell accumulation in the kidneys. Additionally, pretreatment of metformin could enhance both AMPKα phosphorylation and autophagy induction in the kidneys after cisplatin injection. In cultured NRK-52E cells, a rat kidney tubular cell line, metformin could stimulate AMPKα phosphorylation, induce autophagy and inhibit cisplatin-induced cell apoptosis. Blockade of either AMPKα activation or autophagy induction could largely abolish the protective effect of metformin in cisplatin-induced cell death. Together, this study demonstrated that metformin may protect against cisplatin-induced tubular cell apoptosis and AKI through stimulating AMPKα activation and autophagy induction in the tubular cells.

  15. Cisplatin-induced apoptosis inhibits autophagy, which acts as a pro-survival mechanism in human melanoma cells.

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    Barbara Del Bello

    Full Text Available The interplay between a non-lethal autophagic response and apoptotic cell death is still a matter of debate in cancer cell biology. In the present study performed on human melanoma cells, we investigate the role of basal or stimulated autophagy in cisplatin-induced cytotoxicity, as well as the contribution of cisplatin-induced activation of caspases 3/7 and conventional calpains. The results show that, while down-regulating Beclin-1, Atg14 and LC3-II, cisplatin treatment inhibits the basal autophagic response, impairing a physiological pro-survival response. Consistently, exogenously stimulated autophagy, obtained with trehalose or calpains inhibitors (MDL-28170 and calpeptin, protects from cisplatin-induced apoptosis, and such a protection is reverted by inhibiting autophagy with 3-methyladenine or ATG5 silencing. In addition, during trehalose-stimulated autophagy, the cisplatin-induced activation of calpains is abrogated, suggesting the existence of a feedback loop between the autophagic process and calpains. On the whole, our results demonstrate that in human melanoma cells autophagy may function as a beneficial stress response, hindered by cisplatin-induced death mechanisms. In a therapeutic perspective, these findings suggest that the efficacy of cisplatin-based polychemotherapies for melanoma could be potentiated by inhibitors of autophagy.

  16. The protective effect of Nigella sativa against cisplatin-induced nephrotoxicity in rats

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    Sara Hosseinian

    2016-01-01

    Full Text Available Objective: The clinical use of cisplatin is highly restricted, because of its nephrotoxicity.In this study the protective effect of Nigella sativa (N. sativa against cisplatin-induced nephrotoxicity was investigated in rats. Materials and Methods: In the current study, the effects of the administration of aqueous-ethanolic extract of N. sativa (100 and 200 mg/kg, BW and vitamin E (100 mg/kg, BW against blood and urine biochemical alterations and kidney function in rats treated with cisplatin were investigated. Cisplatin was injected at a dose of 6 mg/kg, BW, on the sixth day of the experiment. Results: The results indicated significant changes in serum urea and creatinine concentration, urine glucose concentration, and urine output in cisplatin group compared with control group. Serum urea and creatinine concentration in preventive and preventive+treatment vitamin E and preventive+treatment N. sativa (200 mg/kg, BW groups and also serum creatinine concentration in preventive+treatment N. sativa (100 mg/kg, BW group significantly decreased compared with cisplatin group. Urine glucose concentration in preventive and preventive+treatment N. sativa groups and urine output in preventive and preventive+treatment N. sativa (200 mg/kg, BW groups significantly decreased compared with cisplatin group.Osmolarity excretion rate in preventive and preventive+treatment vitamin E and preventive N. sativa groups was significantly higher than control group. Conclusions: The current study suggests that N. sativa extract and vitamin E in a dose- and time-dependent manner improved the serum and urine biochemical parameters and kidney function in cisplatin-induced nephrotoxicity in rats. However, it needs more investigations to determine the mechanism of N. sativa action on cisplatin-induced kidney toxicity.

  17. Is intratympanic injection of erdosteine protective against cisplatin-induced ototoxicity?

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    Saliba, Issam; El Fata, Fouad

    2012-04-01

    Cisplatin induces ototoxicity in adult and pediatric population. Our aim was (1) to assess the protective effect of intratympanic injections of erdosteine in the prevention of cisplatin-induced ototoxicity and (2) to investigate inner ear protection using a scanning electron microscope. Ears of 20 Hartley guinea pigs were assigned to four subgroups and received an intratympanic injection of: E1-erdosteine 1.125 mg/cc, NS-normal saline, E2-erdosteine 2.25 mg/cc and E4-erdosteine 4.5 mg/cc. After 45 min, an intraperitoneal cisplatin injection of 3 mg/kg was performed and repeated 8 times, once a week to achieve 24 mg/kg. Auditory brainstem responses were recorded before any injection and after 24 mg/kg of cisplatin for the frequencies 1, 2, 4, 6 and 8 kHz. Cochleas were analyzed under scanning electron microscope. Average hearing loss in the NS subgroup was 29.8 dB which was lower than E1, E2 and E4 subgroups (40, 43.9, and 51.7 dB, respectively). Difference in the mean threshold increase was statistically significant between NS and the three erdosteine subgroups (P  0.05). However, difference was significant between E1 and E4 (P erdosteine showed a diffuse inflammatory reaction and osteitis of the middle ear. Low or high concentration of intratympanic erdosteine does not offer protection against cisplatin-induced ototoxicity as it causes a considerable inflammatory reaction.

  18. Risk factors for cisplatin-induced nephrotoxicity and potential of magnesium supplementation for renal protection.

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    Yasuhiro Kidera

    Full Text Available Nephrotoxicity remains a problem for patients who receive cisplatin chemotherapy. We retrospectively evaluated potential risk factors for cisplatin-induced nephrotoxicity as well as the potential impact of intravenous magnesium supplementation on such toxicity.We reviewed clinical data for 401 patients who underwent chemotherapy including a high dose (≥60 mg/m2 of cisplatin in the first-line setting. Nephrotoxicity was defined as an increase in the serum creatinine concentration of at least grade 2 during the first course of cisplatin chemotherapy, as assessed on the basis of National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The severity of nephrotoxicity was evaluated on the basis of the mean change in the serum creatinine level. Magnesium was administered intravenously to 67 patients (17%.Cisplatin-induced nephrotoxicity was observed in 127 patients (32%. Multivariable analysis revealed that an Eastern Cooperative Oncology Group performance status of 2 (risk ratio, 1.876; P = 0.004 and the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs (risk ratio, 1.357; P = 0.047 were significantly associated with an increased risk for cisplatin nephrotoxicity, whereas intravenous magnesium supplementation was associated with a significantly reduced risk for such toxicity (risk ratio, 0.175; P = 0.0004. The development of hypomagnesemia during cisplatin treatment was significantly associated with a greater increase in serum creatinine level (P = 0.0025. Magnesium supplementation therapy was also associated with a significantly reduced severity of renal toxicity (P = 0.012.A relatively poor performance status and the regular use of NSAIDs were significantly associated with cisplatin-induced nephrotoxicity, although the latter association was marginal. Our findings also suggest that the ability of magnesium supplementation to protect against the renal toxicity of cisplatin warrants further

  19. Safety assessment and attenuation of cisplatin induced nephrotoxicity by tuberous roots of Boerhaavia diffusa.

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    Karwasra, Ritu; Kalra, Prerna; Nag, T C; Gupta, Y K; Singh, Surender; Panwar, Anuj

    2016-11-01

    Cisplatin (Cis-diaminedichloroplatinum II) is a chemotherapeutic agent having well documented adverse effect as nephrotoxicity. This study was designed to evaluate the nephroprotective role of Boerhaavia diffusa in cisplatin-induced acute kidney injury. Wistar rats (n = 6) were allocated into six groups constituting normal control, cisplatin-induced, Boerhaavia diffusa root extract in doses 50, 100 and 200 mg/kg and Boerhaavia diffusa per se group, administered orally for a period of ten days. Intraperitoneal injection of cisplatin was administered on day 7, to all groups except normal control and Boerhaavia diffusa per se group. On day 10, cisplatin resulted in substantial nephrotoxicity in Wistar rats with significant (p < 0.001) elevation in serum creatinine and blood urea nitrogen, decline in the concentrations of reduced glutathione and superoxide dismutase, elevation in TNF-α level in renal tissues. Boerhaavia diffusa at a dose of 200 mg/kg body weight significantly (p < 0.001) ameliorates increased in serum creatinine, blood urea nitrogen, oxidative stress and inflammatory markers. In parallel to this, it also exhibits antiapoptotic activity through the reduction of active caspase-3 expression in kidneys. Findings indicate that Boerhaavia diffusa is effective in mitigating cisplatin-induced nephrotoxicity and thus, for this the acute and sub-acute toxicity studies conducted to evaluate the safety profile of Boerhaavia diffusa. The no-observed adverse effect level (NOAEL) of tuberous roots of Boerhaavia diffusa root extract was 1000 mg/kg.

  20. Comment on: A model for prediction of cisplatin induced nephrotoxicity by kidney weight in experimental rats

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    Hamid Nasri

    2013-01-01

    Full Text Available Cisplatin (cis-diamminedichloroplatinum II, as one of the most applicable and potent anticancer medication, is used in the treatment of a various pediatric and adult malignancies. However, it gives side-effects such as renal toxicity which is dose-dependent, and thus limited its usage. Treatment with cisplatin induces the inflammatory mechanisms, which leads to a reduction in the antioxidant levels, leading to a failure of the antioxidant protection against free-radical damage generated by antitumor drugs. The oxidative stress, induced by cisplatin in the kidney was partially inhibited by antioxidant therapy using selenium, glutathione, flavonoids, and superoxide dismutase.

  1. Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway

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    Kilic Ulkan

    2013-01-01

    Full Text Available Abstract Background Cisplatin, one of the most effective and potent anticancer drugs, is used in the treatment of a wide variety of both pediatric and adult malignancies. However, the chemotherapeutic use of cisplatin is limited by its serious side-effects such as nephrotoxicity and ototoxicity. Cisplatin chemotherapy induces a reduction in the antioxidant status, leading to a failure of the antioxidant defense against free-radical damage generated by antitumor drugs. Cisplatin-induced oxidative stress in the kidney was partially prevented by antioxidant treatments using superoxide dismutase, glutathione, selenium and flavonoids. Melatonin and its metabolites possess free-radical scavenging activity and it has been shown that they protect against cisplatin toxicity. However, the mechanism of the protective effects of melatonin against cisplatin-induced nephrotoxicity is still essentially unknown. We therefore designed this study to investigate the underlying mechanism of the protective effect of melatonin against cisplatin-induced renal damage in a rat nephrotoxicity model in vivo. Methods Twenty eight 8-week-old male Wistar rats were divided into four groups of control, melatonin treatment (4 mg/kg b.w i.p. for 10 days, cisplatin treatment (7 mg/kg b.w., i.p. and melatonin and cisplatin combination treatment. Serum urea nitrogen (urea-N and creatinine levels were measured. Histopathological changes were evaluated. In addition, we analyzed the expression levels of HO-1, Nrf2, NF-κB and AP-1 in Western blot analysis. Results Both serum creatinine and urea nitrogen increased significantly following cisplatin administration alone; these values decreased significantly with melatonin co-treatment of cisplatin-treated rats. Histological analysis showed that cisplatin caused damage in the proximal tubular cells in the kidneys of cisplatin-treated rats; these changes were reversed by melatonin co-treatment. Upon Western blot analysis, melatonin

  2. The Effect of Mirtazapine on Cisplatin-Induced Oxidative Damage and Infertility in Rat Ovaries

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    Durdu Altuner; Mine Gulaboglu; Omer Erkan Yapca; Nihal Cetin

    2013-01-01

    Cisplatin causes infertility due to ovarian toxicity. The toxicity mechanism is unknown, but evidence suggests oxidative stress. In this study, the effect of mirtazapine on cisplatin-induced infertility and oxidative stress in rats was investigated. 64 female rats were divided into 4 groups of 16. Except for the controls that received physiologic saline only, all were administered with cisplatin (5 mg/kg i.p.) and mirtazapine (15 mg/kg p.o.) or mirtazapine (30 mg/kg p.o.) for 10 days. After t...

  3. Cisplatin-induced testicular toxicity in rats: the protective effect of arjunolic acid.

    Science.gov (United States)

    Sherif, Iman O; Abdel-Aziz, Azza; Sarhan, Osama M

    2014-11-01

    In the present study, the effect of arjunolic acid on testicular damage induced by intraperitoneal injection of rats with 7 mg/kg cisplatin was studied. Cisplatin induced a significant reduction in testicular weights, plasma testosterone, and testicular reduced glutathione levels in addition to a significant elevation of testicular malondialdehyde levels and testicular gene expressions of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and p38 mitogen-activated protein kinase (MAPK) when compared with the control group (p testicular injury by attenuating oxidative stress parameters along with downregulation of iNOS, TNF-α, and p38-MAPK testicular expressions.

  4. Effect of Matricaria chamomilla Hydroalcoholic Extract on Cisplatin-induced Neuropathy in Mice

    Institute of Scientific and Technical Information of China (English)

    A.Namvaran Abbas Abad; M.H.Kayate Nouri; A.Gharjanie; F.Tavakoli

    2011-01-01

    AIM: Cisplatin-based chemotherapy is a mainstay for the treatment of solid tumors, especially colorectal, ovarian,testicular, bladder, and lung cancer. Studies have shown that cisplatin could have painful effects on human and animal models. Matricaria chamomilla (MC) has analgesic and anti-inflammatory effects. The aim of this study was to investigate the effects of MC hydroalcoholic extract on cisplatin-induced peripheral neuropathy and to compare with morphine in mice. METHODS: Experiments were performed on 60 NMRI male mice weighed 25 g to 30 g which have been divided into 6 groups. The fast group received normal saline;the second group received MC hydroalcoholic extract; the third group received cisplatin; the fourth group received MC hydroalcoholic extract and cisplatin, 96 hours before formalin test; the fifth group received morphine and the sixth group received cisplatin and morphine. The time of injected hind paw biting and licking time were measured in 5-minute interval for an hour. RESULTS: Results showed that formalin induced significant (P<0.05) pain response (the first phase: 0-5 min and the second phase: 15-40 min after injection). Administration of MC extract before formalin injection showed significant (P<0.05) decrease of pain responses in the first and second phase. Administration of cisplatin produced significant (P<0.05) increase in pain response in both phases of formalin test.Injection of MC extract and cisplatin together have shown that MC is able to decrease the second phase of cisplatin-induced pain sig-nificantly (P<0.05). Morphine decreased cisplatin-induced pain in the first and second phase of formalin test significantly(P<0.05).In comparison morphine has analgesic effects in the first phase and MC extract has anti inflammatory effects in the second phase of formalin test significantly (P < 0.05). CONCLUSION: MC and cisplatin have analgesic and painful neuropathic respective effects, and MC hydroalcoholic extract is able to

  5. Fear of pain potentiates nocebo hyperalgesia

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    Aslaksen PM

    2015-10-01

    Full Text Available Per M Aslaksen,1 Peter S Lyby2 1Department of Psychology, Research Group for Cognitive Neuroscience, The Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway; 2Catosenteret Rehabilitation Center, Son, Norway Abstract: Nocebo hyperalgesia has received sparse experimental attention compared to placebo analgesia. The aim of the present study was to investigate if personality traits and fear of pain could predict experimental nocebo hyperalgesia. One hundred and eleven healthy volunteers (76 females participated in an experimental study in which personality traits and fear of pain were measured prior to induction of thermal heat pain. Personality traits were measured by the Big-Five Inventory-10. Fear of pain was measured by the Fear of Pain Questionnaire III. Heat pain was induced by a PC-controlled thermode. Pain was measured by a computerized visual analog scale. Stress levels during the experiment were measured by numerical rating scales. The participants were randomized to a Nocebo group or to a no-treatment Natural History group. The results revealed that pain and stress levels were significantly higher in the Nocebo group after nocebo treatment. Mediation analysis showed that higher levels of the Fear of Pain Questionnaire III factor "fear of medical pain" significantly increased stress levels after nocebo treatment and that higher stress levels were associated with increased nocebo hyperalgesic responses. There were no significant associations between any of the personality factors and the nocebo hyperalgesic effect. The results from the present study suggest that dispositional fear of pain might be a useful predictor for nocebo hyperalgesia and emotional states concomitant with expectations of increased pain. Furthermore, measurement of traits that are specific to pain experience is probably better suited for prediction of nocebo hyperalgesic responses compared to broad measures of personality

  6. Role of CFTR in oxidative stress and suicidal death of renal cells during cisplatin-induced nephrotoxicity.

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    Rubera, I; Duranton, C; Melis, N; Cougnon, M; Mograbi, B; Tauc, M

    2013-10-03

    The clinical use of the antineoplastic drug cisplatin is limited by its deleterious nephrotoxic side effect. Cisplatin-induced nephrotoxicity is associated with an increase in oxidative stress, leading ultimately to renal cell death and irreversible kidney dysfunction. Oxidative stress could be modified by the cystic fibrosis transmembrane conductance regulator protein (CFTR), a Cl(-) channel not only involved in chloride secretion but as well in glutathione (GSH) transport. Thus, we tested whether the inhibition of CFTR could protect against cisplatin-induced nephrotoxicity. Using a renal proximal cell line, we show that the specific inhibitor of CFTR, CFTR(inh)-172, prevents cisplatin-induced cell death and apoptosis by modulating the intracellular reactive oxygen species balance and the intracellular GSH concentration. This CFTR(inh)-172-mediated protective effect occurs without affecting cellular cisplatin uptake or the formation of platinum-DNA adducts. The protective effect of CFTR(inh)-172 in cisplatin-induced nephrotoxicity was also investigated in a rat model. Five days after receiving a single cisplatin injection (5 mg/kg), rats exhibited renal failure, as evidenced by the alteration of biochemical and functional parameters. Pretreatment of rats with CFTR(inh)-172 (1 mg/kg) prior to cisplatin injection significantly prevented these deleterious cisplatin-induced nephrotoxic effects. Finally, we demonstrate that CFTR(inh)-172 does not impair cisplatin-induced cell death in the cisplatin-sensitive A549 cancer cell line. In conclusion, the use of a specific inhibitor of CFTR may represent a novel therapeutic approach in the prevention of nephrotoxic side effects during cisplatin treatment without affecting its antitumor efficacy.

  7. Inhibition of PARP activation by enalapril is crucial for its renoprotective effect in cisplatin-induced nephrotoxicity in rats.

    Science.gov (United States)

    Rani, Neha; Bharti, Saurabh; Tomar, Ameesha; Dinda, Amit Kumar; Arya, D S; Bhatia, Jagriti

    2016-01-01

    Oxidative stress-induced PARP activation has been recognized to be a main factor in the pathogenesis of cisplatin-induced nephrotoxicity. Accumulating literature has revealed that ACE inhibitors may exert beneficial effect in several disease models via preventing PARP activation. Based on this hypothesis, we have evaluated the renoprotective effect of enalapril, an ACE inhibitor, and its underlying mechanism(s) in cisplatin-induced renal injury in rats. Male Albino Wistar rats were orally administered normal saline or enalapril (10, 20 and 40 mg/kg) for 10 days. Nephrotoxicity was induced by a single dose of cisplatin (8 mg/kg; i.p.) on the 7th day. The animals were thereafter sacrificed on the 11th day and both the kidneys were excised and processed for biochemical, histopathological, molecular, and immunohistochemical studies. Enalapril (40 mg/kg) significantly prevented cisplatin-induced renal dysfunction. In comparison to cisplatin-treated group, the elevation of BUN and creatinine levels was significantly less in this group. This improvement in kidney injury markers was well substantiated with reduced PARP expression along with phosphorylation of MAPKs including JNK/ERK/p38. Enalapril, in a dose-dependent fashion, attenuated cisplatin-induced oxidative stress as evidenced by augmented GSH, SOD and catalase activities, reduced TBARS and oxidative DNA damage (8-OHDG), and Nox-4 protein expression. Moreover, enalapril dose dependently inhibited cisplatin-induced inflammation (NF-κB/IKK-β/IL-6/Cox-2/TNF-α expressions), apoptosis (increased Bcl-2 and reduced p53, cytochrome c, Bax and caspase-3 expressions, and TUNEL/DAPI positivity) and preserved the structural integrity of the kidney. Thus, enalapril attenuated cisplatin-induced renal injury via inhibiting PARP activation and subsequent MAPKs/TNF-α/NF-κB mediated inflammatory and apoptotic response.

  8. Thermal hyperalgesia after sciatic nerve block in rat is transient and clinically insignificant.

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    Janda, Allison; Lydic, Ralph; Welch, Kathleen B; Brummett, Chad M

    2013-01-01

    Ropivacaine has been associated with transient heat hyperalgesia in sciatic nerve blocks in rat. The goal of the present study was to evaluate the hypothesized presence of transient heat hyperalgesia after perineural injection of ropivacaine with a secondary subanalysis of 2 published studies. Paw withdrawal latency was used to assess the duration of sensory blockade and presence of heat hyperalgesia at 210, 240, 270, and 300 minutes and 24 hours after injection. The analysis revealed hyperalgesia at a single time point (240 minutes after injection; mean difference, -0.60 seconds; P = 0.012) that resolved within 30 minutes, and there was no other significant hyperalgesia at other time points. Although statistically significant, the single time point measurement represented only an 11% change from baseline and was no longer present 30 minutes later. These data support the need for a reevaluation of the interpretation that pain can be worsened by perineural ropivacaine injection.

  9. Telmisartan ameliorates cisplatin-induced nephrotoxicity by inhibiting MAPK mediated inflammation and apoptosis.

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    Malik, Salma; Suchal, Kapil; Gamad, Nanda; Dinda, Amit Kumar; Arya, Dharamvir Singh; Bhatia, Jagriti

    2015-02-05

    Nephrotoxicity is a major adverse effect of the widely used anticancer drug cisplatin. Oxidative stress, inflammation and apoptosis are implicated in the pathophysiology of cisplatin-induced acute renal injury. Moreover, cisplatin activates many signal transduction pathways involved in cell injury and death, particularly mitogen activated protein kinase (MAPK) pathway. With this background, we aimed to investigate the protective effect of telmisartan, a widely used antihypertensive drug, in cisplatin-induced nephrotoxicity model in rats. To accomplish this, male albino wistar rats (150-200 g) were divided into 6 groups: Normal, cisplatin-control, telmisartan (2.5, 5 and 10 mg/kg) and telmisartan per se treatment groups. Normal saline or telmisartan was administered orally to rats for 10 days and cisplatin was given on 7th day (8 mg/kg; i.p.) to induce nephrotoxicity. On 10th day, rats were killed and both the kidneys were harvested for biochemical, histopathological and molecular studies. Cisplatin injected rats showed depressed renal function, altered proxidant-antioxidant balance and acute tubular necrosis which was significantly normalized by telmisartan co-treatment. Furthermore, cisplatin administration activated MAPK pathway that caused tubular inflammation and apoptosis in rats. Telmisartan treatment significantly prevented MAPK mediated inflammation and apoptosis. Among the three doses studied telmisartan at 10 mg/kg dose showed maximum nephroprotective effect which could be due to maintenance of cellular redox status and inhibition of MAPK activation.

  10. Effect of metformin against cisplatin induced acute renal injury in rats: a biochemical and histoarchitectural evaluation.

    Science.gov (United States)

    Sahu, Bidya Dhar; Kuncha, Madhusudana; Putcha, Uday Kumar; Sistla, Ramakrishna

    2013-09-01

    Although cisplatin has been a mainstay for cancer therapy, its use is limited mainly because of nephrotoxicity. Accumulating literature suggest the antioxidant and cytoprotective effect of metformin, a first line antidiabetic drug. With this background, we investigated the effect of metformin on the cisplatin induced nephrotoxicity in rats. A single injection of cisplatin (7.5 mg/kg, i.p.) caused marked renal damage, characterized by a significant increase in blood urea nitrogen (BUN), serum creatinine (Cr) and abnormal histo-architecture of kidney. These were accompanied by significant elevation of malondialdehyde (MDA), total reactive oxygen species (tROS) and caspase-3 levels and decreased antioxidant levels. Metformin treatment significantly attenuated the increase in malondialdehyde and tROS generation and restores the decrease in both enzymatic and non-enzymatic antioxidants. However metformin treatment did not prevent the cisplatin induced renal injury as there was no significant difference of renal function parameters (BUN and Cr), kidney histopathology as well as caspase-3 activity between cisplatin per se and metformin plus cisplatin treated rats. Histopathology studies revealed that similar glomerular and tubular pathological architecture in both cisplatin per se and cisplatin plus metformin group. In conclusion, the present study demonstrated that metformin is not an adjuvant drug to treat nephrotoxicity associated with cisplatin therapy.

  11. The Preventive Effect of Oxytocin to Cisplatin-Induced Neurotoxicity: An Experimental Rat Model

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    Tulay Akman

    2015-01-01

    Full Text Available Peripheral neurotoxicity is a frequent dose-limiting side effect of the chemotherapeutic agent cisplatin. This study was conducted to investigate the preventive effect of oxytocin (OT on cisplatin-induced neurotoxicity in rats. Forty-four adult female rats were included in the study. Thirty-six rats were administered intraperitoneally (i.p. single dose cisplatin 10 mg/kg and divided in to 3 groups. The first group (n=12 received saline i.p., whereas the second group (n=12 and the third group (n=12 were injected with 80 µg/kg and 160 µg/kg OT, respectively, for 10 days. The remaining 8 rats served as the control group. Electromyography (EMG studies were recorded and blood samples were collected for the measurement of plasma lipid peroxidation (malondialdehyde; MDA, tumor necrosis factor (TNF-α, and glutathione (GSH levels. EMG findings revealed that compound muscle action potential amplitude was significantly decreased and distal latency was prolonged in the nontreated cisplatin-injected rats compared with the control group (P<0.005. Also, nontreated cisplatin-injected rats showed significantly higher TNF-α and MDA levels and lower GSH level than control group. The administration of OT significantly ameliorated the EMG alterations, suppressed oxidative stress and inflammatory parameters, and increased antioxidative capacity. We suggest that oxytocin may have beneficial effects against cisplatin-induced neurotoxicity.

  12. Reduced ghrelin secretion in the hypothalamus of rats due to cisplatin-induced anorexia.

    Science.gov (United States)

    Yakabi, Koji; Sadakane, Chiharu; Noguchi, Masamichi; Ohno, Shino; Ro, Shoki; Chinen, Katsuya; Aoyama, Toru; Sakurada, Tomoya; Takabayashi, Hideaki; Hattori, Tomohisa

    2010-08-01

    Although chemotherapy with cisplatin is a widely used and effective cancer treatment, the undesirable gastrointestinal side effects associated with it, such as nausea, vomiting, and anorexia, markedly decrease patients' quality of life. To elucidate the mechanism underlying chemotherapy-induced anorexia, focusing on the hypothalamic ghrelin secretion-anorexia association, we measured hypothalamic ghrelin secretion in fasted and cisplatin-treated rats. Hypothalamic ghrelin secretion changes after vagotomy or administration of cisplatin. Cisplatin + rikkunshito, a serotonin 2C receptor antagonist or serotonin 3 receptor antagonist, was investigated. The effects of intracerebroventricular (icv) administration of ghrelin or the serotonin 2C receptor antagonist SB242084 on food intake were also evaluated in cisplatin-treated rats. Hypothalamic ghrelin secretion significantly increased in 24-h-fasted rats compared to freely fed rats and was markedly reduced 24 and 48 h after cisplatin treatment in cisplatin-treated rats compared to saline-treated rats, although their plasma ghrelin levels were comparable. In cisplatin-treated rats, icv ghrelin administration reversed the decrease in food intake, vagotomy partially restored hypothalamic ghrelin secretion, and hypothalamic serotonin 2C receptor mRNA expression increased significantly. Administration of rikkunshito (an endogenous ghrelin enhancer) or a serotonin 2C receptor antagonist reversed the decrease in hypothalamic ghrelin secretion and food intake 24 h after cisplatin treatment. Cisplatin-induced anorexia is mediated through reduced hypothalamic ghrelin secretion. Cerebral serotonin 2C receptor activation partially induces decrease in hypothalamic ghrelin secretion, and rikkunshito suppresses cisplatin-induced anorexia by enhancing this secretion.

  13. The HECTD3 E3 ubiquitin ligase suppresses cisplatin-induced apoptosis via stabilizing MALT1.

    Science.gov (United States)

    Li, Yi; Chen, Xi; Wang, Zehua; Zhao, Dong; Chen, Hui; Chen, Wenlin; Zhou, Zhongmei; Zhang, Junran; Zhang, Jing; Li, Hongmin; Chen, Ceshi

    2013-01-01

    Homologous to the E6-associated protein carboxyl terminus domain containing 3 (HECTD3) is an E3 ubiquitin ligase with unknown functions. Here, we show that HECTD3 confers cancer cell resistance to cisplatin. To understand the molecular mechanisms, we performed a yeast two-hybrid analysis and identified mucosa-associated lymphoid tissue 1 (MALT1) as an HECTD3-interacting protein. HECTD3 promotes MALT1 ubiquitination with nondegradative polyubiquitin chains by direct interacting with the MALT1 through its N-terminal destruction of cyclin domain. HECTD3 does not target MALT1 for degradation but stabilize it. HECTD3 depletion dramatically decreases the levels of MALT1 in MCF7 and HeLa cells treated with cisplatin, which is correlated to an increase in apoptosis. Knockdown of MALT1 likewise increases cisplatin-induced apoptosis in these cancer cells. However, HECTD3 over-expression leads to a decreased cisplatin-induced apoptosis, whereas overexpression of MALT1 partially rescues HECTD3 depletion-induced apoptosis. These findings suggest that HECTD3 promotes cell survival through stabilizing MALT1. Our data have important implications in cancer therapy by providing novel molecular targets.

  14. The HECTD3 E3 Ubiquitin Ligase Suppresses Cisplatin-Induced Apoptosis via Stabilizing MALT1

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    Yi Li

    2013-01-01

    Full Text Available Homologous to the E6-associated protein carboxyl terminus domain containing 3 (HECTD3 is an E3 ubiquitin ligase with unknown functions. Here, we show that HECTD3 confers cancer cell resistance to cisplatin. To understand the molecular mechanisms, we performed a yeast two-hybrid analysis and identified mucosa-associated lymphoid tissue 1 (MALT1 as an HECTD3-interacting protein. HECTD3 promotes MALT1 ubiquitination with non-degradative polyubiquitin chains by direct interacting with the MALT1 through its N-terminal destruction of cyclin domain. HECTD3 does not target MALT1 for degradation but stabilize it. HECTD3 depletion dramatically decreases the levels of MALT1 in MCF7 and HeLa cells treated with cisplatin, which is correlated to an increase in apoptosis. Knockdown of MALT1 likewise increases cisplatin-induced apoptosis in these cancer cells. However, HECTD3 overexpression leads to a decreased cisplatin-induced apoptosis, whereas overexpression of MALT1 partially rescues HECTD3 depletion–induced apoptosis. These findings suggest that HECTD3 promotes cell survival through stabilizing MALT1. Our data have important implications in cancer therapy by providing novel molecular targets.

  15. Protective agent, erdosteine, against cisplatin-induced hepatic oxidant injury in rats.

    Science.gov (United States)

    Koc, Ahmet; Duru, Mehmet; Ciralik, Harun; Akcan, Ramazan; Sogut, Sadik

    2005-10-01

    Cisplatin, one of the most active cytotoxic agents against cancer, has several toxicities. Hepatotoxicity is one of them occurred during high doses treatment. The aim of this study was to determine the effects of erdosteine against cisplatin-induced liver injury through tissue oxidant/antioxidant parameters and light microscopic evaluation. The rats were randomly divided into three groups: control (n=5), cisplatin (10 mg/kg, n=6) and cisplatin+erdosteine (50 mg/kg/day oral erdosteine, n=8) groups. The rats were sacrificed at the 5th day of cisplatin treatment. The liver tissues were examined with light microscopy and oxidant/antioxidant biochemical parameters. The malondialdehyde (MDA) and nitric oxide (NO) levels were increased in the cisplatin group in comparison with the control and cisplatin+erdosteine groups (perdosteine groups. The activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were higher in cisplatin+erdosteine group than cisplatin group (perdosteine group, a decrease in cytoplasmic changes with the hepatocytes and sinusoidal dilatations around cells of central vein were noticed in as compared to cisplatin group. In the light of microscopic and biochemical results, it was concluded that cisplatin-induced liver damage in high dose and erdosteine prevented this toxic side effect by the way of its antioxidant and radical scavenging effects.

  16. Cisplatin-induced acute renal failure is ameliorated by erdosteine in a dose-dependent manner.

    Science.gov (United States)

    Ozyurt, Hüseyin; Yildirim, Zeki; Kotuk, Mahir; Yilmaz, H Ramazan; Yağmurca, Murat; Iraz, Mustafa; Söğüt, Sad; Gergerlioglu, Serdar

    2004-01-01

    The aim of this study was to investigate the optimum dosage of erdosteine to ameliorate cisplatin-induced nephrotoxicity. Three different doses of erdosteine at 25, 50 and 75 mg kg(-1) were studied in rats. Intraperitoneal administration of 7 mg kg(-1) cisplatin led to acute renal failure, as indicated by kidney histology and increases in plasma creatinine and blood urea nitrogen (BUN) levels. At 5 days after cisplatin injection the BUN level was increased significantly from 15.1 +/- 4.3 to 126.7 +/- 152.6 mg dl(-1) and plasma creatinine levels increased from 0.37 +/- 0.005 to 1.68 +/- 1.9 mg dl(-1). When the rats were administered 50 and 75 mg kg(-1) erdosteine 24 h before cisplatin injection that was continued until sacrifice (total of 6 days), the BUN and creatinine levels remained similar to control levels and the grade of histology was similar. Erdosteine at doses of 50 and 75 mg kg(-1) ameliorates cisplatin-induced renal failure. The optimum dose of erdosteine may be 50 mg kg(-1) in this study.

  17. Nephroprotective effect of Bauhinia variegata (linn. whole stem extract against cisplatin-induced nephropathy in rats

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    Saumya R Pani

    2011-01-01

    Full Text Available The nephroprotective activity of the ethanolic extract of Bauhinia variegata (Linn. whole stem against cisplatin-induced nephropathy was investigated by an in vivo method in rats. Acute nephrotoxicity was induced by i.p. injection of cisplatin (7 mg/kg of body weight (b.w.. Administration of ethanol extract at dose levels of 400 and 200 mg/kg (b.w. to cisplatin-intoxicated rats for 14 days attenuated the biochemical and histological signs of nephrotoxicity of cisplatin in a dose-dependent fashion. Ethanol extract at 400 mg/kg decreased the serum level of creatinine (0.65 ± 0.09; P<0.001 and urea (32.86 ± 5.88; P<0.001 associated with a significant increase in body weight (7.16 ± 1.10; P<0.001 and urine volume output (11.95 ± 0.79; P<0.05 as compared to the toxic control group. The ethanol extract of B. variegata at 400 mg/kg (b.w. exhibited significant and comparable nephroprotective potential to that of the standard polyherbal drug cystone. The statistically (one-way-ANOVA followed by Tukey-Kramer multiple comparison processed results suggested the protective action of B. variegate whole stem against cisplatin-induced nephropathy.

  18. Mitochondria-Targeted Antioxidant Mitoquinone Reduces Cisplatin-Induced Ototoxicity in Guinea Pigs.

    Science.gov (United States)

    Tate, Alan D; Antonelli, Patrick J; Hannabass, Kyle R; Dirain, Carolyn O

    2017-03-01

    Objective To determine if mitoquinone (MitoQ) attenuates cisplatin-induced hearing loss in guinea pigs. Study Design Prospective and controlled animal study. Setting Academic, tertiary medical center. Subjects and Methods Guinea pigs were injected subcutaneously with either 5 mg/kg MitoQ (n = 9) or normal saline (control, n = 9) for 7 days and 1 hour before receiving a single dose of 10 mg/kg cisplatin. Auditory brainstem response thresholds were measured before MitoQ or saline administration and 3 to 4 days after cisplatin administration. Results Auditory brainstem response threshold shifts after cisplatin treatment were smaller by 28 to 47 dB in guinea pigs injected with MitoQ compared with those in the control group at all tested frequencies (4, 8, 16, and 24 kHz, P = .0002 to .04). Scanning electron microscopy of cochlear hair cells showed less outer hair cell loss and damage in the MitoQ group. Conclusion MitoQ reduced cisplatin-induced hearing loss in guinea pigs. MitoQ appears worthy of further investigation as a means of preventing cisplatin ototoxicity in humans.

  19. Protective Effect of Aqueous and Ethanolic Extracts of Portulaca Oleracea Against Cisplatin Induced Nephrotoxicity

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    Gholamreza Karimi

    2010-04-01

    Full Text Available Objective(sPortulaca oleracea L. is a herbaceous weed from portulacaceae family. It can be found in many parts of the world. Modern pharmacological studies have demonstrated that P. oleracea have antioxidant effects. The protective effect of aqueous and ethanolic extract of P. oleracea against cisplatin-induced renal toxicity was studied in rats.Materials and MethodsSingle intraperitoneal injection of 4 mg/kg cisplatin was administrated to rats. After 5 days, blood urea nitrogen (BUN and serum creatinine (Scr concentration were determined. Effect of aqueous and ethanolic extracts, before and after cisplatin injection on BUN and Scr, as well as morphological renal damage, was evaluated. ResultsIt was indicated that treatment with aqueous and ethanolic extracts of P. oleracea in the highest dose (0.8 and 2 g/ kg, 6 and 12 hr before cisplatin injection reduced BUN and Scr. Tubular necrotic damage was not observed either. ConclusionResults suggest that P. oleracea extract may protect against cisplatin-induced renal toxicity and might serve as a novel combination agent with cisplan to limit renal injury.

  20. Effects of Roselle and Ginger on cisplatin-induced reproductive toxicity in rats

    Institute of Scientific and Technical Information of China (English)

    Amr Amin; AlaaEldin A. Hamza

    2006-01-01

    Aim: To evaluate the protective effects of Hibiscus sabdariffa (Roselle) and Zingiber officinale (Ginger) against cisplatin-induced reproductive toxicity in rats and to study the mechanisms underlying these effects. Methods:which began 21 days before a single cisplatin I.p. Injection (10 mg/kg body weight). Results: Extracts of H. Sabdariffa and Z. Officinale reduced the extent of cisplatin-induced sperm abnormality and enhanced sperm motility. Both extracts restored the control level of malondialdehyde (MDA) (lipid peroxidation marker) in the cisplatin-treated testis.The cisplatin injection induced decline in the levels of superoxide dismutase (SOD), reduced glutathione (GSH) and catalase (CAT) were significantly reversed to control levels in groups where cisplatin was preceded by the administration of either H. Sabdariffa or Z. Officinale. Conclusion: Both H. Sabdariffa and Z. Officinale treatment increased the activities of testicular antioxidant enzymes and restored sperm motility of cisplatin-treated rats. The protective effects of tested plants are, therefore, suggested to be mediated by their potent antioxidant activities.

  1. The preventive effect of oxytocin to Cisplatin-induced neurotoxicity: an experimental rat model.

    Science.gov (United States)

    Akman, Tulay; Akman, Levent; Erbas, Oytun; Terek, Mustafa Cosan; Taskiran, Dilek; Ozsaran, Aydin

    2015-01-01

    Peripheral neurotoxicity is a frequent dose-limiting side effect of the chemotherapeutic agent cisplatin. This study was conducted to investigate the preventive effect of oxytocin (OT) on cisplatin-induced neurotoxicity in rats. Forty-four adult female rats were included in the study. Thirty-six rats were administered intraperitoneally (i.p.) single dose cisplatin 10 mg/kg and divided in to 3 groups. The first group (n=12) received saline i.p., whereas the second group (n=12) and the third group (n=12) were injected with 80 µg/kg and 160 µg/kg OT, respectively, for 10 days. The remaining 8 rats served as the control group. Electromyography (EMG) studies were recorded and blood samples were collected for the measurement of plasma lipid peroxidation (malondialdehyde; MDA), tumor necrosis factor (TNF)-α, and glutathione (GSH) levels. EMG findings revealed that compound muscle action potential amplitude was significantly decreased and distal latency was prolonged in the nontreated cisplatin-injected rats compared with the control group (Pcisplatin-injected rats showed significantly higher TNF-α and MDA levels and lower GSH level than control group. The administration of OT significantly ameliorated the EMG alterations, suppressed oxidative stress and inflammatory parameters, and increased antioxidative capacity. We suggest that oxytocin may have beneficial effects against cisplatin-induced neurotoxicity.

  2. Ellagic acid prevents cisplatin-induced oxidative stress in liver and heart tissue of rats.

    Science.gov (United States)

    Yüce, Abdurrauf; Ateşşahin, Ahmet; Ceribaşi, Ali Osman; Aksakal, Mesut

    2007-11-01

    Cisplatin is one of the most active cytotoxic agents in the treatment of cancer. High doses of cisplatin have also been known to produce hepatotoxicity, and several studies suggest that supplemental antioxidants can reduce cisplatin-induced hepatotoxicity. The present study was designed to determine the effects on the liver and heart oxidant/antioxidant system and the possible protective effects of ellagic acid on liver and heart toxicity induced by cisplatin. The control group received 0.9% saline; animals in the ellagic acid group received only ellagic acid (10 mg/kg); animals in the cisplatin group received only cisplatin (7 mg/kg); animals in cisplatin + ellagic acid group received ellagic acid for 10 days after cisplatin. The rats were killed at the end of the treatment period. Malondialdehyde (MDA) and glutathione (GSH) levels, glutathione-peroxidase (GSH-Px) and catalase (CAT) activities were determined in liver and heart tissue. While administration of cisplatin increased the MDA levels in liver and heart tissues, it decreased the GSH, GSH-Px and CAT in these samples when compared to the control group. The administration of ellagic acid to cisplatin-treated rats decreased the MDA levels, and increased GSH, GSH-Px and CAT in these samples. Cisplatin caused marked damages in the histopathological status of liver and heart tissues. These damages were ameliorated by ellagic acid administration. In conclusion, ellagic acid may be used in combination with cisplatin in chemotherapy to improve cisplatin-induced oxidative stress parameters.

  3. Bucillamine prevents cisplatin-induced ototoxicity through induction of glutathione and antioxidant genes.

    Science.gov (United States)

    Kim, Se-Jin; Ho Hur, Joon; Park, Channy; Kim, Hyung-Jin; Oh, Gi-Su; Lee, Joon No; Yoo, Su-Jin; Choe, Seong-Kyu; So, Hong-Seob; Lim, David J; Moon, Sung K; Park, Raekil

    2015-02-20

    Bucillamine is used for the treatment of rheumatoid arthritis. This study investigated the protective effects of bucillamine against cisplatin-induced damage in auditory cells, the organ of Corti from postnatal rats (P2) and adult Balb/C mice. Cisplatin increases the catalytic activity of caspase-3 and caspase-8 proteases and the production of free radicals, which were significantly suppressed by pretreatment with bucillamine. Bucillamine induces the intranuclear translocation of Nrf2 and thereby increases the expression of γ-glutamylcysteine synthetase (γ-GCS) and glutathione synthetase (GSS), which further induces intracellular antioxidant glutathione (GSH), heme oxygenase 1 (HO-1) and superoxide dismutase 2 (SOD2). However, knockdown studies of HO-1 and SOD2 suggest that the protective effect of bucillamine against cisplatin is independent of the enzymatic activity of HO-1 and SOD. Furthermore, pretreatment with bucillamine protects sensory hair cells on organ of Corti explants from cisplatin-induced cytotoxicity concomitantly with inhibition of caspase-3 activation. The auditory-brainstem-evoked response of cisplatin-injected mice shows marked increases in hearing threshold shifts, which was markedly suppressed by pretreatment with bucillamine in vivo. Taken together, bucillamine protects sensory hair cells from cisplatin through a scavenging effect on itself, as well as the induction of intracellular GSH.

  4. Cisplatin induces cytotoxicity through the mitogen-activated protein kinase pathways and activating transcription factor 3.

    Science.gov (United States)

    St Germain, Carly; Niknejad, Nima; Ma, Laurie; Garbuio, Kyla; Hai, Tsonwin; Dimitroulakos, Jim

    2010-07-01

    The mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are largely undefined. Understanding the mechanisms regulating cisplatin cytotoxicity may uncover strategies to enhance the efficacy of this important therapeutic agent. This study evaluates the role of activating transcription factor 3 (ATF3) as a mediator of cisplatin-induced cytotoxicity. Cytotoxic doses of cisplatin and carboplatin treatments consistently induced ATF3 expression in five tumor-derived cell lines. Characterization of this induction revealed a p53, BRCA1, and integrated stress response-independent mechanism, all previously implicated in stress-mediated ATF3 induction. Analysis of mitogen-activated protein kinase (MAPK) pathway involvement in ATF3 induction by cisplatin revealed a MAPK-dependent mechanism. Cisplatin treatment combined with specific inhibitors to each MAPK pathway (c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38) resulted in decreased ATF3 induction at the protein level. MAPK pathway inhibition led to decreased ATF3 messenger RNA expression and reduced cytotoxic effects of cisplatin as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell viability assay. In A549 lung carcinoma cells, targeting ATF3 with specific small hairpin RNA also attenuated the cytotoxic effects of cisplatin. Similarly, ATF3-/- murine embryonic fibroblasts (MEFs) were shown to be less sensitive to cisplatin-induced cytotoxicity compared with ATF3+/+ MEFs. This study identifies cisplatin as a MAPK pathway-dependent inducer of ATF3, whose expression influences cisplatin's cytotoxic effects.

  5. Protective effect of speman on cisplatin-induced testicular and epididymal toxicity in mice

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    S B Sainath

    2011-01-01

    Full Text Available Testicular cancer is the most common cancer affecting men of reproductive age. Advances in treatment of the disease, which includes the administration of cisplatin, have brought the 5-year survival rate to over 90%. This high cure rate, coupled with young age of patients, makes elucidation of the impact of the treatment on reproduction become increasingly important. The objective of the present study was to investigate the protective effect of speman, a non-hormonal herbal formulation, on cisplatin-induced suppressed male reproductive health in mice. Male mice were treated with cisplatin or speman alone or in combination and assessed for spermatogenesis and steroidogenesis. Significant decrease in the weights of testes and epididymis was observed in cisplatin treated animals. Injection of cisplatin significantly decreased epididymal sperm count, viable sperms, motile sperms and hypo-osmotic swelling (HOS-tail coiled sperms with a significant reduction in the testicular steroidogenic enzyme activities and serum testosterone levels, whereas co-administration of speman with cisplatin showed a significant improvement in the selected reproductive parameters over cisplatin alone treated mice indicating the beneficial effect of speman to combat cisplatin-induced suppressed reproduction in male mice.

  6. Placebo manipulations reduce hyperalgesia in neuropathic pain.

    Science.gov (United States)

    Petersen, Gitte Laue; Finnerup, Nanna Brix; Nørskov, Kathrine Næsted; Grosen, Kasper; Pilegaard, Hans K; Benedetti, Fabrizio; Price, Donald D; Jensen, Troels Staehelin; Vase, Lene

    2012-06-01

    Several studies have shown that placebo analgesia effects can be obtained in healthy volunteers, as well as patients suffering from acute postoperative pain and chronic pain conditions such as irritable bowel syndrome. However, it is unknown whether placebo analgesia effects can be elicited in chronic pain conditions with a known pathophysiology such as a nerve injury. Nineteen patients who had developed neuropathic pain after thoracotomy were exposed to a placebo manipulation in which they received either open or hidden administrations of lidocaine. Before the treatment, the patients rated their levels of spontaneous pain and expected pain and completed a questionnaire on their emotional feelings (Positive Affect Negative Affect Schedule) and went through quantitative sensory testing of evoked pain (brush and cold allodynia, heat pain tolerance, area of pinprick hyperalgesia, wind-up-like pain after pinprick stimulation). The placebo manipulation significantly reduced the area of pinprick hyperalgesia (P=.027), and this placebo effect was significantly related to low levels of negative affect (P=.008; R(2)=0.362) but not to positive affect or expected pain levels. No placebo effect was observed in relation to spontaneous pain or evoked pain, which is most likely due to low pain levels resulting in floor effects. This is the first study to demonstrate a placebo effect in neuropathic pain. The possible mechanisms underlying the placebo effects in hyperalgesia are discussed, and implications for treatment are outlined.

  7. ROLE OF ERK1/2 KINASE IN CISPLATIN-INDUCED APOPTOSIS IN HUMAN OVARIAN CARCINOMA CELLS

    Institute of Scientific and Technical Information of China (English)

    Shu-qin Wei; Li-hua Sui; Jian-hua Zheng; Guang-mei Zhang; Yan-Lin Kao

    2004-01-01

    Objective To investigate the role of extracellular regulated kinase (ERK1/2) pathway in cisplatin-induced apoptosis in human ovarian carcinoma cells.Methods Cisplatin-induced apoptosis were stained with DAPI and was assessed microscopically in human epithelial adenocarcinoma ovarian cell line SKOV3 cells. ERK activation was determined by Western blotting using an anti-phosphoERK antibody to detect ERK activity. The effect of PD98059 on ERK activity induced by cisplatin was detected by MTT assay.Results Marked apoptosis of SKOV3 cells resulted from 48 hours treatment with 20 μg/mL cisplatin. Strong activation of ERK was led to by 15 μg/mL cisplatin. Dose response and time course of cisplatin induced apoptosis in SKOV3 cells.Cisplatin-induced ERK activation occurred at 12 hours and increased to highest induction at 24 hours by Western blotting.The effect of PD 98059 on ERK activity induced by cisplatin at the concentration of 100 μmol/L PD 98059. Statistically significant decreased in cell survival were observed with 100 μmol/L PD 98059 at 15 and 20 μg/mL cisplatin (P< 0.05).Conclusions Cisplatin activates the ERK signaling pathway in ovarian cancer cell line SKOV3. Inhibition of ERK activity enhances sensitivity to cisplatin cytotoxity in ovarian cancer cell line SKOV3. Evaluation of ERK activity could be useful in predicting which ovarian cancer will response most favorably to cisplatin therapy.

  8. The Protective Effect of mammalian Target of Rapamycin (mTOR in Cisplatin Induced Nephropathy

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    Kultigin Turkmen

    2009-05-01

    Full Text Available "nCisplatin, a simple inorganic compound, has been one of the leading antitumor drugs especially for solid tumors for near 30 years. The mechanisms of cisplatin include denaturation of DNA and cell mitochondria, arresting cell cycle in the G2 phase and eventually causing apoptosis, inflammation, necrosis and death in cells. Apoptosis is a process of programmed cell death through cystein proteases named ‘caspases'. Pathways of caspase-mediated apoptosis can classified as ‘mitochondrial' pathway and ‘death receptor' pathway Especially caspase-3 plays a crucial role in cisplatin-induced nephrotoxicity through the pathways of apoptosis. The mammalian target of rapamycin (mTOR, is a serine/threonine kinase that regulates both cell growth and cell cycle progression through the phosphotidyl 3 kinase (PI3K/protein kinase B (Akt signaling pathway. mTOR regulates both cell growth, cell cycle progression and angiogenesis. By targeting mTOR, the immunsuppressant and antiproliferative agent Rapamycin inhibits signals required for cell cycle progression, cell growth, cell proliferation and angiogenesis. Angiogenesis is extremely important in tumor progression and metastasis. Although rapamycin is proapoptotic agent especially in cancers, there is an evidence that rapamycin can also have antiapoptotic properties through pleiotropic function in the regulation of cell death depending on the cell type and activation state as well as downstream targets of antiapoptotic molecules such as p53 and Bcl-2 proteins. Activation of caspase signaling pathways and dysregulation of pro- and antiapoptotic Bcl-2 proteins have been described previously. So there are links between the mTOR and caspase signaling pathways. Despite its effectiveness, the dose of cisplatin that can be administered is limited by its nephrotoxicity such as acute tubuler necrosis (ATN causing acute renal failure (ARF. Several agents have been tested to see whether they could

  9. Demarcation of secondary hyperalgesia zones

    DEFF Research Database (Denmark)

    Ringsted, Thomas K; Enghuus, Casper; Petersen, Morten A;

    2015-01-01

    of analgesic drug effects in humans. However, since the methods applied in demarcating the secondary hyperalgesia zone seem inconsistent across studies, we examined the effect of a standardized approach upon the measurement of SHA following a first degree burn injury (BI). NEW METHOD: The study was a two...... presented. CONCLUSIONS: This is the first study to demonstrate that demarcation of secondary hyperalgesia zones depends on the developed pressure of the punctate stimulator used....

  10. P53 Contributes to Cisplatin Induced Renal Oxidative Damage via Regulating P66shc and MnSOD

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    Yanggang Yuan

    2015-10-01

    Full Text Available Background/Aims: Cisplatin is widely used to treat malignancies. However, its major limitation is the development of dose-dependent nephrotoxicity. The precise mechanisms of cisplatin-induced kidney damage remain unclear. Previous study demonstrated the central role of mitochondrial ROS (mtROS in the pathogenesis of cisplatin nephrotoxicity. The purpose of this study was to explore the mechanism of mtROS regulation in cisplatin nephrotoxicity. Methods: p53, MnSOD and p66shc were detected at mRNA and protein levels by qPCR and western blot in HK2 cells. mtROS levels were determined by DCFDA and MitoSOX staining. Cell viability and cell apoptosis were accessed by CCK-8 assay, TUNEL assay and flow cytometry, respectivesly. siRNAs were used to knock down p53 and p66shc expression and subsequent changes were observed. In vivo assays using a mouse model of cisplatin-induced acute kidney injury were used to validate the in vitro results. Results: In HK2 cells, cisplatin exposure decreased the MnSOD and increased the expression of p53 and p66shc. MnTBAP, a MnSOD mimic, blocked cisplatin-induced the generation of mtROS and cell injury. P66shc and p53 siRNAs rendered renal cells resistant to cisplatin-induced mtROS production and cell death. Furthermore, knockdown of p53 restored MnSOD and inhibiting p66shc. Consistent with these results, we revealed that p53 inhibitor reduced cisplatin-induced oxidative stress and apoptosis by regulating MnSOD and p66shc in the kidney of cisplatin-treated mice. Conclusion: Our study identifies activation of p53 signalling as a potential strategy for reducing the nephrotoxicity associated with cisplatin treatments and, as a result, broadens the therapeutic window of this chemotherapeutic agent.

  11. Protocatechuic aldehyde attenuates cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation

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    Li Gao

    2016-12-01

    Full Text Available Cisplatin is a classic chemotherapeutic agent widely used to treat different types of cancers including ovarian, head and neck, testicular and uterine cervical carcinomas. However, cisplatin induces acute kidney injury by directly triggering an excessive inflammatory response, oxidative stress and programmed cell death of renal tubular epithelial cells. All of which lead to higher mortality rates in patients. In this study we examined the protective effect of protocatechuic aldehyde (PA in vitro in cisplatin-treated tubular epithelial cells and in vivo in cisplatin nephropathy. PA is a monomer of Traditional Chinese Medicine isolated from the root of S. miltiorrhiza. Results show that PA prevented cisplatin-induced decline of renal function and histological damage, which was confirmed by attenuation of KIM1 in both mRNA and protein levels. Moreover, PA reduced renal inflammation by suppressing oxidative stress and programmed cell death in response to cisplatin, which was further evidenced by in vitro data. Of note, PA suppressed NAPDH oxidases, including Nox2 and Nox4, in a dosage-dependent manner. Moreover, silencing Nox4, but not Nox2, removed the inhibitory effect of PA on cisplatin-induced renal injury, indicating that Nox4 may play a pivotal role in mediating the protective effect of PA in cisplatin-induced acute kidney injury. Collectively, our data indicate that PA largely blocked cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation without compromising anti-tumor activity of cisplatin. These findings suggest that PA and its derivatives may serve as potential protective agents for cancer patients with cisplatin treatment.

  12. Breast cancer cells with acquired antiestrogen resistance are sensitized to cisplatin-induced cell death

    DEFF Research Database (Denmark)

    Yde, Christina Westmose; Gyrd-Hansen, Mads; Lykkesfeldt, Anne E

    2007-01-01

    for future breast cancer treatment. In this study, we have investigated the effect of the chemotherapeutic compound cisplatin using a panel of antiestrogen-resistant breast cancer cell lines established from the human breast cancer cell line MCF-7. We show that the antiestrogen-resistant cells...... with parental MCF-7 cells. Our data show that Bcl-2 can protect antiestrogen-resistant breast cancer cells from cisplatin-induced cell death, indicating that the reduced expression of Bcl-2 in the antiestrogen-resistant cells plays a role in sensitizing the cells to cisplatin treatment.......Antiestrogens are currently used for treating breast cancer patients who have estrogen receptor-positive tumors. However, patients with advanced disease will eventually develop resistance to the drugs. Therefore, compounds effective on antiestrogen-resistant tumors will be of great importance...

  13. NEPHROPROTECTIVE ACTIVITY OF CYANOTIS FASCICULATA VAR., FASCICULATA AGAINST CISPLATIN INDUCED NEPHROTOXICITY

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    Murthy R.L.N

    2011-09-01

    Full Text Available Cisplatin is quite effective against various neoplastic diseases, but its potential nephrotoxicity leads to increased morbidity, complications and hospitalization costs. Prevention of nephrotoxicity may allow clinicians to administer higher doses for added therapeutic benefits. So, the present investigation was designed to evaluate the ability of the 70% hydro-alcoholic extract of Cyanotis fasciculata Var., fasciculata (CFEE to combat Cisplatin induced nephrotoxicity. Where, CFEE demonstrated dose dependent decrement of elevated biochemical markers of nephrotoxicity along with significant restoration of protective-GSH levels and suppression of LPO levels in tissues. Further, the remarkable renal-cellular rejuvenation found in histopathological studies also enunciated the organ protective activity of CFEE. It was concluded that, in addition to polyphenolics, some of the phyto-fragments found during GC-MS analysis might also contributed to the protection offered by CFEE.

  14. Chemopreventive Effect of Tadalafil in Cisplatin-Induced Nephrotoxicity in Rats.

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    Adeneye, A A; Benebo, A S

    2016-08-30

    Nephrotoxicity remains a common untoward effect of cisplatin therapy with limited effective chemopreventive options available till date. This study aims to evaluate the possible chemopreventive effect and mechanism(s) of action of 2 mgkg-1 and 5 mgkg-1 of Tadalafil in cisplatin-induced nephrotoxic rats. In this study, twenty-five male Wistar rats were randomly divided into five groups (n = 5 rats per group) and daily pretreated with oral doses of distilled water (10 mLkg-1), ascorbic acid (100 mgkg-1), Tadalafil (2 mgkg-1 and 5 mgkg-1) for 7 days before cisplatin (5 mgkg-1, intraperitoneal) was administered. 72 hours post-cisplatin injections, rats were sacrificed humanely and blood samples for serum electrolytes, urea and creatinine and renal tissues for reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and malonialdehyde dehydrogenase (MAD) assays and histopathology were collected. Results showed that cisplatin injection caused significant decreases in the serum sodium (Na+), potassium (K+), bicarbonate (HCO3-), calcium (Ca2+), phosphate (PO42-) and concomitant significant increases in the serum urea and creatinine levels. In addition, there were significant decreases in the renal tissue GSH, SOD, CAT and increased MAD and GSH-Px levels which were corroborated by histopathological features of tubulonephritis. However, these histo-biochemical alterations were significantly attenuated by ascorbic acid and Tadalafil pretreatments. Overall, results of this study showed the chemopreventive potential of Tadalafil against cisplatin-induced nephrotoxicity which was possibly mediated via antioxidant and anti-lipoperoxidation mechanisms.

  15. Selective Cyclooxygenase-2 Inhibitor Prevents Cisplatin-induced Tumorigenesis in A/J Mice

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    Okada,Toshiaki

    2012-06-01

    Full Text Available Cisplatin is used to treat lung cancer;however, it is also a known carcinogen. Cyclooxygenase-2 (COX-2 inhibitors have been shown to prevent carcinogen-induced experimental tumors. We investigated the effect of a COX-2 inhibitor, celecoxib, on cisplatin-induced lung tumors. One hundred twenty 4-week-old A/J mice were divided into 6 groups:group 1, no treatment;group 2, low-dose celecoxib (150mg/kg;group 3, high-dose celecoxib (1,500mg/kg;group 4, cisplatin alone;group 5, cisplatin plus low-dose celecoxib;and group 6, cisplatin plus high-dose celecoxib. Mice in groups 4-6 were administered cisplatin (1.62mg/kg, i.p. once a week for 10 weeks between 7 and 16 weeks of age. All mice were sacrificed at week 30. Tumor incidence was 15.8% in group 1, 25% in group 2, 26.3% in group 3, 60% in group 4, 50% in group 5, and 50% in group 6. Tumor multiplicity was 0.2, 0.3, 0.3, 1.3, 1.0, and 0.6 in groups 1-6, respectively. Tumor multiplicity in the cisplatin-treated mice was reduced by celecoxib treatment in a dose-dependent manner (p<0.05, group 4 vs. group 6. Celecoxib significantly reduced COX-2 expression in cisplatin-induced tumors (p<0.01, group 4 vs. group 6.

  16. Cisplatin Induces Bmi-1 and Enhances the Stem Cell Fraction in Head and Neck Cancer

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    Carolina Nör

    2014-02-01

    Full Text Available Recent evidence has unveiled a subpopulation of highly tumorigenic, multipotent cells capable of self-renewal in head and neck squamous cell carcinomas (HNSCCs. These unique cells, named here cancer stem cells (CSCs, proliferate slowly and might be involved in resistance to conventional chemotherapy. We have shown that CSCs are found in perivascular niches and rely on endothelial cell-secreted factors [particularly interleukin-6 (IL-6] for their survival and self-renewal in HNSCC. Here, we hypothesized that cisplatin enhances the stem cell fraction in HNSCC. To address this hypothesis, we generated xenograft HNSCC tumors with University of Michigan-squamous cell carcinoma 22B (UM-SCC-22B cells and observed that cisplatin treatment increased (P = .0013 the fraction of CSCs [i.e., aldehyde dehydrogenase activity high and cluster of differentiation 44 high (ALDHhighCD44high]. Cisplatin promoted self-renewal and survival of CSCs in vitro, as seen by an increase in the number of orospheres in ultralow attachment plates and induction in B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1 and octamer-binding transcription factor 4 expression. Cisplatin-resistant cells expressed more Bmi-1 than cisplatinsensitive cells. IL-6 potentiated cisplatin-induced orosphere formation generated when primary human HNSCC cells were sorted for ALDHhighCD44high immediately after surgery and plated onto ultralow attachment plates. IL-6-induced signal transducer and activator of transcription 3 (STAT3 phosphorylation (indicative of stemness was unaffected by treatment with cisplatin in UM-SCC-22B cells, whereas IL-6-induced extracellular signal-regulated kinase (ERK phosphorylation (indicative of differentiation processes was partially inhibited by cisplatin. Notably, cisplatin-induced Bmi-1 was inhibited by interleukin-6 receptor blockade in parental and cisplatin-resistant cells. Taken together, these results demonstrate that cisplatin enhances the fraction of CSCs

  17. Neural regulation of the kidney function in rats with cisplatin induced renal failure

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    Niamh E Goulding

    2015-06-01

    Full Text Available Aim: Chronic kidney disease (CKD is often associated with a disturbed cardiovascular homeostasis. This investigation explored the role of the renal innervation in mediating deranged baroreflex control of renal sympathetic nerve activity (RSNA and renal excretory function in cisplatin-induced renal failure.Methods: Rats were either intact or bilaterally renally denervated four days prior to receiving cisplatin (5mg/kg i.p. and entered a chronic metabolic study for 8 days. At day 8, other groups of rats were prepared for acute measurement of RSNA or renal function with either intact or denervated kidneys.Results: Following the cisplatin challenge, creatinine clearance was 50% lower while fractional sodium excretion and renal cortical and medullary TGF-β1 concentrations were 3-4 fold higher in both intact and renally denervated rats compared to control rats. In cisplatin-treated rats, the maximal gain of the high-pressure baroreflex curve was only 20% that of control rats, but not different from that of renally denervated control rats. Volume expansion reduced RSNA by 50% in control and in cisplatin-treated rats but only following bilateral renal denervation. The volume expansion mediated natriuresis/diuresis was absent in the cisplatin-treated rats but was normalised following renal denervation. Conclusions: Cisplatin-induced renal injury impaired renal function and caused a sympatho-excitation with blunting of high and low pressure baroreflex regulation of RSNA, which was dependent on the renal innervation. It is suggested that in man with CKD there is a dysregulation of the neural control of the kidney mediated by its sensory innervation.

  18. The impact of erdosteine on cisplatin-induced ototoxicity: a proteomics approach.

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    Waissbluth, Sofia; Garnier, Delphine; Akinpelu, Olubunmi V; Salehi, Pezhman; Daniel, Sam J

    2017-03-01

    Cisplatin is a commonly used chemotherapeutic agent and causes serious side effects, including progressive and irreversible hearing loss. No treatment is currently available for cisplatin-induced ototoxicity. We have previously demonstrated that erdosteine, a potent antioxidant, partially protected the cochlea against cisplatin toxicity in vivo. The aims of this study were to (1) evaluate the protein profiles of the cochlea following cisplatin administration and (2) evaluate the impact of erdosteine on the protein profile using a proteomics-based approach. Thirty Sprague-Dawley rats were injected intraperitoneally with saline (n = 10), cisplatin (n = 10) or with cisplatin and erdosteine (n = 10). The cisplatin dosage was 14 mg/kg and for erdosteine, 500 mg/kg. Following euthanasia, protein lysates were obtained from fresh-frozen cochleae and were processed for mass spectrometry and western blotting. We detected 445 proteins that exhibited a twofold change or greater in the cisplatin group as compared to the control group. Of these, 18 proteins showed a fourfold or greater change in expression associated with cisplatin administration, including ras-related protein Rab-2A, Rab-6A, cd81, ribosomal protein S5, and myelin basic protein, which were downregulated, while Ba1-647 and fibrinogen (alpha chain), amongst others, were upregulated. Co-administration of erdosteine revealed a reversal of these changes in the expression of ras-related protein Rab-2A, ribosomal protein S5, myelin basic protein, and fibrinogen (alpha chain); erdosteine also upregulated glutathione reductase. In this study, we identified various proteins that may play a role in cisplatin-induced ototoxicity. We also observed the changes resulting from co-treatment with an antioxidant.

  19. Effect of aqueous extract of Rheum ribes on cisplatin-induced nephrotoxicity in rat

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    Mousa-Al-Reza Hadjzadeh

    2013-01-01

    Full Text Available Objective: The purpose of the present study was to examine whether Rheum ribes extract prevents cisplatin-induced nephrotoxicity. Materials and Methods: The animals were divided into three groups: Group A considered as control group, group B were treated with cisplatin (3 mg/kg B.W. for 3 alternative days, and group C further to cisplatin received the aqueous extract of Rheum ribes (150 mg/rat. Results: Blood urea nitrogen (BUN level increased in group B on days 14 and 42 compared to day 0 ( P < 0.001; it was also increased in group B vs. group A on day 14 ( P < 0.001. Rheum ribes extract decreased the serum BUN level on day 14 compared to group B ( P < 0.001. Serum creatinine level in group B had a similar profile as serum BUN level but Rheum ribes had no effect on blood creatinine level. Serum cholesterol level was increased in group B on days 14 and 42 compared to day 0 ( P < 0.001. Also, cholesterol level was significantly increased in group B when compared to group A on day 14 ( P < 0.001. Rheum ribes decreased the blood cholesterol level on day 42 in comparison to group B ( P < 0.001. Serum glucose level was increased in group B on days 14 and 42 vs. day 0 ( P < 0.001. Also, glucose level was significantly increased in group B when compared to group A on day 42 ( P < 0.001. Rheum ribes increased the serum glucose level on days 14 and 42 compared to day 0 ( P < 0.05. Histology of kidneys exposed to cisplatin showed renal injury, but Rheum ribes had no effect on the kidney architecture. Conclusion: Cisplatin-induced nephrotoxicity was confirmed in our study. Although Rheum ribes had some effects on biochemical parameters; its effect on renal histology in injured kidney was insignificant.

  20. Ameliorative effect of Apodytes dimidiata on cisplatin-induced nephrotoxicity in Wistar rats.

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    Divya, Menon Kunnathully; Lincy, Lawrence; Raghavamenon, Achuthan Chathrattil; Babu, Thekkekara Devassy

    2016-10-01

    Context Nutraceuticals possessing antioxidant potential have been used to alleviate side effects exerted by many chemotherapeutics, including cisplatin. Since Apodytes dimidiata E. Mey. Ex Arn. (Icacinaceae) shows antioxidant potential, it may possess significant chemoprotective effects. Objectives The study investigated whether A. dimidiata could attenuate cisplatin-induced renal damage. Materials and methods Nephrotoxicity was induced by cisplatin (single i.p., 16 mg/kg b wt.) in Wistar rats. Methanolic leaf extract of A. dimidiata (AMF) was administered at a dose of 250 mg/kg b. wt. orally for 5 consecutive days before/after cisplatin administration. Blood and renal parameters were analysed. Total phenolic and flavonoid content in AMF and its NO scavenging effect was determined. Results Significant protective effect of AMF on cisplatin-induced nephrotoxicity was observed in pre-treated animals. The reduction of urea, creatinine and lipid peroxidation was 58.31%, 42.19% and 60%, respectively, and the increase in haemoglobin and leucocyte count was 28.25% and 42.91%, respectively. The increase calculated for GSH, GPx, SOD and catalase was 35.64%, 18.14%, 74.42% and 35.46%, respectively. Tissue architecture of kidney was almost normal in AMF treated animals. The results were comparable to the standard drug, silymarin. AMF contained high level of polyphenols and flavonoids and was found to scavenge NO radicals (IC50 121.8 μg/mL). Discussion and conclusion AMF can effectively counteract cisplatin mediated renal acute toxicity possibly by scavenging reactive oxygen and nitrogen species. Accordingly, the study suggests that AMF can ameliorate free radical-induced damage associated with chemotherapeutic drugs.

  1. Cisplatin Induces Cytotoxicity through the Mitogen-Activated Protein Kinase Pathways ana Activating Transcription Factor 3

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    Carly St. Germain

    2010-07-01

    Full Text Available The mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are largely undefined. Understanding the mechanisms regulating cisplatin cytotoxicity may uncover strategies to enhance the efficacy of this important therapeutic agent. This study evaluates the role of activating transcription factor 3 (ATF3 as a mediator of cisplatin-induced cytotoxicity. Cytotoxic doses of cisplatin and carboplatin treatments consistently induced ATF3 expression in five tumor-derived cell lines. Characterization of this induction revealed a p53, BRCA1, and integrated stress response-independent mechanism, all previously implicated in stress-mediated ATF3 induction. Analysis of mitogenactivated protein kinase (MAPK pathway involvement in ATF3 induction by cisplatin revealed a MAPK-dependent mechanism. Cisplatin treatment combined with specific inhibitors to each MAPK pathway (c-Jun N-terminal kinase, extracellularsignal-regulated kinase, and p38 resulted in decreasedATF3 induction at the protein level. MAPK pathway inhibition led to decreased ATF3 messenger RNA expression and reduced cytotoxic effects of cisplatin as measured by the 3-(4,5-dimethylthiazol-2-ylF2,5-diphenyltetrazolium bromide cell viability assay. In A549 lung carcinoma cells, targeting ATF3 with specific small hairpin RNA also attenuated the cytotoxic effects of cisplatin. Similarly, ATF3-/murine embryonic fibroblasts (MEFs were shown to be less sensitive to cisplatin-induced cytotoxicity compared with ATF3+/+ MEFs. This study identifies cisplatin as a MAPK pathway-dependent inducer of ATF3, whose expression influences cisplatin’s cytotoxic effects.

  2. Fear of pain potentiates nocebo hyperalgesia.

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    Aslaksen, Per M; Lyby, Peter S

    2015-01-01

    Nocebo hyperalgesia has received sparse experimental attention compared to placebo analgesia. The aim of the present study was to investigate if personality traits and fear of pain could predict experimental nocebo hyperalgesia. One hundred and eleven healthy volunteers (76 females) participated in an experimental study in which personality traits and fear of pain were measured prior to induction of thermal heat pain. Personality traits were measured by the Big-Five Inventory-10. Fear of pain was measured by the Fear of Pain Questionnaire III. Heat pain was induced by a PC-controlled thermode. Pain was measured by a computerized visual analog scale. Stress levels during the experiment were measured by numerical rating scales. The participants were randomized to a Nocebo group or to a no-treatment Natural History group. The results revealed that pain and stress levels were significantly higher in the Nocebo group after nocebo treatment. Mediation analysis showed that higher levels of the Fear of Pain Questionnaire III factor "fear of medical pain" significantly increased stress levels after nocebo treatment and that higher stress levels were associated with increased nocebo hyperalgesic responses. There were no significant associations between any of the personality factors and the nocebo hyperalgesic effect. The results from the present study suggest that dispositional fear of pain might be a useful predictor for nocebo hyperalgesia and emotional states concomitant with expectations of increased pain. Furthermore, measurement of traits that are specific to pain experience is probably better suited for prediction of nocebo hyperalgesic responses compared to broad measures of personality.

  3. Attenuation of cisplatin-induced emetogenesis by standardized Bacopa monnieri extracts in the pigeon: behavioral and neurochemical correlations.

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    Ullah, Ihsan; Subhan, Fazal; Rudd, John A; Rauf, Khalid; Alam, Javaid; Shahid, Muhammad; Sewell, Robert D E

    2014-11-01

    Nausea and vomiting are the most distressing and common side effects of cancer chemotherapy which often result in patient noncompliance. In the present study, standardized methanolic and n-butanolic fractions of Bacopa monnieri were evaluated against cisplatin-induced emesis in the pigeon in relation to their activity on central and intestinal neurotransmitters levels. Cisplatin (7.0 mg/kg, i. v.) induced reproducible emesis without lethality in healthy pigeons. The methanolic (10-40 mg/kg) and the bacoside-rich n-butanolic fractions of B. monnieri (5-20 mg/kg), as well as the antioxidant N-(2-mercaptopropionyl) glycine (10 mg/kg), attenuated cisplatin-induced emesis by 66.3% (p bacoside-rich n-butanolic fractions might be a valuable adjunct in the treatment of emetogenic chemotherapy, and this warrants further study in other models of emesis.

  4. Effects of ozone (O3) therapy on cisplatin-induced ototoxicity in rats.

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    Koçak, Hasan Emre; Taşkın, Ümit; Aydın, Salih; Oktay, Mehmet Faruk; Altınay, Serdar; Çelik, Duygu Sultan; Yücebaş, Kadir; Altaş, Bengül

    2016-12-01

    The aim of this study is to investigate the effect of rectal ozone and intratympanic ozone therapy on cisplatin-induced ototoxicity in rats. Eighteen female Wistar albino rats were included in our study. External auditory canal and tympanic membrane examinations were normal in all rats. The rats were randomly divided into three groups. Initially, all the rats were tested with distortion product otoacoustic emissions (DPOAE), and emissions were measured normally. All rats were injected with 5-mg/kg/day cisplatin for 3 days intraperitoneally. Ototoxicy had developed in all rats, as confirmed with DPOAE after 1 week. Rectal and intratympanic ozone therapy group was Group 1. No treatment was administered for the rats in Group 2 as the control group. The rats in Group 3 were treated with rectal ozone. All the rats were tested with DPOAE under general anesthesia, and all were sacrificed for pathological examination 1 week after ozone administration. Their cochleas were removed. The outer hair cell damage and stria vascularis damage were examined. In the statistical analysis conducted, a statistically significant difference between Group 1 and Group 2 was observed in all frequencies according to the DPOAE test. In addition, between Group 2 and Group 3, a statistically significant difference was observed in the DPOAE test. However, a statistically significant difference was not observed between Group 1 and Group 3 according to the DPOAE test. According to histopathological scoring, the outer hair cell damage score was statistically significantly high in Group 2 compared with Group 1. In addition, the outer hair cell damage score was also statistically significantly high in Group 2 compared with Group 3. Outer hair cell damage scores were low in Group 1 and Group 3, but there was no statistically significant difference between these groups. There was no statistically significant difference between the groups in terms of stria vascularis damage score examinations

  5. Protection by ozone preconditioning is mediated by the antioxidant system in cisplatin-induced nephrotoxicity in rats

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    Enys Rojas

    1992-01-01

    Full Text Available Background: Acute renal failure is a dose-limiting factor of cisplatin chemotherapy. Here, we show the protective effect of ozone oxidative preconditioning against cisplatin-induced renal dysfunction in rats. Ozone oxidative preconditioning is a prophylactic approach, which favors the antioxidant–pro-oxidant balance for preservation of the cell redox state by increasing antioxidant endogenous systems in various in vivo and in vitro experimental models.

  6. Role of CFTR in oxidative stress and suicidal death of renal cells during cisplatin-induced nephrotoxicity

    OpenAIRE

    Rubera, I.; Duranton, C; Melis, N; Cougnon, M; Mograbi, B.; Tauc, M

    2013-01-01

    The clinical use of the antineoplastic drug cisplatin is limited by its deleterious nephrotoxic side effect. Cisplatin-induced nephrotoxicity is associated with an increase in oxidative stress, leading ultimately to renal cell death and irreversible kidney dysfunction. Oxidative stress could be modified by the cystic fibrosis transmembrane conductance regulator protein (CFTR), a Cl− channel not only involved in chloride secretion but as well in glutathione (GSH) transport. Thus, we tested whe...

  7. Nephroprotective effect of vanillic acid against cisplatin induced nephrotoxicity in wistar rats: a biochemical and molecular study.

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    Sindhu, Ganapathy; Nishanthi, Emayavaramban; Sharmila, Ramalingam

    2015-01-01

    Cisplatin is one of the extensively used anticancer drugs against various cancers. Dosage dependent nephrotoxicity is the major problem in cisplatin chemotherapy. Cisplatin induced nephrotoxicity results in the depletion of renal antioxidant defence system. Our present study is aimed to investigate the nephroprotective effect of vanilic acid to against cisplatin induced nephrotoxicity in male wistar rats. Elevated levels of serum creatinine, blood urea nitrogen, serum uric acid and reduced antioxidant status were observed as indicatives of nephrotoxicity in cisplatin (7mg/kg bw) alone administered rats. Animals which are pre-treated with vanillic acid (50mg/kg and 100mg/kg) restored the elevated levels of renal function markers and reduced antioxidant status to near normalcy when compared to cisplatin alone treated animals. Cisplatin induced lipid peroxidation was markedly reduced by oral administration of vanillic acid at a high dose. The findings in the present study suggest that vanillic acid is a potential antioxidant that reduce cisplatin nephrotoxicity and can be as a combinatorial regimen in cancer chemotherapy.

  8. Effects of Korean ginseng root extract on cisplatin-induced emesis in a rat-pica model.

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    Raghavendran, Hanumantha Rao Balaji; Rekha, Sathyanath; Shin, Jang-Woo; Kim, Hyeong-Geug; Wang, Jing-Hua; Park, Hye-Jung; Choi, Min-Kyung; Cho, Jung-Hyo; Son, Chang-Gue

    2011-01-01

    In the present study, we investigate the effect of Korean ginseng root extract (KG) on cisplatin-induced pica in a rat model. Rats were treated with KG before (25, 50, and 100 mg/kg) or after (12.5, 25, and 50 mg/kg) a single intraperitoneal injection of cisplatin (7 and 6 mg/kg, respectively). We examined intake of kaolin and normal food as an indicator of the emetic stimulus every 24 h for 120 h. Changes in body weight, haematology and histopathology were additionally assessed. Pre-treatment with KG (25 and 50 mg/kg) significantly attenuated cisplatin-induced kaolin intake (24, 48, and 72 h) and markedly improved intake of normal food by rats at 48, 72, 96, and 120 h. Cisplatin-induced kaolin intake was markedly decreased upon post-treatment of rats with KG (12.5, 25, and 50 mg/kg) at 24 h. Notably, post-treatment with the lowest KG dose resulted in a significant anti-pica effect and improved food intake until 72 h. The magnitude of body weight reduction was significantly diminished in rats pre-treated/post-treated with 25, 50, and 12.5 mg/kg KG. The anti-pica effects of KG were further confirmed with haematological and histopathological findings. Our findings collectively indicate that KG improves the resistance of rats against emesis.

  9. Abrogation of cisplatin-induced nephrotoxicity in rats by Berne date extract through ameliorating oxidative stress, inflammation and apoptosis

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    El-Sayed M. El-Sayed

    2015-09-01

    Full Text Available Our study aimed to investigate the possible protective effect of Berne date extract on cisplatin-induced nephrotoxicity. A single dose of cisplatin (6 mg/kg was given intraperitoneally (i.p to male rats produced significant elevation in serum urea, creatinine and TNF-α levels with significant reduction in serum albumin. It also increased kidney contents of lipid peroxides measured as malondialdehyde (MDA and caspase-3 contents accompanied by a significant decrease in kidney contents of reduced glutathione (GSH as well as enzymatic activities of catalase (CAT and superoxide dismutase (SOD compared to that of the control group. On the other hand, administrations of Berne date extract and vitamin E (a standard reference antioxidant drug given per os (p.o in doses of 300 mg/kg and 1g/kg, respectively for 14 days before cisplatin and 7 consecutive days after cisplatin injection ameliorated the cisplatin-induced nephrotoxicity as indicated by the restoration of kidney function and oxidative stress parameters. Furthermore, they reduced the histopathological changes induced by cisplatin. In conclusion, Berne date extract showed protective effect against cisplatin-induced nephrotoxicity; effects that may be attributed to antioxidant, anti-inflammatory and antiapoptotic activities.

  10. Pioglitazone protects against cisplatin induced nephrotoxicity in rats and potentiates its anticancer activity against human renal adenocarcinoma cell lines.

    Science.gov (United States)

    Mahmoud, Mona F; El Shazly, Shimaa M

    2013-01-01

    Cisplatin-induced nephrotoxicity is a serious problem that limits its use in cancer treatment. The present study aimed to investigate the renal protective capacity of pioglitazone to reduce the cisplatin- induced nephrotoxicity. The underlying suggested mechanism(s) and whether this nephroprotective effect (if any) interferes with the cytotoxic effect of cisplatin on cancer cells were also investigated. Pioglitazone, Bisphenol A diglycidyl ether, BADGE, IP injected (Peroxisome proliferator- activated receptor gamma (PPAR-γ) antagonist), or their combination were administered to rats one hour before cisplatin injection. Moreover, their effects on the cell viability of human renal adenocarcinoma cell models (ACHN) were studied. The obtained results showed that pioglitazone improved the renal function, structural changes, renal malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-κB) genes expression in cisplatin injected rats. It increased both renal reduced glutathione (GSH) content and PPAR-γ gene expression. In contrast to the data obtained by prior administration of BADGE. Pioglitazone also potentiated the cytotoxic effect of cisplatin on human renal adenocarcinoma cells and this effect was abolished by BADGE co administration. In conclusion, these results suggested that pioglitazone protected against cisplatin- induced nephrotoxicity through its interaction with PPAR-γ receptors and antioxidant effects. Furthermore, pioglitazone did not interfere but rather potentiated the cytotoxic effects of cisplatin on human renal adenocarcinoma cells.

  11. Morin Hydrate Mitigates Cisplatin-Induced Renal and Hepatic Injury by Impeding Oxidative/Nitrosative Stress and Inflammation in Mice.

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    K V, Athira; Madhana, Rajaram Mohanrao; Kasala, Eshvendar Reddy; Samudrala, Pavan Kumar; Lahkar, Mangala; Gogoi, Ranadeep

    2016-12-01

    Cisplatin is a widely used chemotherapeutic drug; however, it induces damage on kidney and liver at clinically effective higher doses. Morin hydrate possesses antioxidant, anti-inflammatory, and anticancer properties. Therefore, we aimed to investigate the effects of morin hydrate (50 and 100 mg/kg, orally) against the renohepatic toxicity induced by a high dose of cisplatin (20 mg/kg, intraperitoneally). Renal and hepatic function, oxidative/nitrosative stress, and inflammatory markers along with histopathology were evaluated. Morin hydrate ameliorated cisplatin-induced renohepatic toxicity significantly at 100 mg/kg as evidenced from the significant reversal of cisplatin-induced body weight loss, mortality, functional and structural alterations of kidney, and liver. The protective role offered by morin hydrate against cisplatin-induced renohepatic toxicity is by virtue of its free radical scavenging property, thereby abating the depletion of cellular antioxidant defense components and through modulation of inflammatory cytokines. We speculate morin hydrate as a protective candidate against renohepatic toxicity of cisplatin.

  12. Syzygium Cumini (L. Seeds Extract Ameliorates Cisplatin Induced Hepatotoxicity in Male Wistar Rats

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    R.Maheswari

    2015-02-01

    Full Text Available The discovery of cisplatin, cis-[Pt(II(NH(3(2Cl(2] ([PtCl2(NH32] or CDDP, was a corner stone which triggered the interest in platinum(II-and other metal-containing compounds as potential anticancer drugs. Cisplatin, is one of the most potent chemotherapy drugs widely used for cancer treatment. In our present study, an attempt has been made to study the effect of Cisplatin on biochemical and histopathological parameters and ameliorating effects of the Syzygium cumini (L. aqueous seeds extract or Eugena Jambolana in male wistar rats. Adult male wistar rats were divided into four different groups. Group I Served as vehicle treated normal saline (Control, Group II Rats received single intra-peritoneal (Ip injection of cisplatin (7mg/kg bw, Group III received Syzygium cumini (L. aqueous seeds extract 400mg/kg/bw orally for 7 days beginning one day prior to cisplatin (CP injection. Group IV Rats received alone Syzygium cumini (L. aqueous seeds extract (400mg/kg bw treated. Cisplatin exposure leads to adverse effects on hematological, hepatotoxic parameters including Erythrocytes (RBCs. Cisplatin induction leads to reduction in the levels of Enzymic and Non-Enzymic antioxidants levels. However, on treatment with Syzygium cumini (L. aqueous seeds extract normalized the levels of all the biochemical and hematological parameters. These findings highlight the efficacy of Syzygium cumini (L. aqueous seeds extract as protective effects Cisplatin induced hepatotoxicity.

  13. The Mechanism of Cisplatin-induced Apoptosis in HeLa Cells

    Institute of Scientific and Technical Information of China (English)

    Youqing Liu; Hui Xing; Xiaobing Han; Xiaoyan Shi; Fengqi Liang; Gang Chen; Ding Ma

    2005-01-01

    OBJECTIVE To study the mechanism of apoptosis induced by cisplatin in vitro in HeLa cells cervical cancer cell line.METHODS The inhibitory effect of cisplatin on HeLa cell growth was analyzed by the MTT assay. Cell apoptosis was measured with flow cytometry and Hoechst 33258 staining following cisplatin treatment. The effect of cisplatin on transcription of HPV E6 was analyzed by RT-PCR and protein expression of E6, P53, p21, Bax and Bcl-2 was studied by Western blots.RESULTS Cisplatin inhibited cellular proliferation in a time and dosedependant manner. The sub-G1 peak by flow cytometry showed a higher apoptotic rate in the experimental group compared to the controls and Hoechst 33258 staining indicated that apoptosis was induced by cisplatin. Results of RT-PCR demonstrated that cisplatin decreased transcription of E6. Western Blots showed that cisplatin decreased protein expression of E6 and increased protein expression of P53, p21 and Bax but had no effect on protein expression of Bcl-2.CONCLUSION Cisplatin induces apoptosis and death of HeLa cells through the suppression of HPV E6 and restoration of p53 function.

  14. Cisplatin-induced premature senescence with concomitant reduction of gap junctions in human fibroblasts

    Institute of Scientific and Technical Information of China (English)

    Wei ZHAO; Zhong Xiang LIN; Zhi Qian ZHANG

    2004-01-01

    To examine the role of gap junctions in cell senescence,the changes of gap junctions in cisplatin-induced premature senescence of primary cultured fibroblasts were studied and compared with the replicative senescent human fibroblasts.Dye transfer assay for gap junction function and immunofluorescent staining for connexin 43 protein distribution were done respectively. Furthermore,cytofluorimetry and DAPI fluorescence staining were performed for cell cycle and apoptosis analysis. p53 gene expression level was detected with indirect immunofluorescence. We found that cisplatin (10 mM) treatment could block cell growth cycle at G1 and induced premature senescence. The premature senescence changes included high frequency of apoptosis,elevation of p53 expression,loss of membranous gap junctions and reduction of dye-transfer capacity. These changes were comparable to the changes of replicative senescence of human fibroblasts. It was also concluded that cisplatin could induce premature senescence concomitant with inhibition of gap junctions in the fibroblasts. Loss of functional gap junctions from the cell membrane may account for the reduced intercellular communication in the premature senescent fibroblasts. The cell system we used may provide a model useful for the study of the gap junction thus promoting agents against premature senescence.

  15. Voluntary exercise prevents cisplatin-induced muscle wasting during chemotherapy in mice.

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    Pernille Hojman

    Full Text Available Loss of muscle mass related to anti-cancer therapy is a major concern in cancer patients, being associated with important clinical endpoints including survival, treatment toxicity and patient-related outcomes. We investigated effects of voluntary exercise during cisplatin treatment on body weight, food intake as well as muscle mass, strength and signalling. Mice were treated weekly with 4 mg/kg cisplatin or saline for 6 weeks, and randomized to voluntary wheel running or not. Cisplatin treatment induced loss of body weight (29.8%, P < 0.001, lean body mass (20.6%, P = 0.001, as well as anorexia, impaired muscle strength (22.5% decrease, P < 0.001 and decreased glucose tolerance. In addition, cisplatin impaired Akt-signalling, induced genes related to protein degradation and inflammation, and reduced muscle glycogen content. Voluntary wheel running during treatment attenuated body weight loss by 50% (P < 0.001, maintained lean body mass (P < 0.001 and muscle strength (P < 0.001, reversed anorexia and impairments in Akt and protein degradation signalling. Cisplatin-induced muscular inflammation was not prevented by voluntary wheel running, nor was glucose tolerance improved. Exercise training may preserve muscle mass in cancer patients receiving cisplatin treatment, potentially improving physical capacity, quality of life and overall survival.

  16. Effect of free creatine therapy on cisplatin-induced renal damage.

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    Genc, Gurkan; Okuyucu, Ali; Meydan, Bilge Can; Yavuz, Oguzhan; Nisbet, Ozlem; Hokelek, Murat; Bedir, Abdulkerim; Ozkaya, Ozan

    2014-08-01

    Abstract Cisplatin is one of the commonly used anticancer drugs and nephrotoxicity limits its use. The aim of this study is to investigate the possible protective effect of creatine supplementation on cisplatin-induced nephrotoxicity. Sixty male Sprague-Dawley rats were divided into three groups: Group I: Cisplatin (n=20) (7 mg/kg cisplatin intraperitoneal (i.p.) single dose), group II: Cisplatin+creatine monohydrate (n=20) (7 mg/kg cisplatin i.p. single dose and 300 mg/kg creatine p.o. daily for 30 days starting on first day of cisplatin injection), group III: Control group (n=20) (Serum physiologic, 2.5 mL/kg i.p.). Sacrifications were performed at first week and 30th day. Blood urea nitrogen (BUN) and serum creatinine levels, histopathological evaluation, mitochondrial deoxyribonucleic acid (mtDNA) common deletion rates, and body weights of rats were evaluated. A significant decrease in body weight, higher values of kidney function tests, histopathological scores, and mtDNA deletion ratios were observed in group I compared to control group at days 7 and 30 (pcreatine significantly reversed kidney functions and pathological findings, this improvement was not sufficient to reach normal control group's results at days 7 and 30. In conclusion, the present study demonstrates that creatine administration is a promising adjuvant protective drug for reducing nephrotoxic effect of cisplatin.

  17. Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Cisplatin-Induced Neuropathy in Mice.

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    Harris, Hannah M; Sufka, Kenneth J; Gul, Waseem; ElSohly, Mahmoud A

    2016-08-01

    Sativex, a cannabinoid extract with a 1 : 1 ratio of tetrahydocannabinol and cannabidiol, has been shown to alleviate neuropathic pain associated with chemotherapy. This research examined whether tetrahydocannabinol or cannabidiol alone could attenuate or prevent cisplatin-induced tactile allodynia. In experiment 1, mice (C57BL/6) received eight administrations of 2.3 mg/kg cisplatin or saline solution IP every other day to induce tactile allodynia. Mice were then administered vehicle, 100 mg/kg gabapentin, 2 mg/kg tetrahydocannabinol, or 2 mg/kg cannabidiol IP and tested 60 min later on an electronic Von Frey. In experiment 2, prevention studies, cannabidiol (0.0, 0.5, 1.0, and 2.0 mg/kg) or tetrahydocannabinol (0.0, 0.5, 1.0, and 2.0 mg/kg) was given IP 30 min prior to cisplatin administration (2.3 or 1.0 mg/kg) utilizing a six-dose alternate day protocol. In both studies, tactile responses to the hind paws were quantified in g of force using an electronic Von Frey prior to and after the cisplatin administration protocol. Cisplatin produced a reduction in g of force indicative of neuropathy that was attenuated by gabapentin, tetrahydocannabinol, and cannabidiol but not prevented by either cannabinoid. These data demonstrate that each of the major constituents of Sativex alone can achieve analgesic effects against cisplatin neuropathy.

  18. Mechanism of Cisplatin-Induced Cytotoxicity Is Correlated to Impaired Metabolism Due to Mitochondrial ROS Generation.

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    Yong-Min Choi

    Full Text Available The chemotherapeutic use of cisplatin is limited by its severe side effects. In this study, by conducting different omics data analyses, we demonstrated that cisplatin induces cell death in a proximal tubular cell line by suppressing glycolysis- and tricarboxylic acid (TCA/mitochondria-related genes. Furthermore, analysis of the urine from cisplatin-treated rats revealed the lower expression levels of enzymes involved in glycolysis, TCA cycle, and genes related to mitochondrial stability and confirmed the cisplatin-related metabolic abnormalities. Additionally, an increase in the level of p53, which directly inhibits glycolysis, has been observed. Inhibition of p53 restored glycolysis and significantly reduced the rate of cell death at 24 h and 48 h due to p53 inhibition. The foremost reason of cisplatin-related cytotoxicity has been correlated to the generation of mitochondrial reactive oxygen species (ROS that influence multiple pathways. Abnormalities in these pathways resulted in the collapse of mitochondrial energy production, which in turn sensitized the cells to death. The quenching of ROS led to the amelioration of the affected pathways. Considering these observations, it can be concluded that there is a significant correlation between cisplatin and metabolic dysfunctions involving mROS as the major player.

  19. A H2S Donor GYY4137 Exacerbates Cisplatin-Induced Nephrotoxicity in Mice

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    Mi Liu

    2016-01-01

    Full Text Available Accumulating evidence demonstrated that hydrogen sulfide (H2S is highly involved in inflammation, oxidative stress, and apoptosis and contributes to the pathogenesis of kidney diseases. However, the role of H2S in cisplatin nephrotoxicity is still debatable. Here we investigated the effect of GYY4137, a novel slow-releasing H2S donor, on cisplatin nephrotoxicity in mice. Male C57BL/6 mice were pretreated with GYY4137 for 72 h prior to cisplatin injection. After cisplatin treatment for 72 h, mice developed obvious renal dysfunction and kidney injury as evidenced by elevated blood urea nitrogen (BUN and histological damage. Consistently, these mice also showed increased proinflammatory cytokines such as TNF-α, IL-6, and IL-1β in circulation and/or kidney tissues. Meanwhile, circulating thiobarbituric aid-reactive substances (TBARS and renal apoptotic indices including caspase-3, Bak, and Bax were all elevated. However, application of GYY4137 further aggravated renal dysfunction and kidney structural injury in line with promoted inflammation, oxidative stress, and apoptotic response following cisplatin treatment. Taken together, our results suggested that GYY4137 exacerbated cisplatin-induced nephrotoxicity in mice possibly through promoting inflammation, oxidative stress, and apoptotic response.

  20. Paeonol, a Major Compound of Moutan Cortex, Attenuates Cisplatin-Induced Nephrotoxicity in Mice

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    Hyojung Lee

    2013-01-01

    Full Text Available Cisplatin is an effective chemotherapeutic agent that is used for the treatment of a variety of cancers; however, its nephrotoxicity limits the use of this drug. In the present study, we examined whether paeonol, a major compound of Moutan Cortex, has protective effects on cisplatin-induced acute renal failure in mice. To accomplish this, Balb/c mice (6 to 8 wk of age, weighing 20 to 25 g were administered, Moutan Cortex (300 mg/kg or paeonol (20 mg/kg once a day. At day 4, mice received cisplatin (30, 20, or 10 mg/kg intraperitoneally. The paeonol-treated group showed marked attenuation of serum creatine and blood urea nitrogen levels as well as reduced levels of proinflammatory cytokines and nitric oxide when compared to the control group. In addition, the paeonol-treated group showed prolonged survival and marked attenuation of renal tissue injury. Taken together, these results demonstrated that paeonol can prevent the renal toxic effects of cisplatin.

  1. Amelioration of cisplatin induced nephrotoxicity in Swiss albino mice by Rubia cordifolia extract

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    Joy Jisha

    2008-01-01

    Full Text Available Background: Cisplatin is one of the most effective chemotherapeutics against a wide range of cancers including head, neck, ovarian and lung cancers. But its usefulness is limited by its toxicity to normal tissues, including cells of the kidney proximal tubule. The purpose of the present study is to investigate whether the hydro-alcoholic extract of Rubia cordifolia could decrease the intensity of toxicity in Swiss albino mice. Materials and Methods: Cisplatin at a dose of 12 mg/kg body wt was administered intraperitoneally to Swiss albino mice. Another set of animals was given hydro-alcoholic extract of Rubia cordifolia at different doses along with cisplatin treatment. The antioxidant levels, serum creatinine, serum urea etc. were analyzed. Results: The extract could significantly decrease the cisplatin induced nephrotoxicity as inferred from the tissue antioxidant status in the drug administered animals. Remarkable change was observed in serum creatinine and urea levels. Lipid peroxidation in the kidney and liver tissues was also considerably reduced in Rubia cordifolia extract treated animals. Conclusion: Hydro-alcoholic extracts of Rubia cordifolia are effective in reducing the renal damage caused by the cancer chemotherapeutic drug cisplatin. Since Rubia cordifolia has been in use as an important ingredient in the traditional Ayurvedic system of medicine, it could be safe and beneficial to use this herbal extract as an adjuvant to ameliorate renal damage in patients undergoing cancer chemotherapy with cisplatin.

  2. The Effect of Mirtazapine on Cisplatin-Induced Oxidative Damage and Infertility in Rat Ovaries

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    Durdu Altuner

    2013-01-01

    Full Text Available Cisplatin causes infertility due to ovarian toxicity. The toxicity mechanism is unknown, but evidence suggests oxidative stress. In this study, the effect of mirtazapine on cisplatin-induced infertility and oxidative stress in rats was investigated. 64 female rats were divided into 4 groups of 16. Except for the controls that received physiologic saline only, all were administered with cisplatin (5 mg/kg i.p. and mirtazapine (15 mg/kg p.o. or mirtazapine (30 mg/kg p.o. for 10 days. After this period, six rats from each group were randomly selected, and malondialdehyde (MDA, myeloperoxidase (MPO, nitric oxide (NO, total gluthatione (tGSH, gluthatione peroxidase (GPx, superoxide dismutase (SOD, and 8-hydroxy-2 deoxyguanine (8-OH Gua levels were measured in their ovarian tissues. Reproductive functions of the remaining rats were examined for 6 months. The MDA, MPO, NO groups and 8-OH Gua levels were higher in the cisplatin-treated groups than the controls, which was not observed in the mirtazapine and cisplatin groups. GSH, GPx, and SOD levels were reduced by cisplatin, which was prevented by mirtazapine. Cisplatin caused infertility by 70%. The infertility rates were, respectively, 40% and 10% for the 15 and 30 mg/kg mirtazapine administered groups. In conclusion, oxidative stress induced by cisplatin in the rat ovary tissue causes infertility in the female rats. Mirtazapine reverses this in a dose-dependent manner.

  3. Cisplatin-induced testicular dysfunction and its amelioration by Launaea taraxacifolia leaf extract.

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    Adejuwon, S A; Femi-Akinlosotu, O M; Omirinde, J O

    2015-06-01

    This study investigates the ameliorative potential of Launea taraxacifolia (LT) aqueous leaf extract on cisplatin-induced testicular dysfunction in Wistar rats. Thirty rats were randomly divided into six groups (A-F) of 5 rats each: Group A which served as control received water; Group B was intraperitoneally (ip) injected 10 mg kg(-1) body wt cisplatin on day 21; Groups C and D were given 100 and 400 mg of LT via oral administration, respectively, for 21 days while Groups E and F received similar treatment as Groups C and D, respectively, and then exposed to ip administration of 10 mg kg(-1) body weight cisplatin on the 21st day. Exclusively, Cisplatin-exposed Group B rats showed reduced sperm characteristics and increased sperm morphological abnormalities; distorted histological architecture of seminiferous tubules; significantly increased lipid peroxidation (LPO) and decreased activities of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH)levels in the testes. These parameters in LT alone treated Groups C and D were not markedly different compared with the control group. The rats with the combined treatment in Groups E and F showed significantly improved sperm parameters, testicular histo-architecture and antioxidant enzymatic activities. Conclusively, aqueous extract of L. taraxacifolia has protective potential against cisplatin damage.

  4. The effect of mirtazapine on cisplatin-induced oxidative damage and infertility in rat ovaries.

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    Altuner, Durdu; Gulaboglu, Mine; Yapca, Omer Erkan; Cetin, Nihal

    2013-01-01

    Cisplatin causes infertility due to ovarian toxicity. The toxicity mechanism is unknown, but evidence suggests oxidative stress. In this study, the effect of mirtazapine on cisplatin-induced infertility and oxidative stress in rats was investigated. 64 female rats were divided into 4 groups of 16. Except for the controls that received physiologic saline only, all were administered with cisplatin (5 mg/kg i.p.) and mirtazapine (15 mg/kg p.o.) or mirtazapine (30 mg/kg p.o.) for 10 days. After this period, six rats from each group were randomly selected, and malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NO), total gluthatione (tGSH), gluthatione peroxidase (GPx), superoxide dismutase (SOD), and 8-hydroxy-2 deoxyguanine (8-OH Gua) levels were measured in their ovarian tissues. Reproductive functions of the remaining rats were examined for 6 months. The MDA, MPO, NO groups and 8-OH Gua levels were higher in the cisplatin-treated groups than the controls, which was not observed in the mirtazapine and cisplatin groups. GSH, GPx, and SOD levels were reduced by cisplatin, which was prevented by mirtazapine. Cisplatin caused infertility by 70%. The infertility rates were, respectively, 40% and 10% for the 15 and 30 mg/kg mirtazapine administered groups. In conclusion, oxidative stress induced by cisplatin in the rat ovary tissue causes infertility in the female rats. Mirtazapine reverses this in a dose-dependent manner.

  5. Science behind cisplatin-induced nephrotoxicity in humans:A clinical study

    Institute of Scientific and Technical Information of China (English)

    Arunkumar PA; Viswanatha GL; Radheshyam N; Mukund H; Belliyappa MS

    2012-01-01

    Objective: To investigate the relationship between serum electrolyte changes and cisplatin induced nephrotoxicity. Methods: We collected data from 18 patients undergoing cisplatin chemotherapy including serum electrolytes, creatinine, blood urea nitrogen (BUN) and urine potassium, sodium and pH levels before and after the cisplatin chemotherapy. All the patients had cancer and were treated with 40-50 mg/day cisplatin. Renal injury was assessed by measuring serum electrolytes, creatinine, BUN levels and urine potassium, sodium and pH levels.Results:The five cycles of cisplatin based chemotherapy resulted in hypomagnesia (P=0.029), hypocalcaemia (P=0.001*), hypophosphatemia (P=0.003*), hypokalemia (P=0.001*) and increased serum creatinine (P=0.001*) and BUN (P=0.292*) levels. In urine analysis, decrease in potassium (P=0.024*) was found, except potassium there was no significant changes in sodium and urine pH.Conclusions:The present study demonstrates that, acute nephrotoxicity was observed in patients with different types of cancers undergoing cisplatin based chemotherapy due to electrolyte disturbances, when no corrective measures were initiated.

  6. Mitochondrial modulation by Epigallocatechin 3-Gallate ameliorates cisplatin induced renal injury through decreasing oxidative/nitrative stress, inflammation and NF-kB in mice.

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    Hao Pan

    Full Text Available Cancer chemotherapy drug cisplatin is known for its nephrotoxicity. The aim of this study is to investigate whether Epigallocatechin 3-Gallate (EGCG can reduce cisplatin mediated side effect in kidney and to understand its mechanism of protection against tissue injury. We used a well-established 3-day cisplatin induced nephrotoxicity mice model where EGCG were administered. EGCG is a major active compound in Green Tea and have strong anti-oxidant and anti-inflammatory properties. EGCG protected against cisplatin induced renal dysfunction as measured by serum creatinine and blood urea nitrogen (BUN. EGCG improved cisplatin induced kidney structural damages such as tubular dilatation, cast formation, granulovaculoar degeneration and tubular cell necrosis as evident by PAS staining. Cisplatin induced kidney specific mitochondrial oxidative stress, impaired activities of mitochondrial electron transport chain enzyme complexes, impaired anti-oxidant defense enzyme activities such as glutathione peroxidase (GPX and manganese superoxide dismutase (MnSOD in mitochondria, inflammation (tumor necrosis factor α and interleukin 1β, increased accumulation of NF-κB in nuclear fraction, p53 induction, and apoptotic cell death (caspase 3 activity and DNA fragmentation. Treatment of mice with EGCG markedly attenuated cisplatin induced mitochondrial oxidative/nitrative stress, mitochondrial damages to electron transport chain activities and antioxidant defense enzyme activities in mitochondria. These mitochondrial modulations by EGCG led to protection mechanism against cisplatin induced inflammation and apoptotic cell death in mice kidney. As a result, EGCG improved renal function in cisplatin mediated kidney damage. In addition to that, EGCG attenuated cisplatin induced apoptotic cell death and mitochondrial reactive oxygen species (ROS generation in human kidney tubular cell line HK-2. Thus, our data suggest that EGCG may represent new promising adjunct

  7. Baicalein, a Bioflavonoid, Prevents Cisplatin-Induced Acute Kidney Injury by Up-Regulating Antioxidant Defenses and Down-Regulating the MAPKs and NF-κB Pathways.

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    Bidya Dhar Sahu

    Full Text Available Acute renal failure is a serious complication of the anticancer drug cisplatin. The potential role of baicalein, a naturally occurring bioflavonoid on cisplatin-induced renal injury is unknown. Here, we assessed the effect of baicalein against a murine model of cisplatin-induced acute renal failure and investigated the underlying possible mechanisms. Renal function, kidney histology, inflammation, oxidative stress, renal mitochondrial function, proteins involved in apoptosis, nuclear translocation of Nrf2 and effects on intracellular signaling pathways such as MAPKs, and NF-κB were assessed. Pretreatment with baicalein ameliorated the cisplatin-induced renal oxidative stress, apoptosis and inflammation and improved kidney injury and function. Baicalein inhibited the cisplatin-induced expression of iNOS, TNF-α, IL-6 and mononuclear cell infiltration and concealed redox-sensitive transcription factor NF-κB activation via reduced DNA-binding activity, IκBα phosphorylation and p65 nuclear translocation in kidneys. Further studies demonstrated baicalein markedly attenuated cisplatin-induced p38 MAPK, ERK1/2 and JNK phosphorylation in kidneys. Baicalein also restored the renal antioxidants and increased the amount of total and nuclear accumulation of Nrf2 and downstream target protein, HO-1 in kidneys. Moreover, baicalein preserved mitochondrial respiratory enzyme activities and inhibited cisplatin-induced apoptosis by suppressing p53 expression, Bax/Bcl-2 imbalance, cytochrome c release and activation of caspase-9, caspase-3 and PARP. Our findings suggest that baicalein ameliorates cisplatin-induced renal damage through up-regulation of antioxidant defense mechanisms and down regulation of the MAPKs and NF-κB signaling pathways.

  8. Baicalein, a Bioflavonoid, Prevents Cisplatin-Induced Acute Kidney Injury by Up-Regulating Antioxidant Defenses and Down-Regulating the MAPKs and NF-κB Pathways.

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    Sahu, Bidya Dhar; Mahesh Kumar, Jerald; Sistla, Ramakrishna

    2015-01-01

    Acute renal failure is a serious complication of the anticancer drug cisplatin. The potential role of baicalein, a naturally occurring bioflavonoid on cisplatin-induced renal injury is unknown. Here, we assessed the effect of baicalein against a murine model of cisplatin-induced acute renal failure and investigated the underlying possible mechanisms. Renal function, kidney histology, inflammation, oxidative stress, renal mitochondrial function, proteins involved in apoptosis, nuclear translocation of Nrf2 and effects on intracellular signaling pathways such as MAPKs, and NF-κB were assessed. Pretreatment with baicalein ameliorated the cisplatin-induced renal oxidative stress, apoptosis and inflammation and improved kidney injury and function. Baicalein inhibited the cisplatin-induced expression of iNOS, TNF-α, IL-6 and mononuclear cell infiltration and concealed redox-sensitive transcription factor NF-κB activation via reduced DNA-binding activity, IκBα phosphorylation and p65 nuclear translocation in kidneys. Further studies demonstrated baicalein markedly attenuated cisplatin-induced p38 MAPK, ERK1/2 and JNK phosphorylation in kidneys. Baicalein also restored the renal antioxidants and increased the amount of total and nuclear accumulation of Nrf2 and downstream target protein, HO-1 in kidneys. Moreover, baicalein preserved mitochondrial respiratory enzyme activities and inhibited cisplatin-induced apoptosis by suppressing p53 expression, Bax/Bcl-2 imbalance, cytochrome c release and activation of caspase-9, caspase-3 and PARP. Our findings suggest that baicalein ameliorates cisplatin-induced renal damage through up-regulation of antioxidant defense mechanisms and down regulation of the MAPKs and NF-κB signaling pathways.

  9. Fetal kidney stem cells ameliorate cisplatin induced acuterenal failure and promote renal angiogenesis

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    AIM To investigate whether fetal kidney stem cells(fKSC) ameliorate cisplatin induced acute renal failure(ARF) in rats and promote renal angiogenesis.METHODS: The fKSC were isolated from rat fetusesof gestation day 16 and expanded in vitro up to 3rdpassage. They were characterized for the expressionof mesenchymal and renal progenitor markers by flowcytometry and immunocytochemistry, respectively.The in vitro differentiation of fKSC towards epitheliallineage was evaluated by the treatment with specificinduction medium and their angiogenic potential bymatrigel induced tube formation assay. To study theeffect of fKSC in ARF, fKSC labeled with PKH26 wereinfused in rats with cisplatin induced ARF and, the bloodand renal tissues of the rats were collected at differenttime points. Blood biochemical parameters werestudied to evaluate renal function. Renal tissues wereevaluated for renal architecture, renal cell proliferationand angiogenesis by immunohistochemistry, renal cellapoptosis by terminal deoxynucleotidyl transferase nickendlabeling assay and early expression of angiogenicmolecules viz . vascular endothelial growth factor (VEGF),hypoxia-inducible factor (HIF)-1α and endothelial nitricoxide synthase (eNOS) by western blot.RESULTS: The fKSC expressed mesenchymal markersviz . CD29, CD44, CD73, CD90 and CD105 as well as renal progenitor markers viz . Wt1, Pax2 and Six2. Theyexhibited a potential to form CD31 and Von Willebrandfactor expressing capillary-like structures and could bedifferentiated into cytokeratin (CK)18 and CK19 positiveepithelial cells. Administration of fKSC in rats with ARF ascompared to administration of saline alone, resulted in asignificant improvement in renal function and histology onday 3 (2.33 ± 0.33 vs 3.50 ± 0.34, P 〈 0.05) and on day7 (0.83 ± 0.16 vs 2.00 ± 0.25, P 〈 0.05). The infusedPKH26 labeled fKSC were observed to engraft in damagedrenal tubules and showed increased proliferation andreduced

  10. Chronic low vitamin intake potentiates cisplatin-induced intestinal epithelial cell apoptosis in WNIN rats

    Institute of Scientific and Technical Information of China (English)

    Bodiga Vijayalakshmi; Boindala Sesikeran; Putcha Udaykumar; Subramaniam Kalyanasundaram; Manchala Raghunath

    2006-01-01

    AIM: To investigate if cisplatin alters vitamin status and if VR modulates cisplatin induced intestinal apoptosis and oxidative stress in Wistar/NIN (WNIN) male rats.METHODS: Weanling, WNIN male rats (n = 12 per group) received adlibitum for 17 wk: control diet (20%protein) or the same with 50% vitamin restriction. They were then sub-divided into two groups of six rats each and administered cisplatin (2.61 mg/kg bodyweight)once a week for three wk or PBS (vehicle control).Intestinal epithelial cell (IEC) apoptosis was monitored by morphometry, Annexin-V binding, M30 cytodeath assay and DNA fragmentation. Structural and functional integrity of the villus were assessed by villus height /crypt depth ratio and activities of alkaline phosphatase,lys, ala-dipeptidyl amino-peptidase, respectively. To assess the probable mechanism(s) of altered apoptosis,oxidative stress parameters, caspase-3 activity, and expression of Bcl-2 and Bax were determined.RESULTS: Cisplatin per se decreased plasma vitamin levels and they were the lowest in VR animals treated with cisplatin. As expected VR increased only villus apoptosis, whereas cisplatin increased stem cell apoptosis in the crypt. However, cisplatin treatment of VR rats increased apoptosis both in villus and crypt regions and was associated with higher levels of TBARS,protein carbonyls and caspase-3 activity, but lower GSH concentrations. VR induced decrease in Bcl-2 expression was further lowered by cisplatin. Bax expression,unaffected by VR was increased on cisplatin treatment.Mucosal functional integrity was severely compromised in cisplatin treated VR-rats.CONCLUSION: Low intake of vitamins increases the sensitivity of rats to cisplatin and promotes intestinal epithelial cell apoptosis.

  11. Rikkunshito, a traditional Japanese medicine, suppresses cisplatin-induced anorexia in humans

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    Ohno T

    2011-12-01

    Full Text Available Tetsuro Ohno, Mitsuhiro Yanai, Hiroyuki Ando, Yoshitaka Toyomasu, Atsushi Ogawa, Hiroki Morita, Kyoichi Ogata, Erito Mochiki, Takayuki Asao, Hiroyuki KuwanoDepartment of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, JapanBackground: The aim of this study was to investigate the effects of Rikkunshito on ghrelin secretion and on cisplatin-induced anorexia in humans.Methods: The study was performed as a crossover design, and ten unresectable or relapsed gastric cancer patients were randomly divided into two groups. Group A (n = 5 was started on Rikkunshito (2.5 g three times daily, orally from the first course of chemotherapy and followed by a second course without Rikkunshito. A treatment with reversed order was performed for Group B (n = 5. All patients received combined chemotherapy with S-1 plus cisplatin. The primary endpoint was the amount of oral intake, and the categories of scales of anorexia, nausea, and vomiting; secondary endpoints included the plasma concentration of acylated ghrelin.Results: In the Rikkunshito-on period, no decrease of the plasma concentration of acylated ghrelin induced by cisplatin was observed. The average oral intake in the Rikkunshito-on period was significantly larger than that in the Rikkunshito-off period, and the grade of anorexia was significantly lower in the Rikkunshito-on period than in the Rikkunshito-off period.Conclusion: Rikkunshito appeared to prevent anorexia induced by cisplatin, resulting in effective prophylactic administration of chemotherapy with cisplatin, and patients could continue their treatments on schedule.Keywords: Rikkunshito, cisplatin, ghrelin, anorexia, stomach cancer

  12. Modulation of Nrf2/HO-1 by Thymoquinone During Cisplatin-Induced Nephrotoxicity

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    Ramazan ULU

    2013-05-01

    Full Text Available OBJECTIVE: Side effects of cisplatin, such as nephrotoxicity, limit its use in chemotherapeutic regimens and indicate an agent that suppresses its toxicity. Thymoquinone (TQ, the predominant bioactive constituent present in black seed oil (Nigella sativa, has antiinfl ammatory, antioxidant and antitumor effects. We propose a protective mechanism of of TQ on cisplatin-nephrotoxicity in rats that is through modulation of Nrf2-mediated antioxidant induction and reduced inflammation. MATERIAL and METHODS: Twenty-eight male Wistar rats (8 weeks-old were divided into four groups; Control (vehicle; 0.9% saline, 1 ml/kg body wt., p.o., TQ (10 mg/kg body weight/day in drinking water for 5 days, cisplatin (a single injection of 7mg/kg body wt, i.p. and TQ for 5 days in drinking water then a single injection of cisplatin. On day 10, all rats were sacrificed by cervical dislocation, kidneys were removed, and serum urea and creatinine were collected. RESULTS: Serum urea and creatinine levels were significantly higher in cisplatin-treated rats compared with control rats. TQ-treatment significantly decreased serum urea and creatinine levels. Cisplatin-treatment caused significant downregulation of the nuclear NF-E2-related factor-2 (Nrf2, heme oxygenase-1(HO-1 and caused an increase in the levels of nuclear factor-kappa B (NF-κB. Interestingly, TQ supplementation significantly improved the changes associated with cisplatin nephrotoxicity by increasing the levels of Nrf-2 and HO-1 and decreasing the levels of NF-κB. CONCLUSION: This study demonstrates the TQ targets NRF2/HO-1 and can be used as a potential agent against cisplatin-induced nephrotoxicity.

  13. Hepatoprotective effect of Ficus religiosa latex on cisplatin induced liver injury in Wistar rats

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    Yogesh C. Yadav

    2015-06-01

    Full Text Available AbstractFicus religiosa L., Moraceae, is widely planted in the tropics. The chemical constituents of F. religiosa include tannin, saponin gluanol acetate, β-sitosterol, leucoanthocyanidin, and leucoanthocyanin. These are used for the treatment of pain, inflammation, impotence, menstrual disturbances, and urine related problems, and as uterine tonic. The present study aimed to evaluate hepatoprotective effects of F. religiosa latex on cisplatin induced liver injury in Wistar rats. In experimental protocol contained five groups of rats (n = 6. In which, group I (control was administered acacia (2%, w/v of 5 ml/kg throughout the experiment for 16 days. The group II (cisplatin treated was administered single dose of cisplatin (7.5 mg/kg i.p. on 1st day. Group III (extract control was administered 300 mg/kg p.o. of extract for 1stto 10th day. Group IV (Protective was administered extract (300 mg/kg p.o. of F. religiosa latex for 1st to 10th day and administered single dose of cisplatin (7.5 mg/kg i.p. on 11th day and group V (Curative received single dose of cisplatin (7.5 mg/kg i.p. on day 1st, and administered extract (300 mg/kg p.o. from 7th to 16thdays. On the 6th day in cisplatin treated, 10th day in extract control and 16th day in control, protective and curative, blood withdrawn from retro-orbital sinus of rats for biochemical estimation for serum and dissected out the livers for estimation of antioxidant enzymes and histopathological works. The cisplatin-treated group 2 showed a significant increase in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and hepatocytes cells degeneration inflammatory infiltrate and necrosis it's were significantly (**p < 0.01 alleviates by protective groups.

  14. ATP sensitizes H460 lung carcinoma cells to cisplatin-induced apoptosis.

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    Swennen, Els L R; Ummels, Vanessa; Buss, Irina; Jaehde, Ulrich; Bast, Aalt; Dagnelie, Pieter C

    2010-03-30

    Platinum resistance of cancer cells may evolve due to a decrease in intracellular drug accumulation, decreased cell permeability or by an increased deactivation of the drug by glutathione (GSH). The aim of this study was (1) to investigate the effect of adenosine 5'-triphosphate (ATP) on the cytotoxicity of cisplatin in a large cell lung carcinoma cell line (H460), and (2) to examine the potential involvement of increased cisplatin uptake, GSH depletion and pyrimidine starvation by ATP in this effect. H460 cells were harvested and seeded (5% CO(2); 37 degrees C). Subsequently, cells were incubated with medium or ATP followed by an incubation with cisplatin. Cytotoxicity screening was analyzed by the sulforhodamine B (SRB) colorimetric assay, lactate dehydrogenase and caspase-3/7 activity. Pre-incubation for 72h with 0.3 and 3mM ATP strongly enhanced the anti-proliferative potency of cisplatin 2.9- and 7.6-fold, respectively. Moreover, after incubation of H460 cells with 0.3mM ATP the intracellular platinum concentration increased, indicating increased cisplatin uptake by ATP. ATP, despite lowering the LD(50) of cisplatin, did not modulate GSH levels in H460 cells. ATP itself showed a biphasic effect on H460 cell growth: 0.3mM inhibited H460 cell growth via the pyrimidine starvation effect, activation of caspase-3/7 and LDH leakage, while 3mM ATP showed no effect on cell growth. In conclusion, ATP sensitizes the H460 cells to cisplatin-induced apoptosis. The effect of 0.3mM ATP is not due to GSH depletion but involves increased cisplatin uptake and pyrimidine starvation due to ATP conversion to adenosine followed by cellular uptake.

  15. Protective effect of riboflavin on cisplatin induced toxicities: a gender-dependent study.

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    Naseem, Imrana; Hassan, Iftekhar; Alhazza, Ibrahim M; Chibber, Sandesh

    2015-01-01

    The toxicity exerted by the anticancer drug, cisplatin in vivo is functional to many factors such as dose, duration, gender and age etc. The present study is aimed to investigate if ameliorative potential of riboflavin on cisplatin induced toxicity is gender dependent. Eighty four adult mice from male and female sex were divided into seven groups (n=6) for both sexes. They were treated with riboflavin (2mg/kg), cisplatin (2mg/kg) and their two different combinations (cisplatin at 2mg/kg with 1mg/kg and 2mg/kg of riboflavin) under photoillumination with their respective controls for the combination groups without photoillumination. After treatment, all groups were sacrificed and their kidney, liver and serum were collected for biochemical estimations, comet assay and histopathology. In the present investigation, it was evident from antioxidant and detoxification studies (SOD, CAT, GSH, GST, MDA and carbonyl level) that the female mice exhibited better tolerance towards cisplatin inducted toxicity and the ameliorative effect of riboflavin against cisplatin toxicity was found stronger in their combination groups as compared to the male groups as the activity of all antioxidant enzymes were found better concomitant with lower level of MDA and carbonyl contents in the female combination groups than their male counterparts. Furthermore, single cell gel electrophoresis and histopathological examination confirmed that restoration of normal nuclear and cellular integrity was more prominent in female with respect to the males after treatment in the combination groups in a dose-dependent manner. Hence, this study reveals that cisplatin is more toxic in male mice and the ameliorative effect of riboflavin against cisplatin toxicity is stronger in female mice.

  16. P2X7 receptor blockade protects against cisplatin-induced nephrotoxicity in mice by decreasing the activities of inflammasome components, oxidative stress and caspase-3

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yuanyuan; Yuan, Fahuan; Cao, Xuejiao [Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037 (China); Zhai, Zhifang [Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Gang Huang [Department of Medical Genetics, Third Military Medical University, Chongqing 430038 (China); Du, Xiang; Wang, Yiqin; Zhang, Jingbo; Huang, Yunjian; Zhao, Jinghong [Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037 (China); Hou, Weiping, E-mail: hwp0518@aliyun.com [Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037 (China)

    2014-11-15

    Nephrotoxicity is a common complication of cisplatin chemotherapy and thus limits the use of cisplatin in clinic. The purinergic 2X7 receptor (P2X7R) plays important roles in inflammation and apoptosis in some inflammatory diseases; however, its roles in cisplatin-induced nephrotoxicity remain unclear. In this study, we first assessed the expression of P2X7R in cisplatin-induced nephrotoxicity in C57BL/6 mice, and then we investigated the changes of renal function, histological injury, inflammatory response, and apoptosis in renal tissues after P2X7R blockade in vivo using an antagonist A-438079. Moreover, we measured the changes of nod-like receptor family, pyrin domain containing proteins (NLRP3) inflammasome components, oxidative stress, and proapoptotic genes in renal tissues in cisplatin-induced nephrotoxicity after treatment with A-438079. We found that the expression of P2X7R was significantly upregulated in the renal tubular epithelial cells in cisplatin-induced nephrotoxicity compared with that of the normal control group. Furthermore, pretreatment with A-438079 markedly attenuated the cisplatin-induced renal injury while lightening the histological damage, inflammatory response and apoptosis in renal tissue, and improved the renal function. These effects were associated with the significantly reduced levels of NLRP3 inflammasome components, oxidative stress, p53 and caspase-3 in renal tissues in cisplatin-induced nephrotoxicity. In conclusions, our studies suggest that the upregulated activity of P2X7R might play important roles in the development of cisplatin-induced nephrotoxicity, and P2X7R blockade might become an effective therapeutic strategy for this disease. - Highlights: • The P2X7R expression was markedly upregulated in cisplatin-induced nephrotoxicity. • P2X7R blockade significantly attenuated the cisplatin-induced renal injury. • P2X7R blockade reduced activities of NLRP3 inflammasome components in renal tissue. • P2X7R blockade

  17. Peripheral contributions to visceral hyperalgesia.

    Science.gov (United States)

    Gebhart, G F

    1999-03-01

    Hyperalgesia has long been recognized clinically as a consequence of tissue injury. Primary hyperalgesia (arising from the site of injury) is generally considered to be due to sensitization of sensory receptors (eg, nociceptors) and perhaps activation of so-called 'silent nociceptors' by mediators released, synthesized or attracted to the site of tissue injury. Key questions associated with understanding visceral hyperalgesia relate to whether the viscera are innervated by nociceptors (ie, sensory receptors that respond selectively to noxious intensities of stimulation), whether visceral receptors and/or afferent fibres sensitize after tissue injury and whether silent nociceptors exist in the viscera. Studies in nonhuman animals have revealed that hollow organs such as the esophagus, gall bladder, stomach, urinary bladder, colon and uterus are innervated by mechanically sensitive receptors with low or high thresholds for response. Accordingly, it appears that the viscera are innervated by nociceptors, although the issue is far from settled. One characteristic of cutaneous nociceptors is their ability to be sensitized when tissue is injured. Mechanosensitive visceral receptors also sensitize when the viscera are experimentally inflamed, but both visceral receptors with low thresholds and those with high thresholds for response are sensitized. Moreover, it is often not appreciated that visceral receptors are likely polymodal rather than unimodal - that is, mechanically sensitive visceral receptors typically are also sensitive to chemical and/or thermal stimuli. In this sense, visceral receptors may be considered evolutionarily older than more highly developed, specialized cutaneous receptors. Finally, there are mechanically insensitive receptors that innervate the viscera and, when tissue is injured, develop spontaneous activity and acquire sensitivity to mechanical stimuli. In the aggregrate, visceral receptors change their behaviour in the presence of tissue injury

  18. The Effects of Pretreatment with Various Doses of L-Arginine on Cisplatin-Induced Nephropathy of Male Rats

    Directory of Open Access Journals (Sweden)

    B Rasoulian

    2016-09-01

    Full Text Available Introduction: Cisplatin is a widely used anti-cancer drug, which its application is limited by nephrotoxicity. In this study, the effect of pretreatment with different l-arginine doses on Cisplatin-induced renal functional injury was investigated. Methods: 63 male rats were divided into 7 groups: In groups 3, 4, 5 and 6, 60 min before the Cisplatin injection (5mg/kg; L-Arginine with doses of 50,100,200 or 400mg/kg was injected, respectively. In group7, normal saline was injected before Cisplatin administration. In groups 1 and 2, normal saline was injected instead of Cisplatin. In group 2, 60min before normal saline injection, 400mg/kg L-Arginine was administered and in group1, instead of L-arginine, normal saline was injected too. Injections were intraperitoneal. 72h after Cisplatin injection, blood sampling and plasma separation were done. Urine sample was collected 24 hours before blood sampling by metabolic cage. The mean of plasma urea and creatinine levels and creatinine clearance (ml/day.kg and fractional excretion of Na (FENa, % were compared among different groups as renal functional parameters. Results: In comparison to group 7, L-arginine injection in a dose of 400mg/kg led to significant amelioration of all parameters. 200 mg/kg L-arginine administration led to significant decrease in plasma urea level and FENa. 100mg/kg L-arginine caused significant improvement in fractional excretion of sodium. L-arginine injection with 50mg/kg dose, significantly ameliorate all renal function tests instead of creatinine clearance. Conclusion: Pretreatment with L-arginine administration with 400 or 50 mg/kg doses, respectively, had the highest effect on reducing Cisplatin-induced nephropathy. L-arginine injection with intermediate doses i.e. 200 or 100 mg/kg had less effect in reducing Cisplatin-induced nephropathy and it needs more investigations.

  19. Tempol, a superoxide dismutase mimetic agent, ameliorates cisplatin-induced nephrotoxicity through alleviation of mitochondrial dysfunction in mice.

    Directory of Open Access Journals (Sweden)

    Lamiaa A Ahmed

    Full Text Available Mitochondrial dysfunction is a crucial mechanism by which cisplatin, a potent chemotherapeutic agent, causes nephrotoxicity where mitochondrial electron transport complexes are shifted mostly toward imbalanced reactive oxygen species versus energy production. In the present study, the protective role of tempol, a membrane-permeable superoxide dismutase mimetic agent, was evaluated on mitochondrial dysfunction and the subsequent damage induced by cisplatin nephrotoxicity in mice.Nephrotoxicity was assessed 72 h after a single i.p. injection of cisplatin (25 mg/kg with or without oral administration of tempol (100 mg/kg/day. Serum creatinine and urea as well as glucosuria and proteinuria were evaluated. Both kidneys were isolated for estimation of oxidative stress markers, adenosine triphosphate (ATP content and caspase-3 activity. Moreover, mitochondrial oxidative phosphorylation capacity, complexes I-IV activities and mitochondrial nitric oxide synthase (mNOS protein expression were measured along with histological examinations of renal tubular damage and mitochondrial ultrastructural changes. Tempol was effective against cisplatin-induced elevation of serum creatinine and urea as well as glucosuria and proteinuria. Moreover, pretreatment with tempol notably inhibited cisplatin-induced oxidative stress and disruption of mitochondrial function by restoring mitochondrial oxidative phosphorylation, complexes I and III activities, mNOS protein expression and ATP content. Tempol also provided significant protection against apoptosis, tubular damage and mitochondrial ultrastructural changes. Interestingly, tempol did not interfere with the cytotoxic effect of cisplatin against the growth of solid Ehrlich carcinoma.This study highlights the potential role of tempol in inhibiting cisplatin-induced nephrotoxicity without affecting its antitumor activity via amelioration of oxidative stress and mitochondrial dysfunction.

  20. Selectivity analysis of protein kinase CK2 inhibitors DMAT, TBB and resorufin in cisplatin-induced stress responses

    DEFF Research Database (Denmark)

    Fritz, Gerhard; Issinger, Olaf-Georg; Olsen, Birgitte Brinkmann

    2009-01-01

    Targeting protein kinases as a therapeutic approach to treat various diseases, especially cancer is currently a fast growing business. Although many inhibitors are available, exhibiting remarkable potency, the major challenge is their selectivity. Here we show that the protein kinase CK2 inhibitors...... viability and inhibition of endogenous CK2 activity in the absence and presence of the anti-cancer drug cisplatin. The strongest effect on viability was observed with resorufin. In contrast to resorufin, TBB protected cells from cisplatin-induced cell killing. Furthermore, the inhibition of endogenous CK2...

  1. Pre-treatment with cardamonin protects against cisplatin-induced nephrotoxicity in rats: Impact on NOX-1, inflammation and apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    El-Naga, Reem N., E-mail: reemelnaga@hotmail.com

    2014-01-01

    Cisplatin is an effective anti-cancer drug; however, its clinical use is usually associated with nephrotoxicity as a dose-limiting side effect. Several molecular mechanisms have been found to be involved in this nephrotoxicity such as oxidative stress, inflammation and apoptosis. The aim of this study was to explore the potential nephroprotective effect of cardamonin, a flavone found in Alpinia plant, in a rat model of cisplatin-induced nephrotoxicity. The possible mechanisms underlying this nephroprotective effect were investigated. Cardamonin was given at two different doses; 10 and 30 mg/kg orally for two weeks, starting one week before giving a single nephrotoxic dose of cisplatin (7 mg/kg). Acute nephrtoxicity was evident by significantly increased blood urea nitrogen and serum creatinine levels. Also, cisplatin increased lipid peroxidation and depleted reduced glutathione level and superoxide dismutase. Additionally, cisplatin showed a marked pro-inflammatory response as evidenced by significant increase in tissue levels of IL-1β, TNF-α, NF-kB, iNOS, ICAM-1 and MCP-1. Pre-treatment with cardamonin significantly attenuated the nephrotoxic effects, oxidative stress and inflammation induced by cisplatin, in a dose-dependent manner. Also, cardamonin decreased caspase-3 expression and Bax/Bcl-2 ratio as compared to cisplatin group. Besides, cradamonin reversed cisplatin-induced decrease in EGF. Furthermore, up-regulation of NOX-1 was found to be involved in cisplatin-induced nephrotoxicity and its expression was significantly reduced by cardamonin. Histopathological examination further confirmed the nephroprotective effect of cardamonin. Moreover, pre-treatment with subtoxic concentration of cardamonin has significantly enhanced cisplatin cytotoxic activity in four different human cancer cell lines; hela, hepG2, PC3 and HCT116 cancer cell lines. In conclusion, these findings suggest that cardamonin improves therapeutic index of cisplatin and that NOX-1 is

  2. Hyperalgesia in a human model of acute inflammatory pain: a methodological study

    DEFF Research Database (Denmark)

    Pedersen, J L; Kehlet, H

    1998-01-01

    thresholds, (ii) mechanical and heat pain thresholds, (iii) pain to heat (43 degrees C and 45 degrees C, 5 s), (iv) secondary hyperalgesia, and (v) skin erythema were made 1.75 and 0.5 h before, and 0, 1, 2, 4, and 6 h after a burn injury. Sensory thresholds and hyperalgesia to heat and mechanical stimuli...... was demonstrated by significantly higher pain thresholds and lower pain responses on the second and third day of the study. The burn model is a sensitive psychophysical model of acute inflammatory pain, when cross-over designs and within-day comparisons are used, and the model is suitable for double-blind, placebo...

  3. Effects of perceived and exerted pain control on neural activity during pain relief in experimental heat hyperalgesia: a fMRI study.

    Science.gov (United States)

    Mohr, C; Leyendecker, S; Petersen, D; Helmchen, C

    2012-04-01

    Perceived control over pain can attenuate pain perception by mechanisms of endogenous pain control and emotional reappraisal irrespective of whether this control is exerted or only perceived. Self-initiated termination of pain elicits different expectations of subsequent pain relief as compared to perceived pain control. It is unknown whether and how this perceived vs. exerted control on pain differs and affects subsequent pain relief. Using fMRI, we studied two factors of pain control on pain relief: the (i) sense of control (perceived control but no execution) and (ii) the execution of control (exerted control). To account for the impact of factual execution of pain control on pain relief we applied bearable short and hardly bearable long contact-heat stimuli which were applied either controllable or not. Using controllability as factor, there was dissociable neural activity during pain relief: following the perceived control condition neural activity was found in the orbitofrontal and mediofrontal cortex and, following the exerted control condition, in the anterolateral and dorsolateral prefrontal cortex and posterior parietal cortex. We conclude that (i) pain controllability has an impact on pain relief and (ii) the prefrontal cortex shows dissociable neural activity during pain relief following exerted vs. perceived pain control. This might reflect the higher grade of uncertainty during pain relief following perceived pain control mediated by the orbitofrontal and medial prefrontal cortex and processes of working memory and updating expectations during pain relief following exerted control mediated by the lateral prefrontal cortex.

  4. Induction of heme oxygenase-1 with hemin alleviates cisplatin-induced reproductive toxicity in male rats and enhances its cytotoxicity in prostate cancer cell line.

    Science.gov (United States)

    Heeba, Gehan Hussein; Hamza, Alaaeldin Ahmed; Hassanin, Soha Osama

    2016-12-15

    Cisplatin-induced testicular damage is a major obstacle in the application of cisplatin as chemotherapeutic agent. However, it remains as one of the most widely employed anticancer agents in treating various solid tumors including prostate cancer. Since heme-oxygenase-1 (HO-1) is a cytoprotective enzyme with anti-oxidative stress, anti-inflammatory and anticancer activities, we investigated the effects of up-regulation of HO-1 by hemin and its inhibition by zinc protoporphyrin-IX (ZnPP) on cisplatin-induced testicular toxicity in adult rats. Furthermore, the anticancer effect of hemin and ZnPP, with and without cisplatin, was evaluated on human prostate cancer cell line, PC3. Results of the animal study showed that hemin reversed cisplatin-induced perturbations in sperm characteristics, normalized serum testosterone level, and ameliorated cisplatin-induced alterations in testicular and epididymal weights, and restored normal testicular architecture. Moreover, hemin increased the expression and activity of HO-1 protein and prevented cisplatin-induced testicular toxicity by virtue of its antioxidant and anti-inflammatory effects. This effect was evidenced by amelioration of testicular oxidative stress markers (malondialdehyde, nitric oxide, reduced glutathione contents, and catalase activity) and inflammatory mediators (tumor necrosis factor-α and nitric oxide synthase expressions). In contrast, administration of ZnPP (HO-1 inhibitor) did not show significant improvement against cisplatin-induced testicular toxicity. Finally, in vitro analyses showed that, hemin augmented the anticancer efficacy of cisplatin, while ZnPP inhibited its apoptotic effect in PC3 cells. In conclusion, the induction of HO-1 represents a potential therapeutic approach to protect the testicular tissue from the detrimental effects of cisplatin without repressing, but rather augmenting, its cytotoxic effects on PC3 cells.

  5. Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs)

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qing [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Institute of Clinical Pharmacology, Central South University, Hunan 410078 (China); Guo, Dong [Institute of Clinical Pharmacology, Central South University, Hunan 410078 (China); Dong, Zhongqi [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Zhang, Wei [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Institute of Clinical Pharmacology, Central South University, Hunan 410078 (China); Zhang, Lei; Huang, Shiew-Mei [Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD (United States); Polli, James E. [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Shu, Yan, E-mail: yshu@rx.umaryland.edu [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States)

    2013-11-15

    The nephrotoxicity limits the clinical application of cisplatin. Human organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins (MATEs) work in concert in the elimination of cationic drugs such as cisplatin from the kidney. We hypothesized that co-administration of ondansetron would have an effect on cisplatin nephrotoxicity by altering the function of cisplatin transporters. The inhibitory potencies of ondansetron on metformin accumulation mediated by OCT2 and MATEs were determined in the stable HEK-293 cells expressing these transporters. The effects of ondansetron on drug disposition in vivo were examined by conducting the pharmacokinetics of metformin, a classical substrate for OCTs and MATEs, in wild-type and Mate1−/− mice. The nephrotoxicity was assessed in the wild-type and Mate1−/− mice received cisplatin with and without ondansetron. Both MATEs, including human MATE1, human MATE2-K, and mouse Mate1, and OCT2 (human and mouse) were subject to ondansetron inhibition, with much greater potencies by ondansetron on MATEs. Ondansetron significantly increased tissue accumulation and pharmacokinetic exposure of metformin in wild-type but not in Mate1−/− mice. Moreover, ondansetron treatment significantly enhanced renal accumulation of cisplatin and cisplatin-induced nephrotoxicity which were indicated by increased levels of biochemical and molecular biomarkers and more severe pathohistological changes in mice. Similar increases in nephrotoxicity were caused by genetic deficiency of MATE function in mice. Therefore, the potent inhibition of MATEs by ondansetron enhances the nephrotoxicity associated with cisplatin treatment in mice. Potential nephrotoxic effects of combining the chemotherapeutic cisplatin and the antiemetic 5-hydroxytryptamine-3 (5-HT{sub 3}) receptor antagonists, such as ondansetron, should be investigated in patients. - Highlights: • Nephrotoxicity significantly limits clinical use of the chemotherapeutic

  6. SIRT1 overexpression decreases cisplatin-induced acetylation of NF-{kappa}B p65 subunit and cytotoxicity in renal proximal tubule cells

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Yu Jin; Lee, Jung Eun; Lee, Ae Sin [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Kang, Kyung Pyo; Lee, Sik; Park, Sung Kwang [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Lee, Sang Yong [Department of Diagnostic Radiology, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Han, Myung Kwan [Department of Microbiology, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Kim, Duk Hoon [Division of Forensic Medicine, National Forensic Service, Seoul (Korea, Republic of); Kim, Won, E-mail: kwon@jbnu.ac.kr [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of)

    2012-03-09

    Highlights: Black-Right-Pointing-Pointer Cisplatin increases acetylation of NF-{kappa}B p65 subunit in HK2 cells. Black-Right-Pointing-Pointer SIRT1 overexpression decreases cisplatin-induced p65 acetylation and -cytotoxicity. Black-Right-Pointing-Pointer Resveratrol decreased cisplatin-induced cell viability through deacetylation of p65. -- Abstract: As the increased acetylation of p65 is linked to nuclear factor-{kappa}B (NF-{kappa}B) activation, the regulation of p65 acetylation can be a potential target for the treatment of inflammatory injury. Cisplatin-induced nephrotoxicity is an important issue in chemotherapy of cancer patients. SIRT1, nicotinamide adenine dinucleotide (NAD{sup +})-dependent protein deacetylase, has been implicated in a variety of cellular processes such as inflammatory injury and the control of multidrug resistance in cancer. However, there is no report on the effect of SIRT1 overexpression on cisplatin-induced acetylation of p65 subunit of NF-{kappa}B and cell injury. To investigate the effect of SIRT1 in on cisplatin-induced acetylation of p65 subunit of NF-{kappa}B and cell injury, HK2 cells were exposed with SIRT1 overexpression, LacZ adenovirus or dominant negative adenovirus after treatment with cisplatin. While protein expression of SIRT1 was decreased by cisplatin treatment compared with control buffer treatment, acetylation of NF-{kappa}B p65 subunit was significantly increased after treatment with cisplatin. Overexpression of SIRT1 ameliorated the increased acetylation of p65 of NF-{kappa}B during cisplatin treatment and cisplatin-induced cytotoxicity. Further, treatment of cisplatin-treated HK2 cells with resveratrol, a SIRT1 activator, also decreased acetylation of NF-{kappa}B p65 subunit and cisplatin-induced increase of the cell viability in HK2 cells. Our findings suggests that the regulation of acetylation of p65 of NF-{kappa}B through SIRT1 can be a possible target to attenuate cisplatin-induced renal cell damage.

  7. Effect of riluzole on acute pain and hyperalgesia in humans

    DEFF Research Database (Denmark)

    Hammer, N A; Lillesø, J; Pedersen, J L;

    1999-01-01

    Riluzole modulates several transmitter systems which may be involved in nociception. Antinociceptive effects have been shown in animal studies, but there are no human data. Therefore, we have examined the acute analgesic effect of riluzole in a human model of inflammatory pain induced by a thermal...... injury on the distal leg (47 degrees C, 7 min, 12.5 cm2) in 20 healthy volunteers. Hyperalgesia to mechanical and heat stimuli were examined by von Frey hairs and thermodes. We used a randomized, double-blind, placebo-controlled design, and subjects received riluzole 100 mg or placebo for 2 days...... with a 14-day interval. The burns produced significant hyperalgesia, but riluzole had no acute analgesic effects in normal or hyperalgesic skin....

  8. Pre-stimulation of the kallikrein system in cisplatin-induced acute renal injury: An approach to renoprotection

    Energy Technology Data Exchange (ETDEWEB)

    Aburto, Andrés [Program of M.Sc., Faculty of Medicine, Universidad Austral de Chile, Valdivia (Chile); Barría, Agustín [School of Biochemistry, Faculty of Sciences, Universidad Austral de Chile, Valdivia (Chile); Cárdenas, Areli [Ph.D. Program, Faculty of Sciences, Universidad Austral de Chile, Valdivia (Chile); Carpio, Daniel; Figueroa, Carlos D. [Department of Anatomy, Histology and Pathology, Universidad Austral de Chile, Valdivia (Chile); Burgos, Maria E. [Department of Nephrology, Faculty of Medicine, Universidad Austral de Chile, Valdivia (Chile); Ardiles, Leopoldo, E-mail: leopoldoardiles@gmail.com [Department of Nephrology, Faculty of Medicine, Universidad Austral de Chile, Valdivia (Chile)

    2014-10-15

    Antineoplastic treatment with cisplatin is frequently complicated by nephrotoxicity. Although oxidative stress may be involved, the pathogenic mechanisms responsible for renal damage have not been completely clarified. In order to investigate the role of the renal kinin system in this condition, a group of rats was submitted to high potassium diet to stimulate the synthesis and excretion of tissue kallikrein 1 (rKLK1) previous to an intraperitoneal injection of 7 mg/kg cisplatin. A significant reduction in lipoperoxidation, evidenced by urinary excretion of malondialdehyde and renal immunostaining of hidroxy-nonenal, was accompanied by a decline in apoptosis. Coincident with these findings we observed a reduction in the expression of renal KIM-1 suggesting that renoprotection may be occurring. Stimulation or indemnity of the renal kinin system deserves to be evaluated as a complementary pharmacological measure to diminish cisplatin nephrotoxicity. - Highlights: • Mechanisms of cisplatin-induced-renal damage have not been completely clarified. • Cisplatin induces oxidative stress and apoptosis. • The renal kallikrein-kinin system is protective in experimental acute renal damage. • Kallikrein stimulation reduces oxidative stress and apoptosis induced by cisplatin. • Protection of the kallikrein-kinin system may reduce cisplatin toxicity.

  9. Assessment of the possible role of iron and copper in cisplatin-induced nephrotoxicity in the rat.

    Science.gov (United States)

    Goudie, J; Chandra, M; Lawrence, G D; Williams, P

    1994-01-01

    Nephrotoxic lesions induced by cisplatin in rats are characterized by acute tubular necrosis in the outer stripe of the medulla. The purpose of this study was to examine the potential role of changes in metal binding proteins, and iron and copper content in urine and renal tissue in cisplatin-induced nephrotoxicity. Cisplatin was administered intravenously to groups of 20 rats at single doses of 0, 1, 2.5, and 5 mg/kg and rats were sacrificed at 1, 2, 3 and 6 days after treatment. Increased serum BUN and creatinine were observed at a dose of 5 mg/kg cisplatin on day 2 through day 6. Increased urinary copper excretion coincided with necrosis and increased BUN and creatinine on day 3 in the high-dose group. Evidence of renal injury was apparent histologically as karyomegaly at all dose levels as early as 48 hours after injection of cisplatin, prior to increases in urinary copper levels. No change in the distribution of metal binding proteins (transferrin, ferritin, ceruloplasmin, and metallothionein) evaluated by immunohistochemical staining, was seen. Based upon these results, it is unlikely that changes in metal excretion play a primary role in cisplatin-induced nephrotoxicity however, changes in nuclear function indicated by karyomegaly may be involved in early renal injury.

  10. Bee Venom Mitigates Cisplatin-Induced Nephrotoxicity by Regulating CD4+CD25+Foxp3+ Regulatory T Cells in Mice

    Directory of Open Access Journals (Sweden)

    Hyunseong Kim

    2013-01-01

    Full Text Available Cisplatin is used as a potent anticancer drug, but it often causes nephrotoxicity. Bee venom (BV has been used for the treatment of various inflammatory diseases, and its renoprotective action was shown in NZB/W mice. However, little is known about whether BV has beneficial effects on cisplatin-induced nephrotoxicity and how such effects might be mediated. In the present study, the BV-injected group showed a significant increase in the population of Tregs in spleen. Although there was no significant difference in the numbers of Tregs 3 days after cisplatin injection between the BV- and PBS-injected groups, more migration of Tregs into the kidney was observed 6 hours after cisplatin administration in BV group than in PBS group. In addition, BV-injected mice showed reduced levels of serum creatinine, blood urea nitrogen, renal tissue damage, proinflammatory cytokines, and macrophage infiltration into the kidney 3 days after cisplatin administration. These renoprotective effects were abolished by the depletion of Tregs. The anticancer effect of repeated administrations of cisplatin was not affected by BV injection. These results suggest that BV has protective effects on cisplatin-induced nephrotoxicity in mice, at least in part, through the regulation of Tregs without a big influence on the antitumor effects of cisplatin.

  11. Sorghum [Sorghum bicolor (L.) Moench] leaf sheath dye protects against cisplatin-induced hepatotoxicity and oxidative stress in rats.

    Science.gov (United States)

    Ademiluyi, Adedayo O; Oboh, Ganiyu; Agbebi, Oluwaseun J; Boligon, Aline A; Athayde, Margareth L

    2014-12-01

    This study sought to determine the protective effect of dietary inclusion of sorghum leaf sheath dye on cisplatin-induced hepatotoxicity and oxidative stress in rats. Adult male rats were randomly divided into four groups with six animals in each group. Groups I and II were fed a basal diet, while groups III and IV were fed diets containing 0.5% and 1% sorghum leaf sheath dye, respectively, for 20 days before cisplatin administration. Hepatotoxicity was induced by a single dose of cisplatin (7 mg/kg body weight, i.p.), and the experiment was terminated at 3 days after cisplatin injection. The liver and plasma were studied for hepatotoxicity and antioxidant capacity. Cisplatin caused a significant (Pinduced alteration of both plasma and liver antioxidant indices suggests an antioxidant mechanism of action. Hence, this protective effect of Sorghum bicolor leaf sheath dye against cisplatin-induced hepatotoxicity in rats reflects its potential and beneficial role in the prevention of liver damage associated with cisplatin administration.

  12. Protective role of turmeric on histological, ultrastructural and serobiochemical changes in cisplatin-induced nephrotoxicity in female rats

    Directory of Open Access Journals (Sweden)

    B. Ramya

    2013-10-01

    Full Text Available Aim: Protective role of turmeric was assessed against cisplatin-induced histological and ultra-structural changes in kidney.Materials and Methods: A total of 48 rats were divided into 4 groups of 12 rats in each. Group 1 was kept as sham control,group 2 was treated with cisplatin (@ 2 mg/kg b.wt, intraperitoneally on day 1, 7, 14 and 21, group 3 with turmeric (@ 0.05mg/kg b.wt. p.o. once daily for 28 days and group 4 with cisplatin + turmeric (as per above schedule. Blood was collected atfortnight intervals and serum was separated for estimation of kidney biomarkers. Six rats in each group were then euthanizedon day 14 and 28 for histopathology, and tissue parameters were assayed on day 28.Results: Thibarbituric acid reacting substances (TBARS, protein carbonyls, serum creatinine, blood urea nitrogen (BUNwere significantly (P < 0.05 increased, while GSH was significantly (P < 0.05 decreased in group 2 as compared to othergroups. Histological sections of kidney from group 2 rats showed marked inter-tubular haemorrhages, congestion, markeddilation of tubules, and other lesions of pathological significance. Ultrastructural changes of pathological significance werealso recorded in group 2. Kidney sections of group 4 showed nucleus with uniform size with well differentiated nuclearmembrane and nucleolus, and prominent inter tubular and inter cellular junctions.Conclusion: The study revealed that cisplatin induces nephrotoxicity due to oxidative stress and turmeric was foundbeneficial in countering the adverse effects.

  13. miR-203 inhibits cell proliferation and promotes cisplatin induced cell death in tongue squamous cancer.

    Science.gov (United States)

    Lin, Jiong; Lin, Yao; Fan, Li; Kuang, Wei; Zheng, Liwei; Wu, Jiahua; Shang, Peng; Wang, Qiaofeng; Tan, Jiali

    2016-04-29

    Oral squamous cell carcinoma (OSCC) is one of the most common types of the head and neck cancer. Chemo resistance of OSCC has been identified as a substantial therapeutic hurdle. In this study, we analyzed the role of miR-203 in the OSCC and its effects on cisplatin-induced cell death in an OSCC cell line, Tca8113. There was a significant decrease of miR-203 expression in OSCC samples, compared with the adjacent normal, non-cancerous tissue. After 3 days cisplatin treatment, the survived Tca8113 cells had a lower expression of miR-203 than that in the untreated control group. In contrast, PIK3CA showed an inverse expression in cancer and cisplatin survived Tca8113 cells. Transfection of Tca8113 cells with miR-203 mimics greatly reduced PIK3CA expression and Akt activation. Furthermore, miR-203 repressed PIK3CA expression through targeting the 3'UTR. Restoration of miR-203 not only suppressed cell proliferation, but also sensitized cells to cisplatin induced cell apoptosis. This effect was absent in cells that were simultaneously treated with PIK3CA RNAi. In summary, these findings suggest miR-203 plays an important role in cisplatin resistance in OSCC, and furthermore delivery of miR-203 analogs may serve as an adjuvant therapy for OSCC.

  14. Prevention of cisplatin induced nephrotoxicity by terpenes isolated from Ganoderma lucidum occurring in Southern Parts of India.

    Science.gov (United States)

    Pillai, Thulasi G; John, Mathew; Sara Thomas, Gifty

    2011-01-01

    Investigations were carried out to determine the protective effect of terpenes isolated from the fruiting bodies of Ganoderma lucidum (Fr) P.Karst against nephrotoxicity caused by the cisplatin, in mice. Intraperitoneal administration of cisplatin (16 mg/kg body wt) resulted in significant nephrotoxicity in mice. Serum urea, creatinine and ALP levels were drastically elevated indicating severe nephrotoxicity . The renal antioxidant defense system such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and concentration of reduced glutathione (GSH) were depleted by cisplatin injection. The oral administration of terpenes at a dose of 100mg/kg body weight prevented increase in urea, creatinine levels and ALP activity and also maintained the renal antioxidant defense. The Ganoderma terpenes also imparted protection against cisplatin induced renal tissue lipid peroxidation. The results indicated that the total terpenes isolated from G. lucidum possessed significant in vivo antioxidant activity and rendered protection against cisplatin induced nephrotoxicity. The results suggest the potential therapeutic use of Ganoderma terpenes to prevent nephrotoxicity caused during chemotherapy using cisplatin.

  15. Contribution of transient receptor potential vanilloid subfamily 1 to endothelin-1-induced thermal hyperalgesia.

    Science.gov (United States)

    Kawamata, T; Ji, W; Yamamoto, J; Niiyama, Y; Furuse, S; Namiki, A

    2008-06-26

    Endothelin-1 (ET-1) plays an important role in peripheral pain processing. However, the mechanisms of the nociceptive action of ET-1 have not been fully elucidated. In this study, we investigated the contribution of transient receptor potential vanilloid subfamily 1 (TRPV1) to ET-1-induced thermal hyperalgesia. Intraplantar ET-1-induced thermal hyperalgesia was examined by assessing the paw withdrawal latency to noxious heat stimuli. In electrophysiological study, whole-cell patch-clamp recordings were performed to investigate the interaction of ET-1 and TRPV1 using human embryonic kidney 293 (HEK293) cells expressing endothelin type A receptor (ET(A)) and TRPV1. Intraplantar ET-1 (3, 10 and 30 pmol) produced thermal hyperalgesia in a dose-dependent manner. Thermal hyperalgesia was attenuated by the inhibition of ET(A) and protein kinase C (PKC) but not that of ET(B). ET-1-induced thermal hyperalgesia was significantly attenuated in TRPV1-deficient mice compared with that in wild-type mice. In voltage-clamp experiments, 10 nM capsaicin evoked small inward currents in HEK293 cells expressing TRPV1 and ET(A). In the presence of ET-1, capsaicin produced much larger current responses (Pthermal hyperalgesia.

  16. Effect of tunicamycin on cisplatin induced apoptosis of HeLa cells

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    Ye XU

    2013-04-01

    Full Text Available Objective  To investigate the effect of endoplasmic reticulum stress (ER stress in cisplatin-induced apoptosis of human cervical cancer HeLa cells. Methods  HeLa cells were used as the study object which were divided into four groups: TUNI (5mg/L group, cisplatin (6mg/L group, TUNI(5mg/L+cisplatin(6mg/L group, and negative control group (no drug treatment. MTT assay was employed to examine the growth status of the cells. Hoechst staining was used to observe the morphological change in the nucleus. Immunoblotting was used to detect the activation of apoptotic proteins, caspase-3 and caspase-4. Indirect immunofluorescence was used to assess the expression of the protein disulfide isomerase (PDI and phosphorylated histone H2AX (γ-H2AX. Results  MTT assay showed that the growth inhibition rates were 2.65%±2.71%, 19.60%±4.34%, 44.69%±7.07% and 0% in TUNI group, cisplatin group, TUNI+cisplatin group and control group, respectively (P<0.05. Cisplatin showed a significant inhibitory effect on the growth of HeLa cells, and TUNI enhanced the effect of cisplatin. Statistical significance was found between TUNI+cisplatin group and cisplatin group (P<0.05. Hoechst staining showed that the fluorescence of the nucleus in control group was weak and well-distributed. At 12h after treatment, the nuclei in some HeLa cells in cisplatin group and TUNI+cisplatin group diminished in size, thus showing dense hyperfluorescence, and some of them were broken. The proportion of karyorrhexis cells in TUNI+cisplatin group (44.5%±5.1% was significantly higher than that in cisplatin group (22.7%±3.9%, P<0.05. Immunoblotting showed the expressions of activated caspase-3 and caspase-4 were up-regulated obviously in cisplatin group. Compared to cisplatin group, the expressions of those proteins significantly increased in TUNI+cisplatin group (P<0.05. Indirect immunofluorescence staining showed no PDI expression and weak fluorescence was found in control group. PDI

  17. Possible (enzymatic) routes and biological sites for metabolic reduction of BNP7787, a new protector against cisplatin-induced side-effects.

    NARCIS (Netherlands)

    Verschraagen, M.; Boven, E.; Torun, E; Hausheer, FH; Vijgh, van der WJ

    2004-01-01

    Disodium 2,2'-dithio-bis-ethane sulfonate (BNP7787) is under investigation as a potential new chemoprotector against cisplatin-induced nephrotoxicity. The selective protection of BNP7787 appears to arise from the preferential uptake of the drug in the kidneys, where BNP7787 would undergo intracellul

  18. Post-treatment effects of erythropoietin and nordihydroguaiaretic acid on recovery from cisplatin-induced acute renal failure in the rat.

    Science.gov (United States)

    Lee, Dong Won; Kwak, Ihm Soo; Lee, Soo Bong; Song, Sang Heon; Seong, Eun Young; Yang, Byeong Yun; Lee, Min Young; Sol, Mee Young

    2009-01-01

    5-lipoxygenase inhibitor and human recombinant erythropoietin might accelerate renal recovery in cisplatin-induced acute renal failure rats. Male Sprague-Dawley rats were randomized into four groups: 1) normal controls; 2) Cisplatin group-cisplatin induced acute renal failure (ARF) plus vehicle treatment; 3) Cisplatin+nordihydroguaiaretic acid (NDGA) group-cisplatin induced ARF plus 5-lipoxygenase inhibitor treatment; 4) Cisplatin+erythropoietin (EPO) group-cisplatin induced ARF plus erythropoietin treatment. On day 10 (after 7 daily injections of NDGA or EPO), urea nitrogen and serum Cr concentrations were significantly lower in the Cisplatin+NDGA and Cisplatin+EPO groups than in the Cisplatin group, and 24 hr urine Cr clearances were significantly higher in the Cisplatin+EPO group than in the Cisplatin group. Semi-quantitative assessments of histological lesions did not produce any significant differences between the three treatment groups. Numbers of PCNA(+) cells were significantly higher in Cisplatin, Cisplatin+NDGA, and Cisplatin+EPO groups than in normal controls. Those PCNA(+) cells were significantly increased in Cisplatin+NDGA group. These results suggest that EPO and also NDGA accelerate renal function recovery by stimulating tubular epithelial cell regeneration.

  19. Melatonin prevents cisplatin-induced primordial follicle loss via suppression of PTEN/AKT/FOXO3a pathway activation in the mouse ovary.

    Science.gov (United States)

    Jang, Hoon; Lee, Ok-Hee; Lee, Youngeun; Yoon, Hyemin; Chang, Eun Mi; Park, Miseon; Lee, Jeong-Woong; Hong, Kwonho; Kim, Jung Oh; Kim, Nam Keun; Ko, Jung Jae; Lee, Dong Ryul; Yoon, Tae Ki; Lee, Woo Sik; Choi, Youngsok

    2016-04-01

    Premature ovarian failure (POF) is a major side effect of chemotherapy in young cancer patients. To develop pharmaceutical agents for preserving fertility, it is necessary to understand the mechanisms responsible for chemotherapy-induced follicle loss. Here, we show that treatment with cisplatin, a widely used anticancer drug, depleted the dormant follicle pool in mouse ovaries by excessive activation of the primordial follicles, without inducing follicular apoptosis. Moreover, we show that co-treatment with the antioxidant melatonin prevented cisplatin-induced disruption of the follicle reserve. We quantified the various stages of growing follicles, including primordial, primary, secondary, and antral, to demonstrate that cisplatin treatment alone significantly decreased, whereas melatonin co-treatment preserved, the number of primordial follicles in the ovary. Importantly, analysis of the PTEN/AKT/FOXO3a pathway demonstrated that melatonin significantly decreased the cisplatin-mediated inhibitory phosphorylation of PTEN, a key negative regulator of dormant follicle activation. Moreover, melatonin prevented the cisplatin-induced activating phosphorylation of AKT, GSK3β, and FOXO3a, all of which trigger follicle activation. Additionally, we show that melatonin inhibited the cisplatin-induced inhibitory phosphorylation and nuclear export of FOXO3a, which is required in the nucleus to maintain dormancy of the primordial follicles. These findings demonstrate that melatonin attenuates cisplatin-induced follicle loss by preventing the phosphorylation of PTEN/AKT/FOXO3a pathway members; thus, melatonin is a potential therapeutic agent for ovarian protection and fertility preservation during chemotherapy in female cancer patients.

  20. Antrodia cinnamomea alleviates cisplatin-induced hepatotoxicity and enhances chemo-sensitivity of line-1 lung carcinoma xenografted in BALB/cByJ mice.

    Science.gov (United States)

    Huang, Tse-Hung; Chiu, Yi-Han; Chan, Yi-Lin; Wang, Hang; Li, Tsung-Lin; Liu, Chien-Yin; Yang, Cheng-Ta; Lee, Tzung-Yan; You, Jyh-Sheng; Hsu, Kuang-Hung; Wu, Chang-Jer

    2015-09-22

    Whereas cisplatin (cis-diamminedichloroplatinum II) is a first-line medicine to treat solid cancerous tumors, it often causes serious side effects. New medicines that have an equivalent or even better therapeutic effect but with free or less side effects than cisplatin are highly anticipated in cancer therapy. Recent reports revealed that Antrodia cinnamomea (AC) possesses hepatoprotective activity in addition to anticancer. In this study, we wanted to know whether AC enhances chemo-sensitivity of cisplatin and/or alleviates cisplatin-induced hepatotoxicity, as well as the underlying mechanisms thereof. Our results indicated that AC inhibited proliferation of line-1 lung carcinoma cells and rescued hepatic HepG2 cells from cisplatin-induced cell death in vitro. The fact is that AC and cisplatin synergized to constrain growth of line-1 lung carcinoma cells in BALB/cByJ mice. Quantitative real-time PCR further revealed that AC promoted expression of apoptosis-related genes, while it decreased expression of NF-κB and VEGF in tumor tissues. In liver, AC reduced cisplatin-induced liver dysfunctions, liver inflammation and hepatic apoptosis in addition to body weight restoration. In summary, AC is able to increase cisplatin efficacy by triggering expression of apoptosis-related genes in line-1 lung cancer cells as well as to protect liver from tissue damage by avoiding cisplatin-induced hepatic inflammation and cell death.

  1. Protective effect of curcumin and vitamin C each alone and in combination on cisplatin-induced sperm abnormalities in male albino rats

    Directory of Open Access Journals (Sweden)

    Sabha Elsayed Elballat

    2016-08-01

    The results of the present investigation concluded that the combination between curcumin and vitamin C in cisplatin treatment afforded the best ameliorative effect on cisplatin induced sperm shape abnormalities. This may be due to the synergistic effect between curcumin and vitamin C as both of them have antioxidant properties which in turn lead to repairing of sperm abnormalities.

  2. Pathogenesis of spinally mediated hyperalgesia in diabetes.

    Science.gov (United States)

    Ramos, Khara M; Jiang, Yun; Svensson, Camilla I; Calcutt, Nigel A

    2007-06-01

    Hyperalgesia to noxious stimuli is accompanied by increased spinal cyclooxygenase (COX)-2 protein in diabetic rats. The present studies were initiated to establish causality between increased spinal COX-2 activity and hyperalgesia during diabetes and to assess the potential involvement of polyol pathway activity in the pathogenesis of spinally mediated hyperalgesia. Rats with 1, 2, or 4 weeks of streptozotocin-induced diabetes exhibited significantly increased levels of spinal COX-2 protein and activity, along with exaggerated paw flinching in response to 0.5% paw formalin injection. Increased flinching of diabetic rats was attenuated by intrathecal pretreatment with a selective COX-2 inhibitor immediately before formalin injection, confirming the involvement of COX-2 activity in diabetic hyperalgesia. Chronic treatment with insulin or ICI222155, an aldose reductase inhibitor (ARI) previously shown to prevent spinal polyol accumulation and formalin-evoked hyperalgesia in diabetic rats, prevented elevated spinal COX-2 protein and activity in diabetic rats. In contrast, the ARI IDD676 had no effect on spinal polyol accumulation, elevated spinal COX-2, or hyperalgesia to paw formalin injection. In the spinal cord, aldose reductase immunoreactivity was present solely in oligodendrocytes, which also contained COX-2 immunoreactivity. Polyol pathway flux in spinal oligodendrocytes provides a pathogenic mechanism linking hyperglycemia to hyperalgesia in diabetic rats.

  3. Evidence for different mechanisms of ‘unhooking’ for melphalan and cisplatin-induced DNA interstrand cross-links in vitro and in clinical acquired resistant tumour samples

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    Spanswick Victoria J

    2012-09-01

    Full Text Available Abstract Background DNA interstrand cross-links (ICLs are critical lesions produced by several cancer chemotherapy agents including platinum drugs and nitrogen mustards. We have previously shown in haematological (multiple myeloma and solid tumours (ovarian cancer that clinical sensitivity to such agents can result from a defect in DNA ICL processing leading to their persistence. Conversely, enhanced repair can result in clinical acquired resistance following chemotherapy. The repair of ICLs is complex but it is assumed that the ‘unhooking’ step is common to all ICLs. Methods Using a modification of the single cell gel electrophoresis (Comet assay we measured the formation and unhooking of melphalan and cisplatin-induced ICLs in cell lines and clinical samples. DNA damage response in the form of γ-H2AX foci formation and the formation of RAD51 foci as a marker of homologous recombination were also determined. Real-time PCR of 84 genes involved in DNA damage signalling pathways was also examined pre- and post-treatment. Results Plasma cells from multiple myeloma patients known to be clinically resistant to melphalan showed significant unhooking of melphalan-induced ICLs at 48 hours, but did not unhook cisplatin-induced ICLs. In ovarian cancer cells obtained from patients following platinum-based chemotherapy, unhooking of cisplatin-induced ICLs was observed at 48 hours, but no unhooking of melphalan-induced ICLs. In vitro, A549 cells were proficient at unhooking both melphalan and cisplatin-induced ICLs. γ-H2AX foci formation closely followed the formation of ICLs for both drugs, and rapidly declined following the peak of formation. RPMI8226 cells unhooked melphalan, but not cisplatin-induced ICLs. In these cells, although cross-links form with cisplatin, the γ-H2AX response is weak. In A549 cells, addition of 3nM gemcitabine resulted in complete inhibition of cisplatin-induced ICL unhooking but no effect on repair of melphalan ICLs. The

  4. Amelioration of cisplatin-induced nephrotoxicity by ethanolic extract of Bauhinia purpurea: An in vivo study in rats.

    Science.gov (United States)

    Rana, Md Azmat; Khan, Rahat Ali; Nasiruddin, Mohammad; Khan, Aijaz Ahmed

    2016-01-01

    Our objective is to study the nephroprotective activity and antioxidant potential of Bauhinia purpurea unripe pods and bark against cisplatin-induced nephrotoxicity. Healthy adult albino rats of either sex (150-200 g) were randomly divided into six groups of six animals each Group I (vehicle control) and Group II (negative control). Group III (BBE200) and Group IV (BBE400) were administered the ethanolic extract of Bauhinia purpurea bark in doses of 200 and 400 mg/kg/day p.o., respectively, and Group V (BPE200) and Group VI (BPE400) were administered the ethanolic extract of Bauhinia purpurea unripe pods at doses of 200 and 400 mg/kg/day p.o., respectively. All the treatments were given for nine days. Cisplatin in a single dose of 6 mg/kg i.p. was given on the 4 th day to all groups, except the vehicle control group. On the 10 th day, blood and urine were collected for biochemical tests and the rats were sacrificed. The kidney was removed for histology and lipid peroxidation-antioxidant test. Cisplatin caused nephrotoxicity as evidenced by elevated blood urea, serum creatinine and urine glucose, and there was decreased creatinine clearance in Group II as compared with Group I. Administration of BBE and BPE at doses of 200 and 400 mg/kg in Group III and Group VI caused a dose-dependant reduction in the rise of blood urea, serum creatinine and urine glucose, and there was a dose-dependant increase in creatinine clearance compared with Group II. There was increased catalase and glutathione and decreased malondialdehyde levels in Group II, while BBE 400 (Group IV) and BPE 400 (Group VI) treatments significantly reversed the changes toward normal values. Histological examination of the kidney revealed protection in Group IV and Group VI compared with Group II. The ethanolic extract of Bauhinia purpurea unripe pods and bark has a nephroprotective activity against cisplatin-induced nephrotoxicity in rats.

  5. D-Methionine attenuated cisplatin-induced vestibulotoxicity through altering ATPase activities and oxidative stress in guinea pigs.

    Science.gov (United States)

    Cheng, Po-Wen; Liu, Shing-Hwa; Young, Yi-Ho; Lin-Shiau, Shoei-Yn

    2006-09-01

    Cisplatin has been used as a chemotherapeutic agent to treat many kinds of malignancies. Its damage to the vestibulo-ocular reflex (VOR) system has been reported. However, the underlying biochemical change in the inner ear or central vestibular nervous system is not fully understood. In this study, we attempted to examine whether cisplatin-induced vestibulotoxicity and D-methionine protection were correlated with the changes of ATPase activities and oxidative stress of ampullary tissue of vestibules as well as cerebellar cortex (the inhibitory center of VOR system) of guinea pigs. By means of a caloric test coupled with electronystagmographic recordings, we found that cisplatin exposure caused a dose-dependent (1, 3, or 5 mg/kg) vestibular dysfunction as revealed by a decrease of slow phase velocity (SPV). In addition, cisplatin significantly inhibited the Na(+), K(+)-ATPase and Ca(2+)-ATPase activities in the ampullary tissue with a good dose-response relationship but not those of cerebellar cortex. Regression analysis indicated that a decrease of SPV was well correlated with the reduction of Na(+), K(+)-ATPase and Ca(2+)-ATPase activities of the ampullary tissue. D-Methionine (300 mg/kg) reduced both abnormalities of SPV and ATPase activities in a correlated manner. Moreover, cisplatin exposure led to a significant dose-dependent increase of lipid peroxidation and nitric oxide concentrations of the vestibules, which could be significantly suppressed by D-methionine. However, cisplatin did not alter the levels of lipid peroxidation and nitric oxide of the cerebellum. In conclusion, cisplatin inhibited ATPase activities and increased oxidative stress in guinea pig vestibular labyrinths. D-Methionine attenuated cisplatin-induced vestibulotoxicity associated with ionic disturbance through its antioxidative property.

  6. Ameliorating effect of DL-α-lipoic acid against cisplatin-induced nephrotoxicity and cardiotoxicity in experimental animals.

    Science.gov (United States)

    Hussein, Asmma; Ahmed, Amany A E; Shouman, Samia A; Sharawy, Sabry

    2012-06-01

    Cisplatin is a potent chemotherapeutic agent with a wide range of activities. Nephrotoxicity and cardiotoxicity represent it's major complication upon clinical use. The present study was carried out to evaluate the possible protective effect of DL-α-lipoic acid (LA) against cisplatin-induced nephrotoxicity and cardiotoxicity. Different groups of rats (n = 10) were administered either saline (control), cisplatin (10 mg/kg, i.p.), LA (100 mg/kg, i.p.) or their combination (LA 30 min prior to cisplatin administration). Twenty-four hours later all animals were decapitated and sera were used for estimation of activities of urea (BUN), creatinine (Cr), lactate dehydrogenase (LDH), and creatine kinase (CK). Homogenates of the kidney and heart were used for estimation of oxidative stress markers (reduced glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), and nitric oxide (NO)). Additionally, caspase-3 activities and DNA-fragmentation were investigated in renal tissues. The results showed that cisplatin produced significant elevation in serum activities of LDH, CK, BUN, and Cr and also induced significant elevation in the oxidative stress makers (MDA and NO) accompanied by significant reduction in GSH and SOD in both kidney and heart. The integrity of DNA was heavily damaged and caspase-3 was activated in renal tissues. The results emphasized nephrotoxicty and cardiotoxicity of cisplatin. On the other hand, prior administration of LA significantly attenuated the cisplatin-evoked disturbances in the above mentioned parameters and protected both kidney and heart tissues. The histopathological examination emphasized the obtained results. In conclusion, LA is suggested to be a potential candidate to ameliorate cisplatin-induced nephrotoxicity and cardiotoxicity without altering the antitumor efficacy of cisplatin.

  7. Ginsenoside Rg5 Ameliorates Cisplatin-Induced Nephrotoxicity in Mice through Inhibition of Inflammation, Oxidative Stress, and Apoptosis

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    Wei Li

    2016-09-01

    Full Text Available Although cisplatin is an effective anti-cancer agent that is widely used for treating various types of malignant solid tumors, the nephrotoxicity induced by cisplatin severely limits its clinical application. The present study was designed to explore the potential protective effect of ginsenoside Rg5, a rare ginsenoside generated during steaming ginseng, on cisplatin-induced nephrotoxicity in a mouse experimental model. The possible mechanisms underlying this nephroprotective effect were also investigated for the first time. Rg5 was given at doses of 10 and 20 mg/kg for 10 consecutive days. On Day 7, a single nephrotoxic dose of cisplatin (25 mg/kg was injected to mice. Cisplatin administration resulted in renal dysfunction as evidenced by increase in serum creatinine (CRE and blood urea nitrogen (BUN levels. In addition, cisplatin increased the level of malondialdehyde (MDA and 4-hydroxynonenal (4-HNE, the makers of lipid peroxidation, and depleted glutathione (GSH content and superoxide dismutase (SOD activity in renal tissues. These effects were associated with the significantly increased levels of cytochrome P450 E1 (CYP2E1, 4-hydroxynonenal (4-HNE, tumor necrosis factor (TNF-α, interleukin (IL-1β, nuclear factor-kappa B (NF-κB p65, and cyclooxygenase-2 (COX-2 in renal tissues. However, pretreatment with ginsenoside Rg5 significantly attenuated the renal dysfunction, oxidative stress and inflammation response induced by cisplatin. Furthermore, ginsenoside Rg5 supplementation inhibited activation of apoptotic pathways through increasing Bcl-2 and decreasing Bax expression levels. Histopathological examination further confirmed the nephroprotective effect of Rg5. Collectively, these results clearly suggest that Rg5-mediated alleviation of cisplatin-induced nephrotoxicity may be related to its anti-oxidant, anti-apoptotic and anti-inflammatory effects.

  8. Effect of sympathetic nerve block on acute inflammatory pain and hyperalgesia

    DEFF Research Database (Denmark)

    Pedersen, J L; Rung, G W; Kehlet, H

    1997-01-01

    BACKGROUND: Sympathetic nerve blocks relieve pain in certain chronic pain states, but the role of the sympathetic pathways in acute pain is unclear. Thus the authors wanted to determine whether a sympathetic block could reduce acute pain and hyperalgesia after a heat injury in healthy volunteers....

  9. The role of apoptosis in cisplatin-induced ototoxicity in rats Papel da apoptose na ototoxicidade por cisplatina em ratos

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    Marcos Rabelo De Freitas

    2009-10-01

    Full Text Available Cisplatin is a chemotherapy agent frequently used to treat different types of neoplasia. Ototoxicity is one of the side-effects which cause significant morbidity and limits its use. This study aimed at assessing the role of apoptosis in cisplatin-induced ototoxicity. DESIGN: experimental study. MATERIALS AND METHODS: male Wistar rats were treated with intraperitoneal cisplatin, in the doses of 24 and 16 mg/kg. The animals were assessed by means of distortion product evoked otoacoustic emissions (DPEOAE or brainstem evoked auditory potentials (BEAP in the third (D3 and fourth (D4 days after drug infusion onset. Following that, their cochleas were removed for immunohistochemical studies of apoptosis - TUNEL method. RESULTS: the group treated with 24 mg/kg showed a significant reduction in DPEOAE amplitude, and such fact was not seen with the 16 mg/kg. Both doses caused an increase in BEAP electrophysiological threshold in D3 and D4. Apoptosis was the injury mechanism responsible for the cisplatin-induced ototoxicity - 16 mg/kg dose, when the animals were assessed on D3. CONCLUSION: apoptosis may be involved in the cisplatin-induced ototoxicity, depending on the dose and time of injury assessment.Cisplatina é um agente quimioterápico frequentemente usado para o tratamento de várias linhagens de neoplasias. A ototoxicidade é um dos efeitos colaterais causadores de significativa morbidade e que limita sua utilização. Este estudo teve por objetivo avaliar o papel da apoptose na ototoxicidade por cisplatina. DESENHO DO ESTUDO: Estudo experimental. MATERIAL E MÉTODO: Ratos Wistar machos foram tratados com cisplatina, via intraperitoneal, nas doses de 24 e 16 mg/kg. Os animais foram avaliados através de emissões otoacústicas evocadas produtos de distorção (EOAPD ou potenciais auditivos evocados de tronco encefálico (PAETE no terceiro (D3 e quarto (D4 dias após o início da infusão das drogas. Em seguida suas cócleas foram removidas para

  10. In vivo evidence suggesting a role for purine-catabolizing enzymes in the pathogenesis of cisplatin-induced nephrotoxicity in rats and effect of erdosteine against this toxicity.

    Science.gov (United States)

    Söğüt, Sadik; Kotuk, Mahir; Yilmaz, H Ramazan; Ulu, Ramazan; Ozyurt, Hüseyin; Yildirim, Zeki

    2004-01-01

    The aim of this experimental study was to investigate the possible role of adenosine deaminase (AD) and xanthine oxidase (XO) in the pathogenesis of cisplatin-induced nephrotoxicity and the effect of erdosteine in decreasing the toxicity. The intraperitoneal injection of cisplatin (7 mg kg(-1) body weight) induced a significant increase in plasma creatinine level and blood urea nitrogen (BUN), and plasma and damaged renal tissue activities of AD and XO in rats. Co-treatment with erdosteine (10 mg kg(-1)day(-1)) attenuated the increase in the plasma creatinine and BUN levels, and significantly prevented the increase in tissue and plasma AD and XO activities (Perdosteine may have protective potential in this process and it will become a promising drug in the prevention of this undesired side-effect of cisplatin, but further studies are needed to illuminate the exact protection mechanism of erdosteine against cisplatin-induced nephrotoxicity.

  11. Amelioration of cisplatin-induced nephrotoxicity by ethanolic extract of Bauhinia purpurea: An in vivo study in rats

    Directory of Open Access Journals (Sweden)

    Md Azmat Rana

    2016-01-01

    Full Text Available Our objective is to study the nephroprotective activity and antioxidant potential of Bauhinia purpurea unripe pods and bark against cisplatin-induced nephrotoxicity. Healthy adult albino rats of either sex (150-200 g were randomly divided into six groups of six animals each Group I (vehicle control and Group II (negative control. Group III (BBE200 and Group IV (BBE400 were administered the ethanolic extract of Bauhinia purpurea bark in doses of 200 and 400 mg/kg/day p.o., respectively, and Group V (BPE200 and Group VI (BPE400 were administered the ethanolic extract of Bauhinia purpurea unripe pods at doses of 200 and 400 mg/kg/day p.o., respectively. All the treatments were given for nine days. Cisplatin in a single dose of 6 mg/kg i.p. was given on the 4 th day to all groups, except the vehicle control group. On the 10 th day, blood and urine were collected for biochemical tests and the rats were sacrificed. The kidney was removed for histology and lipid peroxidation-antioxidant test. Cisplatin caused nephrotoxicity as evidenced by elevated blood urea, serum creatinine and urine glucose, and there was decreased creatinine clearance in Group II as compared with Group I. Administration of BBE and BPE at doses of 200 and 400 mg/kg in Group III and Group VI caused a dose-dependant reduction in the rise of blood urea, serum creatinine and urine glucose, and there was a dosedependant increase in creatinine clearance compared with Group II. There was increased catalase and glutathione and decreased malondialdehyde levels in Group II, while BBE 400 (Group IV and BPE 400 (Group VI treatments significantly reversed the changes toward normal values. Histological examination of the kidney revealed protection in Group IV and Group VI compared with Group II. The ethanolic extract of Bauhinia purpurea unripe pods and bark has a nephroprotective activity against cisplatin-induced nephrotoxicity in rats.

  12. Antioxidantes da dieta como inibidores da nefrotoxicidade induzida pelo antitumoral cisplatina Dietary antioxidants as inhibitors of cisplatin-induced nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Lusânia Maria Greggi Antunes

    2004-03-01

    Full Text Available A cisplatina é uma droga antineoplásica altamente efetiva contra vários tipos de cânceres humanos, tais como tumores do testículo e ovário, câncer da cabeça e pescoço e câncer do pulmão. Entretanto, a nefrotoxicidade é um dos principais efeitos colaterais da terapia com a cisplatina. A gravidade da nefrotoxicidade induzida pela cisplatina está relacionada com a concentração de platina nos rins. As evidências mostram que a nefrotoxicidade induzida pela cisplatina é atribuída ao dano oxidativo resultante da geração de radicais livres, e que a administração de antioxidantes é eficiente na inibição destes efeitos colaterais. Uma abordagem alternativa para proteger os roedores dos efeitos colaterais da cisplatina é o uso de conhecidos antioxidantes da dieta. Alguns estudos têm sido realizados para diminuir a peroxidação lipídica e os efeitos citotóxicos induzidos pela cisplatina, com o emprego de antioxidantes da dieta, tais como, selenito de sódio, vitaminas C e E, curcumina e o carotenóide bixina. Nós sugerimos que aqueles antioxidantes da dieta têm efeito nefroprotetor, e que os mecanismos antioxidantes destes compostos deveriam ser explorados durante a quimioterapia com a cisplatina.Cisplatin is a highly effective antineoplastic drug used against several types of human cancers, such as testicular and ovarian tumors; head and neck; and lung cancer. However, nephrotoxicity is one of the most important side-effects of cisplatin therapy. The severity of cisplatin nephrotoxicity is related to platinum concentration in the kidneys. There is a growing amount of evidence that cisplatin-induced nephrotoxicity is ascribed to oxidative damage resulting from free radical generation and that the administration of antioxidants is efficient in inhibiting these side effects. An alternative approach aiming to protect rodents against cisplatin side-effects is the introduction of known dietary antioxidants. Some studies have been

  13. Protective effect of cysteine and vitamin E, Crocus sativus and Nigella sativa extracts on cisplatin-induced toxicity in rats.

    Science.gov (United States)

    el Daly, E S

    1998-01-01

    Cisplatin [cis-dichlorodiammineplatinum (II)] is a widely used chemotherapeutic drug that is toxic to the kidney. Concurrent administration of cysteine together with vitamin E, Crocus sativus and Nigella sativa reduced the toxicity of cisplatin in rats. When administered i.p. for 5 alternate days with 3 mg/kg cisplatin, cysteine (20 mg/kg) together with vitamin E (2 mg/rat) an extract of Crocus sativus stigmas (50 mg/kg) and Nigella sativa seed (50 mg/kg) significantly reduced blood urea nitrogen (BUN) and serum creatinine levels as well as cisplatin-induced serum total lipids increases. In contrast, the protective agents given together with cisplatin led to an even greater decrease in blood glucose than that seen with cisplatin alone. The serum activities of alkaline phosphatase, lactate dehydrogenase, malate dehydrogenase, aspartate aminotransferase and alanine aminotransferase of cisplatin-treated rats were significantly decreased, whereas the activities of glutathione reductase and isocitrate dehydrogenase were significantly increased. Addition of cysteine and vitamin E, Crocus sativus and Nigella sativa in combination with cisplatin partially prevented many changes in the activities of serum enzymes. In cisplatin-treated rats, the liver activities of isocitrate dehydrogenase and aspartate aminotransferase were significantly increased, whereas much greater changes were found in the kidneys, with increased activity of glucose-6-phosphate dehydrogenase and decreased activities of alkaline phosphatase, isocitrate dehydrogenase, malate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, sorbitol dehydrogenase and gamma-glutamyl transferase, as well as a decreased phosphorylation to oxidation ratio in the mitochondria, indicating reduced adenosine triphosphate production. Also, administration of cysteine and vitamin E, Crocus sativus and Nigella sativa together with cisplatin partially reversed many of the kidney enzymes changes induced by cisplatin

  14. CCR9 interactions support ovarian cancer cell survival and resistance to cisplatin-induced apoptosis in a PI3K-dependent and FAK-independent fashion

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    Johnson Erica L

    2010-06-01

    Full Text Available Abstract Background Cisplatin is more often used to treat ovarian cancer (OvCa, which provides modest survival advantage primarily due to chemo-resistance and up regulated anti-apoptotic machineries in OvCa cells. Therefore, targeting the mechanisms responsible for cisplatin resistance in OvCa cell may improve therapeutic outcomes. We have shown that ovarian cancer cells express CC chemokine receptor-9 (CCR9. Others have also shown that CCL25, the only natural ligand for CCR9, up regulates anti-apoptotic proteins in immature T lymphocytes. Hence, it is plausible that CCR9-mediated cell signals might be involved in OvCa cell survival and inhibition of cisplatin-induced apoptosis. In this study, we investigated the potential role and molecular mechanisms of CCR9-mediated inhibition of cisplatin-induced apoptosis in OvCa cells. Methods Cell proliferation, vibrant apoptosis, and TUNEL assays were performed with or without cisplatin treatment in presence or absence of CCL25 to determine the role of the CCR9-CCL25 axis in cisplatin resistance. In situ Fast Activated cell-based ELISA (FACE assays were performed to determine anti-apoptotic signaling molecules responsible for CCL25-CCR9 mediated survival. Results Our results show interactions between CCR9 and CCL25 increased anti-apoptotic signaling cascades in OvCa cells, which rescued cells from cisplatin-induced cell death. Specifically, CCL25-CCR9 interactions mediated Akt, activation as well as GSK-3β and FKHR phosphorylation in a PI3K-dependent and FAK-independent fashion. Conclusions Our results suggest the CCR9-CCL25 axis plays an important role in reducing cisplatin-induced apoptosis of OvCa cells.

  15. Biochemical changes associated with ascorbic acid–cisplatin combination therapeutic efficacy and protective effect on cisplatin-induced toxicity in tumor-bearing mice

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    Amenla Longchar

    2015-01-01

    Full Text Available Cisplatin is one of the well-established anticancer drugs being used against a wide spectrum of cancers. However, full therapeutic efficacy of the drug is limited due to development of various toxicities in the host. This study examines the comparative therapeutic effectiveness and toxicities of cisplatin alone and in combination of dietary ascorbic acid (AA in ascites Dalton's lymphoma-bearing mice. The findings show that the combination treatment of mice with ascorbic acid plus cisplatin has much better therapeutic efficacy against murine ascites Dalton's lymphoma (DL in comparison to cisplatin alone and this may involve a decrease in reduced glutathione (GSH, catalase activity and increased lipid peroxidation (LPO in Dalton's lymphoma tumor cells. At the same time, combination treatment indicates a protective role of ascorbic acid against cisplatin-induced tissue toxicities (side effects in the hosts. Cisplatin-induced histopathological changes in liver, kidney and testes were decreased after combination treatment. The analysis of renal function test (RFT, liver function test (LFT and sperm abnormalities also suggest an improvement in these parameters after combination treatment. Therefore, it may be concluded that the increased GSH level, catalase activity and decreased LPO in the tissues, i.e., liver, kidney and testes after combination treatment may be involved in its protective ability against cisplatin-induced tissue toxicities in the host.

  16. The potential role of Azadirachta indica treatment on cisplatin-induced hepatotoxicity and oxidative stress in female rats.

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    Dkhil, Mohamed A; Al-Quraishy, Saleh; Aref, Ahmed M; Othman, Mohamed S; El-Deib, Kamal M; Abdel Moneim, Ahmed E

    2013-01-01

    Azadirachta indica A. Juss. (neem, family: Meliaceae) is perhaps the most commonly used traditional medicinal plant of India. In this study we investigated the protective effect of methanolic neem leaves extract (MNLE; 500 mg/Kg bwt) on rats treated with cisplatin (CDDP)-induced hepatotoxicity. Adult rats were randomly divided into four groups. CDDP was given to rats by intraperitoneal injection, while MNLE was given by oral gavage for 5 days after the CDDP injection. The injury and oxidative stress caused by CDDP on the liver and the effect of MNLE were evaluated by measuring (a) histological changes, (b) tissue biochemical oxidant and antioxidant parameters, and (c) investigating apoptosis markers immunohistochemically and by real time PCR. After treatment with MNLE, the histological damage and apoptosis induction caused by cisplatin were improved. Malondialdehyde and nitric oxide were significantly decreased; the antioxidant system, namely, glutathione content, glutathione-S-transferase, glutathione peroxidase, catalase, and superoxide dismutase activities were significantly elevated. In conclusion, MNLE may have a potential role when combined with cisplatin in chemotherapy to alleviate cisplatin-induced damage and oxidative stress in liver.

  17. Effects of Rhus tripartitum fruit extract on CCl4-induced hepatotoxicity and cisplatin-induced nephrotoxicity in rats.

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    Tlili, Nizar; Feriani, Anouar; Allagui, Mohamed Salah; Saadoui, Ezzeddine; Khaldi, Abdelhamid; Nasri, Nizar

    2016-08-01

    Rhus tripartitum D.C., Anacardiaceae, has traditionally been used in Tunisia against many illnesses. The present study investigates, for the first time, the protective effects of the methanol extract of Rhus tripartitum fruit (MERT) against CCl4-induced hepatotoxicity and cisplatin-induced nephrotoxicty in Wistar rats. ALT, AST, LDH, GGT, creatinin, urea, and uric acid levels were studied. The changes in antioxidant parameters such as malondialdehyde (MDA) and protein carbonyl contents were also determined. The increased levels of MDA (30.97 and 11.50 nmol MDA/mg protein in liver and kidney, respectively) and protein carbonyls (13.4 and 17.95 nmol/mg protein in liver and kidney, respectively) were attenuated by MERT pretreatment (19.35 and 6.1 nmol MDA/mg protein and 9.15 and 12 nmol/mg protein in liver and kidney, respectively). The MERT pretreatment significantly reduced the increased biochemical parameters of liver and kidney caused by CCl4 and cisplatin treatment. The histopathologic observation showed that MERT pretreatment restores the altered tissues. The observed results could be due to the high phenolic content and to MERT's important antioxidant potential. This study supports the hepatoprotective and nephroprotective effects of R. tripartitum.

  18. The Potential Role of Azadirachta indica Treatment on Cisplatin-Induced Hepatotoxicity and Oxidative Stress in Female Rats

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    Mohamed A. Dkhil

    2013-01-01

    Full Text Available Azadirachta indica A. Juss. (neem, family: Meliaceae is perhaps the most commonly used traditional medicinal plant of India. In this study we investigated the protective effect of methanolic neem leaves extract (MNLE; 500 mg/Kg bwt on rats treated with cisplatin (CDDP-induced hepatotoxicity. Adult rats were randomly divided into four groups. CDDP was given to rats by intraperitoneal injection, while MNLE was given by oral gavage for 5 days after the CDDP injection. The injury and oxidative stress caused by CDDP on the liver and the effect of MNLE were evaluated by measuring (a histological changes, (b tissue biochemical oxidant and antioxidant parameters, and (c investigating apoptosis markers immunohistochemically and by real time PCR. After treatment with MNLE, the histological damage and apoptosis induction caused by cisplatin were improved. Malondialdehyde and nitric oxide were significantly decreased; the antioxidant system, namely, glutathione content, glutathione-S-transferase, glutathione peroxidase, catalase, and superoxide dismutase activities were significantly elevated. In conclusion, MNLE may have a potential role when combined with cisplatin in chemotherapy to alleviate cisplatin-induced damage and oxidative stress in liver.

  19. Cisplatin-Induced Non-Oliguric Acute Kidney Injury in a Pediatric Experimental Animal Model in Piglets.

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    Maria José Santiago

    Full Text Available To design an experimental pediatric animal model of acute kidney injury induced by cisplatin.Prospective comparative observational animal study in two different phases. Acute kidney injury was induced using three different doses of cisplatin (2, 3 and 5 mg/kg. The development of nephrotoxicity was assessed 2 to 4 days after cisplatin administration by estimating biochemical parameters, diuresis and renal morphology. Analytical values and renal morphology were compared between 15 piglets treated with cisplatin 3 mg/kg and 15 control piglets in the second phase of the study.41 piglets were studied. The dose of 3 mg/kg administered 48 hours before the experience induced a significant increase in serum creatinine and urea without an increase in potassium levels. Piglets treated with cisplatin 3 mg/kg had significantly higher values of creatinine, urea, phosphate and amylase, less diuresis and lower values of potassium, sodium and bicarbonate than control piglets. Histological findings showed evidence of a dose-dependent increase in renal damage.a dose of 3 mg/kg of cisplatin induces a significant alteration in renal function 48 hours after its administration, so it can be used as a pediatric animal model of non-oliguric acute kidney injury.

  20. Protective effects of the aqueous leaf extract of Aloe barbadensis on gentamicin and cisplatin-induced nephrotoxic rats

    Institute of Scientific and Technical Information of China (English)

    Paoulomi Chatterjee﹡; Aniruddha Mukherjee; Subhangkar Nandy

    2012-01-01

    Objective: To study the protective effects of the aqueous leaf extract of Aloe barbadensis (AEAB) on gentamicin and Cisplatin-induced nephrotoxic Wistar rats. Methods: In each model of nephrotoxicity, thirty adult male Wistar rats were evenly divided into 5 groups. Groups I and II served as untreated and model controls, respectively while groups III-V were the treatment groups which were pretreated with 100-200 mg/kg bodyweight per day of AEAB 1 h before each dose of the nephrotoxicants. On the 8th day(in case of gentamicin) and on 6th day(in case of Cisplatin), blood samples for serum urea, total protein and creatinine as well as some ions like sodium, potassium, chloride and uric acid while the rat kidneys for histology were obtained under inhaled diethyl ether anesthesia. Results: In the gentamicin nephrotoxic rats, 100-200 mg/kg bodyweight per day significantly attenuated elevations in the serum creatinine, total protein and blood urea nitrogen levels in dose related fashion and no treatment related effect on uric acid and ions, and attenuated the gentamicin-induced tubulonephrosis. Similar effects were also recorded in the Cisplatin model of acute renal injury. Conclusions:The nephroprotective effect of AEAB could be due to the inherent antioxidant and free-radical-scavenging principle(s) contained in the extract.In the near future, AEAB could constitute a lead to discovery of a novel drug for the treatment of drug-induced nephrotoxicity.

  1. Rutin ameliorates cisplatin-induced reproductive damage via suppression of oxidative stress and apoptosis in adult male rats.

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    Aksu, E H; Kandemir, F M; Özkaraca, M; Ömür, A D; Küçükler, S; Çomaklı, S

    2017-02-01

    Cisplatin (CP) treatment causes damage in the male reproductive system. Rutin (RUT) is a naturally occurring flavonoid glycoside that has antioxidant and anti-inflammatory properties. This study aimed to investigate effects of RUT against cisplatin-induced reproductive toxicity in male rats. Twenty-one adult male Sprague Dawley rats were used. The control group received physiological saline with oral gavage during 14 days, and physiological saline was injected intraperitoneally (IP) in 10th days of study. CP Group received physiological saline during 14 days, and 10 mg kg(-1) CP was injected IP in 10th day. RUT + CP group received RUT (150 mg kg(-1) ) during 14 days, and 10 mg kg(-1) CP was injected IP in 10th day. Spermatological parameters (including motility, cauda epididymal sperm density, dead sperm percentage and morphological sperm abnormalities), biochemical (MDA, GSH, GSH-px, SOD and CAT), histological (H&E dye) and immunochemistry evaluations of testicles were evaluated. CP treatment caused damage on some spermatological parameters, increased the oxidative stress and induced testicular degeneration and apoptosis when compared to the control group. However, RUT treatment mitigates these side effects when compared to the CP alone group. IT is concluded that RUT treatment may reduce CP-induced reproductive toxicity as a potential antioxidant compound.

  2. EZH2-mediated Puma gene repression regulates non-small cell lung cancer cell proliferation and cisplatin-induced apoptosis.

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    Liu, Haidan; Li, Wei; Yu, Xinfang; Gao, Feng; Duan, Zhi; Ma, Xiaolong; Tan, Shiming; Yuan, Yunchang; Liu, Lijun; Wang, Jian; Zhou, Xinmin; Yang, Yifeng

    2016-08-30

    Polycomb group (PcG) proteins are highly conserved epigenetic effectors that maintain the silenced state of genes. EZH2 is the catalytic core and one of the most important components of the polycomb repressive complex 2 (PRC2). In non-small cell lung cancer (NSCLC) cells and primary lung tumors, we found that PRC2 components, including EZH2, are overexpressed. High levels of EZH2 protein were associated with worse overall survival rate in NSCLC patients. RNA interference mediated attenuation of EZH2 expression blunted the malignant phenotype in this setting, exerting inhibitory effects on cell proliferation, anchorage-independent growth, and tumor development in a xenograft mouse model. Unexpectedly, we discovered that, in the suppression of EZH2, p53 upregulated modulator of apoptosis (PUMA) expression was concomitantly induced. This is achieved through EZH2 directly binds to the Puma promoter thus epigenetic repression of PUMA expression. Furthermore, cisplatin-induced apoptosis of EZH2-knocking down NSCLC cells was elevated as a consequence of increased PUMA expression. Our work reveals a novel epigenetic regulatory mechanism controlling PUMA expression and suggests that EZH2 offers a candidate molecular target for NSCLC therapy and EZH2-regulated PUMA induction would synergistically increase the sensitivity to platinum agents in non-small cell lung cancers.

  3. Andrographolide sensitizes cisplatin-induced apoptosis via suppression of autophagosome-lysosome fusion in human cancer cells.

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    Zhou, Jing; Hu, Shuai-Er; Tan, Shi-Hao; Cao, Ruoxi; Chen, Yiyang; Xia, Dajing; Zhu, Xinqiang; Yang, Xing-Fen; Ong, Choon-Nam; Shen, Han-Ming

    2012-03-01

    Suppression of autophagy has been increasingly recognized as a novel cancer therapeutic approach. Andrographolide (Andro), a diterpenoid lactone isolated from an herbal plant Andrographis paniculata, is known to possess anti-inflammatory and anticancer activity. In this study, we sought to examine the effect of Andro on autophagy, and to evaluate whether such effect is relevant to the sensitization effect of Andro on apoptosis induced by DNA damage agents in cancer cells. First, we found that Andro is able to significantly enhance autophagic markers in various cancer cell lines, including GFP-LC3 puncta and LC3-II level. Interestingly, Andro treatment also led to marked increase of p62 protein level and addition of chloroquine (CQ) failed to further enhance either LC3-II or p62 level, indicating that Andro is likely to suppress autophagic flux at the maturation and degradation stage. Next, we provided evidence that Andro inhibits autophagosome maturation not by affecting the lysosomal function, but by impairing autophagosome-lysosome fusion. Lastly, we demonstrated that treatment with cisplatin, a DNA damage agent, induces autophagy in cancer cells. Importantly, Andro is capable of sensitizing cisplatin-induced cell killing determined with both short-term apoptosis assays and long-term clonogenic test, via suppression of autophagy, a process independent of p53. In summary, these observations collectively suggest that Andro could be a promising anti-cancer agent in combination therapy via its potent inhibitory effect on autophagy by disrupting autophagosome-lysosome fusion.

  4. Involvement of spinal somatostatin receptor SST(2A) in inflammation-induced thermal hyperalgesia: ultrastructural and behavioral studies in rats.

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    Zhao, Jun; Hu, Jiang-Yuan; Zhang, Yu-Qiu; Zhao, Zhi-Qi

    2008-10-01

    Our previous results have shown that somatostatin receptor subtype SST(2A) is responsible for thermal, but not mechanical nociceptive transmission in the rat spinal cord. The present study was undertaken to further examine the ultrastructural localization of SST(2A) receptor in lamina II of the spinal dorsal horn and the role of SST(2A) receptor in thermal hyperalgesia following Complete Freund's Adjuvant (CFA)-induced inflammation. We found that SST(2A) receptors in lamina II are located primarily in postsynaptic dendrites and soma, but not in axons or synaptic terminals. CFA-induced inflammation markedly increased SST(2A) receptor-like immunoreactivity in lamina II. Paw withdrawal latency (PWL) evoked by noxious heating was obviously shortened 1 h after intraplantar injection of CFA, exhibiting thermal hyperalgesia. Pre-blocking SST(2A) activity by intrathecal pre-administration of CYN154806, a broad-spectrum antagonist of SST(2) receptor, or specific antiserum against SST(2A) receptor (anti-SST(2A)) significantly attenuated thermal hyperalgesia in a dose-dependent fashion in CFA-treated rats. But, administration of anti-SST(2A) or CYN154806 after CFA treatment had no effect upon thermal hyperalgesia. Intrathecal application of SST(2A) agonist SOM-14 at different doses prior to CFA treatment did not influence thermal hyperalgesia in inflamed rats, but at a low dose shortened PWL evoked by noxious heating in normal rats. These results suggest that spinal SST(2A) receptors play a key role in triggering the generation, but not maintenance, of thermal hyperalgesia evoked by CFA-induced inflammation. The up-regulation of SST(2A) receptors in the spinal cord may be one of the mechanisms underlying inflammation-induced thermal hyperalgesia.

  5. Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin.

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    Ma, Junxiong; Yu, Hailong; Liu, Jun; Chen, Yu; Wang, Qi; Xiang, Liangbi

    2015-10-05

    Painful diabetic neuropathy is a common complication of diabetes mellitus, which often makes the patients suffer from severe hyperalgesia and allodynia. Thus far, the treatment of painful diabetic neuropathy remains unsatisfactory. Metformin, which is the first-line drug for type-2 diabetes, has been proved to attenuate hyperexcitability in sensory neurons linked to chemotherapy-induced neuropathic pain, highlighting its potential in alleviating pain related with painful diabetic neuropathy. The present study was designed to investigate the potential beneficial effect of metformin on hyperalgesia and allodynia in diabetic rats. The mechanical sensitivity, heat nociception, and cold allodynia were examined. The levels of malondialdehyde, superoxide dismutase, and advanced glycation end-products in the blood were measured. The expression of adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and AMPK target genes were examined in the sciatic nerves of the animals. It was found that metformin was capable of attenuating diabetes-induced mechanical hyperalgesia, heat hyperalgesia and cold allodynia. In addition, metformin was capable of decreasing malondialdehyde and glycation end-products levels in blood, as well as increasing superoxide dismutas activity, indicating the inhibitory effect of metformin against diabetes-induced oxidative stress. Further studies showed that metformin could activate AMPK and increase the AMPK target genes in sciatic nerves in diabetic rats. In conclusion, metformin is able to attenuate diabetes-induced hyperalgesia and allodynia, which might be associated its anti-oxidative effect through AMPK pathway. Metformin might be used as an effective drug, especially with fewer side effects, for abnormal sensation in painful diabetic neuropathy.

  6. Dissociable neural activity to self- vs. externally administered thermal hyperalgesia: a parametric fMRI study.

    Science.gov (United States)

    Mohr, C; Leyendecker, S; Helmchen, C

    2008-02-01

    Little is known regarding how cognitive strategies help to modulate neural responses of the human brain in ongoing pain syndromes to alleviate pain. Under pathological pain conditions, any self-elicited contact with usually non-painful stimuli may become painful. We examined whether the human brain is capable of dissociating self-controlled from externally administered thermal hyperalgesia in the experimental capsaicin model. Using functional magnetic resonance imaging, 17 male subjects were investigated in a parametric design with heat stimuli at topically capsaicin-sensitized skin. In contrast to external stimulation, self-administered pain was controllable. For both conditions application trials without noticeable thermal stimulation were introduced and used as high-level baseline (HLB) to account for the capsaicin-induced ongoing pain and other covariables. Following subtraction of the HLB, the anterior insula and the anterior cingulate cortex (ACC) but not the somatosensory cortices maintained parametric neural responses to thermal hyperalgesia. A stronger pain-related activity increase during self-administered stimuli was observed in the posterior insula. In contrast, prefrontal cortex showed stronger increases to uncontrollable external heat stimuli. In the state of ongoing pain (capsaicin), pain-intensity-encoding regions (anterior insula, ACC) but not those with sensory discriminative functions (SI, SII) showed graded, pain-intensity-related neural responses in thermal hyperalgesia. Some areas were able to dissociate between self- and externally administered stimuli in thermal hyperalgesia, which might be related to differences in perceived controllability. Thus, neural mechanisms maintain the ability to dissociate external from self-generated states of injury in thermal hyperalgesia. This may help to understand how cognitive strategies potentially alleviate chronic pain syndromes.

  7. The Effects of Nifedipine on Renal Perfusion Pressure and Kidney During Cisplatin-Induced Nephrotoxicity in Rats

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    Meral Erdinç

    2007-01-01

    Full Text Available Cisplatin is one of the most effective cancer chemotherapeutic agent used against various solid tumors. Nephrotoxicity is one of the major dose-limiting side effects of cisplatin. It has been known that different mechanisms as oxidative stress may play an important role in cisplatin induced nephrotoxicity resulted with changes in renal haemodynamics. This study was performed to investigate the effect of nifedipine –one of the dihydropyridine calcium antagonist on changes in renal perfusion pressures and kidneys of rats with cisplatin nephrotoxicity. Male wistar albino rats were divided into 3 groups (n=8:1-Control group(1 ml saline. i.p 2-Cisplatin group (a single dose of cisplatin (5 mg/kg, i.p 3- A single dose of cisplatin (5 mg/kg, i.p + Nifedipine (2 mg/kg/day, i.p for five days. When those pre-treated groups compared with control group, perfusion pressures, serum urea and creatinine levels and tissue MDA levels were found significantly higher in cisplatin group (p<0.001. Histopathological examination showed widespread tubular necrosis and dilatation in cisplatin-treated group versus other groups. In cisplatin + nifedipine pretreated group, perfusion pressures, serum urea and creatinine levels and tissue MDA levels found significantly lower than cisplatin group (p<0. 001 and less tubular dilatation and necrosis was observed. As a result it was demonstrated that Nifedipine has protective effects against cisplatin nephrotoxicity. We suggest that this is partly provided by the beneficial effects of nifedipine on altered renal haemodynamics during cisplatin nephrotoxicity.

  8. Chemoprotective effect of a nuclear factor-kappaB inhibitor, pyrrolidine dithiocarbamate, against cisplatin-induced testicular damage in rats.

    Science.gov (United States)

    Ilbey, Yusuf Ozlem; Ozbek, Emin; Simsek, Abdulmuttalip; Cekmen, Mustafa; Otunctemur, Alper; Somay, Adnan

    2009-01-01

    The objective of this study was to evaluate inducible nitric oxide synthase (iNOS) and nuclear factor-kappaB inhibitor (NF-kappaB) expression and the potential chemoprotective effects of an NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), against cisplatin-induced testicular damage in rats. Rats were divided into 4 equal groups: group 1, control; group 2, injected with cisplatin (CIS) for 5 days (7 mg/kg/day intraperitoneally [IP]); group 3, injected with PDTC alone; group 4, injected with CIS plus PDTC (100 mg/kg IP). Body and testicular weights, plasma testosterone levels, and histopathologic structure of the testicular tissue were determined. The iNOS and NF-kappaB activity were evaluated immunohistochemically by staining p65 to define NF-kappaB activity. Malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO) levels and glutathione peroxidase (GSH-Px) activity were assessed in testicular tissue. Body and testicular weights, plasma testosterone levels, activity of GSH-Px, and GSH levels were all significantly decreased, whereas the levels of MDA and NO were significantly increased in rats of the CIS group. PDTC treatment increased plasma testosterone levels. A significant increase in GSH levels and GSH-Px activity and a decrease in MDA and NO levels in testicular tissue were observed in the CIS + PDTC group. Immunohistochemically, there was a marked staining for iNOS and NF-kappaB/p65 expression in rats injected with CIS compared with the control (P < .001). CIS caused irregular seminiferous tubules, reduction of seminiferous epithelial layers, significant arrest of maturation, and perivascular fibrosis. Moreover, PDTC administration to CIS-treated rats significantly prevented these histopathologic chances, as well. CIS induces iNOS expression through activation of NF-kappaB/p65, and CIS-induced testicular toxicity may be prevented by PDTC, which is a selective NF-kappaB inhibitor.

  9. The peroxisome proliferator-activated receptor-γ agonist pioglitazone protects against cisplatin-induced renal damage in mice.

    Science.gov (United States)

    Jesse, Cristiano R; Bortolatto, Cristiani F; Wilhelm, Ethel A; Roman, Silvane Souza; Prigol, Marina; Nogueira, Cristina W

    2014-01-01

    Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists not only improve metabolic abnormalities of diabetes and consequent diabetic nephropathy, but they also protect against non-diabetic kidney disease in experimental models. Here, we investigated the effect of PPAR-γ agonist pioglitazone against acute renal injury on a cisplatin model in mice. Nephrotoxicity was induced by a single intraperitoneal (i.p.) injection of cisplatin (10 mg kg(-1)). Pioglitazone was administered for six consecutive days in doses of 15 or 30 mg kg(-1)  day(-1), per os (p.o.), starting 3 days before cisplatin injection. Cisplatin treatment to mice induced a marked renal failure, characterized by a significant increase in serum urea and creatinine levels and alterations in renal tissue architecture. Cisplatin exposure induced oxidative stress as indicated by decreased levels of non-enzymatic antioxidant defenses [glutathione (GSH) and ascorbic acid levels] and components of the enzymatic antioxidant defenses [superoxide dismutase (SOD), catalase (CAT) glutathione peroxidase (GPx), glutathione reductase (GR) and and glutathione S-transferase(GST) activities)] in renal tissue. Administration of pioglitazone markedly protected against the increase in urea and creatinine levels and histological alterations in kidney induced by cisplatin treatment. Pioglitazone administration ameliorated GSH and ascorbic acid levels decreased by cisplatin exposure in mice. Pioglitazone protected against the inhibition of CAT, SOD, GPx, GR and GST activities induced by cisplatin in the kidneys of mice. These results indicated that pioglitazone has a protective effect against cisplatin-induced renal damage in mice. The protection is mediated by preventing the decline of antioxidant status. The results have implications in use of PPAR-γ agonists in human application for protecting against drugs-induced nephrotoxicity.

  10. Nerve growth factor induced hyperalgesia in the rat hind paw is dependent on circulating neutrophils.

    Science.gov (United States)

    Bennett, G; al-Rashed, S; Hoult, J R; Brain, S D

    1998-09-01

    The mechanisms by which nerve growth factor (NGF) induces thermal hyperalgesia and neutrophil accumulation have been investigated in the rat. Thermal nociceptive thresholds in rat hind paw were measured as the time taken for paw withdrawal from a heat source and neutrophil accumulation was measured in hind paw and dorsal skin samples using a myeloperoxidase assay. NGF (23-80 pmol intraplantar (i.pl.) injection) induced a significant (P NGF (40 pmol). In dorsal skin, where multiple samples can be assessed, intradermal (i.d.) NGF was 10-30 times less potent than interleukin-1beta in inducing neutrophil accumulation. The 5-lipoxygenase inhibitor ZM230487 (10 nmol co-injected with NGF) significantly attenuated neutrophil accumulation and hyperalgesia induced by NGF; unlike the histamine and 5-hydroxytryptamine antagonists (mepyramine and methysergide) which were without effect at the times measured. Furthermore, depletion of circulating neutrophils (using a rabbit anti-rat neutrophil antibody) abolished NGF induced hyperalgesia. These results indicate that neutrophils, which accumulate in response to a 5-lipoxygenase product, play a crucial role in NGF-induced hyperalgesia.

  11. Nordihydroguaiaretic acid ameliorates cisplatin induced nephrotoxicity and potentiates its anti-tumor activity in DMBA induced breast cancer in female Sprague-Dawley rats.

    Science.gov (United States)

    Mundhe, Nitin Arunrao; Kumar, Parveen; Ahmed, Sahabuddin; Jamdade, Vinayak; Mundhe, Sanjay; Lahkar, Mangala

    2015-09-01

    Cisplatin is a widely used antineoplastic drug, but its clinical usefulness is limited due to dose dependent nephrotoxicity. Nordihydroguaiaretic acid (NDGA) is a natural compound with broad pharmacological properties like antioxidant, anti-inflammatory and anticancer activity. The present study was undertaken to evaluate the possible beneficial effects of NDGA on cisplatin induced nephrotoxicity as well as its anticancer activity in rats bearing DMBA induced mammary tumors. The effect of NDGA on cisplatin induced nephrotoxicity was evaluated by checking serum nephrotoxicity markers, antioxidant enzymes and inflammatory markers level and kidney histopathology. NDGA induced amelioration of cisplatin nephrotoxicity was clearly visible from significant reductions in serum blood urea nitrogen (86.51 g/dl) and creatinine (5.30 g/dl) levels and significant improvement in body weight change (-10.34 g) and kidney weight (728 mg/kg). The protective effect of NDGA against cisplatin induced nephrotoxicity in the rats was further confirmed by significant restoration of antioxidant enzymes like SOD (86.28% inhibition), inflammatory markers like TNF-α (34.6 pg/ml) and histopathological examination. Moreover, our results showed that NDGA potentiated anti-breast cancer activity of cisplatin through an increment in the expression of antioxidant enzymes like SOD (85.35% inhibition) in breast cancer tissue. These results indicated that NDGA potentiated the anti-breast cancer activity of cisplatin, which was clearly evident from the tumor volume and % tumor inhibition in breast cancer rats. The current study demonstrated that NDGA may modify the therapeutic effect of cisplatin in DMBA induced breast cancer in female Sprague-Dawley rats.

  12. Ameliorative effect of fisetin on cisplatin-induced nephrotoxicity in rats via modulation of NF-κB activation and antioxidant defence.

    Science.gov (United States)

    Sahu, Bidya Dhar; Kalvala, Anil Kumar; Koneru, Meghana; Mahesh Kumar, Jerald; Kuncha, Madhusudana; Rachamalla, Shyam Sunder; Sistla, Ramakrishna

    2014-01-01

    Nephrotoxicity is a dose-dependent side effect of cisplatin limiting its clinical usage in the field of cancer chemotherapy. Fisetin is a bioactive flavonoid with recognized antioxidant and anti-inflammatory properties. In the present study, we investigated the potential renoprotective effect and underlying mechanism of fisetin using rat model of cisplatin-induced nephrotoxicity. The elevation in serum biomarkers of renal damage (blood urea nitrogen and creatinine); degree of histopathological alterations and oxidative stress were significantly restored towards normal in fisetin treated, cisplatin challenged animals. Fisetin treatment also significantly attenuated the cisplatin-induced IκBα degradation and phosphorylation and blocked the NF-κB (p65) nuclear translocation, with subsequent elevation of pro-inflammatory cytokine, TNF-α, protein expression of iNOS and myeloperoxidase activities. Furthermore, fisetin markedly attenuated the translocation of cytochrome c protein from the mitochondria to the cytosol; decreased the expression of pro-apoptotic proteins including Bax, cleaved caspase-3, cleaved caspase-9 and p53; and prevented the decline of anti-apoptotic protein, Bcl-2. The cisplatin-induced mRNA expression of NOX2/gp91phox and NOX4/RENOX and the NADPH oxidase enzyme activity were also significantly lowered by fisetin treatment. Moreover, the evaluated mitochondrial respiratory enzyme activities and mitochondrial antioxidants were restored by fisetin treatment. Estimation of platinum concentration in kidney tissues revealed that fisetin treatment along with cisplatin did not alter the cisplatin uptake in kidney tissues. In conclusion, these findings suggest that fisetin may be used as a promising adjunct candidate for cisplatin use.

  13. Ameliorative effect of fisetin on cisplatin-induced nephrotoxicity in rats via modulation of NF-κB activation and antioxidant defence.

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    Bidya Dhar Sahu

    Full Text Available Nephrotoxicity is a dose-dependent side effect of cisplatin limiting its clinical usage in the field of cancer chemotherapy. Fisetin is a bioactive flavonoid with recognized antioxidant and anti-inflammatory properties. In the present study, we investigated the potential renoprotective effect and underlying mechanism of fisetin using rat model of cisplatin-induced nephrotoxicity. The elevation in serum biomarkers of renal damage (blood urea nitrogen and creatinine; degree of histopathological alterations and oxidative stress were significantly restored towards normal in fisetin treated, cisplatin challenged animals. Fisetin treatment also significantly attenuated the cisplatin-induced IκBα degradation and phosphorylation and blocked the NF-κB (p65 nuclear translocation, with subsequent elevation of pro-inflammatory cytokine, TNF-α, protein expression of iNOS and myeloperoxidase activities. Furthermore, fisetin markedly attenuated the translocation of cytochrome c protein from the mitochondria to the cytosol; decreased the expression of pro-apoptotic proteins including Bax, cleaved caspase-3, cleaved caspase-9 and p53; and prevented the decline of anti-apoptotic protein, Bcl-2. The cisplatin-induced mRNA expression of NOX2/gp91phox and NOX4/RENOX and the NADPH oxidase enzyme activity were also significantly lowered by fisetin treatment. Moreover, the evaluated mitochondrial respiratory enzyme activities and mitochondrial antioxidants were restored by fisetin treatment. Estimation of platinum concentration in kidney tissues revealed that fisetin treatment along with cisplatin did not alter the cisplatin uptake in kidney tissues. In conclusion, these findings suggest that fisetin may be used as a promising adjunct candidate for cisplatin use.

  14. Hydroxyl radical scavenger ameliorates cisplatin-induced nephrotoxicity by preventing oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria.

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    Santos, N A G; Bezerra, C S Catão; Martins, N M; Curti, C; Bianchi, M L P; Santos, A C

    2008-01-01

    Nephrotoxicity is the major dose-limiting factor of cisplatin chemotherapy. Reactive oxygen species generated in mitochondria are thought to be the main cause of cellular damage in such injury. The present study examined, in vivo, the protective potential of the hydroxyl radical scavenger dimethylthiourea (DMTU) against cisplatin-induced effects on renal mitochondrial bioenergetics, redox state and oxidative stress. Adult male Wistar rats (200 to 220 g) were divided into four groups of eight animals each. The control group was treated only with an intraperitoneal (i.p.) injection of saline solution (1 ml/100 g body weight). The second group was given only DMTU (500 mg/kg body weight, i.p, followed by 125 mg/Kg, i.p., twice a day until they were killed). The third group was given a single injection of cisplatin (10 mg/kg body weight, i.p.). The fourth group was given DMTU (500 mg/kg body weight, i.p.), just before the cisplatin injection (10 mg/kg body weight, i.p.), followed by injections of DMTU (125 mg/kg body weight, i.p.) twice a day until they were killed. Animals were killed 72 h after the treatment. Besides not presenting any direct effect on mitochondria, DMTU substantially inhibited cisplatin-induced mitochondrial injury and cellular death by apoptosis, suppressing the occurrence of acute renal failure. All the following cisplatin-induced effects were prevented by DMTU: (1) increased plasmatic levels of creatinine and blood urea nitrogen (BUN); (2) decreased ATP content, calcium uptake and electrochemical potential; (3) oxidation of lipids, including cardiolipin; and oxidation of proteins, including sulfhydryl, and aconitase enzyme, as well as accumulation of carbonyl proteins; (4) depletion of the antioxidant defense (NADPH and GSH) and (5) increased activity of the apoptosis executioner caspase-3. Our findings show the important role played by mitochondria and hydroxyl radicals in cisplatin-induced nephrotoxicity, as well as the effectiveness of DMTU in

  15. Long Term Study of Protective Mechanisms of Human Adipose Derived Mesenchymal Stem Cells on Cisplatin Induced Kidney injury in Sprague-Daweley Rats

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    Elhusseini FM

    2016-05-01

    Full Text Available Background/Aims: Long-term evaluation of cisplatin induced nephrotoxicity and the probable renal protective activities of stem cells are lacking up until now. We evaluated the early and long-term role of human adipose derived mesenchymal stem cells (ADMSCs in prevention or amelioration of cisplatin induced acute kidney injury (AKI in Sprague-Dawley rats. For this, we determined the kidney tissue level of oxidative stress markers in conjugation with a renal histopathological scoring system of both acute and chronic renal changes. Methods: This study used eighty Sprague-Dawley (SD rats weighing 250-300g. They were assigned into four equal groups (each group n=20: (I Negative control group, rats injected with single dose of 1 ml normal saline. (II Positive control cisplatin, rats injected with a single dose of 5 mg/kg I.P in 1 ml saline. (III Cisplatin and culture media group, rats injected with 0.5 ml of culture media single dose into the tail vein and (IV Cisplatin and ADMSCs group, rats injected with a single dose of 0.5 ml of culture media containing 5 x106ADMSCs into the tail vein one day after cisplatin administration. Each main group was further divided according to the timing of sacrifice into four subgroups (each subgroup n=5. Rats in the subgroup A were sacrificed after 4 days; subgroup B were sacrificed after 7 days; subgroup C were sacrificed after 11 days; and subgroup D were sacrificed after 30 days. Before sacrifice, 24 hrs.-urine was collected using a metabolic cage. Renal function was evaluated through blood urea nitrogen (BUN, serum creatinine and creatinine clearance. Kidney tissue homogenate oxidative stress parameters, Malondialdehyde (MDA, Superoxide dismutase (SOD and Glutathione (GSH were determined. In addition, histopathological analysis for active injury, regenerative and chronic changes was performed. Results: ADMSCs were characterized and their capability of differentiation was proved. Cisplatin induced a significant

  16. Chrysin protects against cisplatin-induced colon. toxicity via amelioration of oxidative stress and apoptosis: Probable role of p38MAPK and p53

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    Khan, Rehan; Khan, Abdul Quaiyoom; Qamar, Wajhul; Lateef, Abdul; Tahir, Mir; Rehman, Muneeb U; Ali, Farrah; Sultana, Sarwat, E-mail: sarwat786@rediffmail.com

    2012-02-01

    Cisplatin, an antineoplastic drug, is widely used as a foremost therapy against numerous forms of cancer but it has pronounced adverse effects viz., nephrotoxicity, ototoxicity etc. CDDP-induced emesis and diarrhea are also marked toxicities that may be due to intestinal injury. Chrysin (5,7-dihydroxyflavone), a natural flavone commonly found in many plants possesses multiple biological activities, such as antioxidant, anti-inflammatory and anti-cancer effects. In the present study, we investigated the protective effect of chrysin against CDDP-induced colon toxicity. The plausible mechanism of CDDP-induced colon toxicity and damage includes oxidative stress, activation of p38MAPK and p53, and colonic epithelial cell apoptosis via upregulating the expression of Bak and cleaved caspase-3. Chrysin was administered to Wistar rats once daily for 14 consecutive days at the doses of 25 and 50 mg/kg body weight orally in corn oil. On day 14, a single intraperitoneal injection of cisplatin was given at the dose of 7.5 mg/kg body weight and animals were euthanized after 24 h of cisplatin injection. Chrysin ameliorated CDDP-induced lipid peroxidation, xanthine oxidase activity, glutathione depletion, decrease in antioxidant (catalase, glutathione reductase, glutathione peroxidase and glucose-6 phosphate dehydrogenase) and phase-II detoxifying (glutathione-S-transferase and quinone reductase) enzyme activities. Chrysin also attenuated goblet cell disintegration, expression of phospho-p38MAPK and p53, and apoptotic tissue damage which were induced by CDDP. Histological findings further supported the protective effects of chrysin against CDDP-induced colonic damage. The results of the present study suggest that the protective effect of chrysin against CDDP-induced colon toxicity was related with attenuation of oxidative stress, activation of p38MAPK and p53, and apoptotic tissue damage. Highlights: ► Cisplatin-induced colon toxicity is associated with oxidative stress and

  17. Fear of pain potentiates nocebo hyperalgesia

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    Aslaksen PM; Lyby PS

    2015-01-01

    Per M Aslaksen,1 Peter S Lyby2 1Department of Psychology, Research Group for Cognitive Neuroscience, The Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway; 2Catosenteret Rehabilitation Center, Son, Norway Abstract: Nocebo hyperalgesia has received sparse experimental attention compared to placebo analgesia. The aim of the present study was to investigate if personality traits and fear of pain could predict experimental noc...

  18. Subjects with Knee Osteoarthritis Exhibit Widespread Hyperalgesia to Pressure and Cold.

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    Penny Moss

    Full Text Available Hyperalgesia to mechanical and thermal stimuli are characteristics of a range of disorders such as tennis elbow, whiplash and fibromyalgia. This study evaluated the presence of local and widespread mechanical and thermal hyperalgesia in individuals with knee osteoarthritis, compared to healthy control subjects. Twenty-three subjects with knee osteoarthritis and 23 healthy controls, matched for age, gender and body mass index, were recruited for the study. Volunteers with any additional chronic pain conditions were excluded. Pain thresholds to pressure, cold and heat were tested at the knee, ipsilateral heel and ipsilateral elbow, in randomized order, using standardised methodology. Significant between-groups differences for pressure pain and cold pain thresholds were found with osteoarthritic subjects demonstrating significantly increased sensitivity to both pressure (p = .018 and cold (p = .003 stimuli, compared with controls. A similar pattern of results extended to the pain-free ipsilateral ankle and elbow indicating widespread pressure and cold hyperalgesia. No significant differences were found between groups for heat pain threshold, although correlations showed that subjects with greater sensitivity to pressure pain were also likely to be more sensitive to both cold pain and heat pain. This study found widespread elevated pain thresholds in subjects with painful knee osteoarthritis, suggesting that altered nociceptive system processing may play a role in ongoing arthritic pain for some patients.

  19. Comparative analysis of cisplatin-induced nephrotoxicity in head and neck cancer and carcinoma cervix during concurrent chemoradiotherapy

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    Puneet Kumar Bagri

    2014-01-01

    Full Text Available Background: Cisplatin is widely used as radio sensitizer in head and neck cancer (HNC and carcinoma cervix (CaCx. This study aims to see comparative nephrotoxicity of cisplatin in HNC and in CaCx without obstructive uropathy treated by concurrent chemoradiotherapy (CCRT. Materials and Methods: Fifty patients of HNC and 50 patients of CaCx stage II/III without obstructive uropathy were included in this study. Cisplatin 50 mg intravenous weekly was given before EBRT with adequate hydration and premedication in both groups. Before chemotherapy; blood urea, serum creatinine, and glomerular filtration rate (GFR were measured. GFR was measured using 99m Tc diethylene triamine pentacaetic acid (DTPA renogram study. Results: At the end of 4 th week, blood urea level 41-45 mg% was in 40 and 4% in HNC and CaCx, respectively (P = 0.018. At the end of 3 rd and 4 th week, blood urea level >45 mg% was 10 and 6% in HNC cases, respectively. At the end of 4 th week, serum creatinine level 1.1-1.5 mg% was 50 and 8% in HNC and CaCx, respectively (P = 0.047. Serum creatinine level >1.5 mg% was 6, 8, and 22% in HNC at the end of 2 nd , 3 rd , and 4 th week, respectively. GFR <80 ml/min at the end of 4 th week was 14% in HNC and only 2% in CaCx. GFR <100ml/min was significant at the end of 4 th week (P = 0.04. Univariate analysis showed significant relation between reduced oral fluid intake and reduced GFR (P < 0.001. Conclusion: In HNC, during concurrent chemoradiation, as the 3 rd -4 th week is reached, oral mucosal reactions increase and affect oral intake which further add to the cisplatin-induced nephrotoxicity. In CaCx without obstructive uropathy, renal function impairment is less severe as oral intake of water and liquid is not much impaired.

  20. Antiapoptotic mechanism of cannabinoid receptor 2 agonist on cisplatin-induced apoptosis in the HEI-OC1 auditory cell line.

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    Jeong, Hyun-Ja; Kim, Su-Jin; Moon, Phil-Dong; Kim, Na-Hyun; Kim, Jung-Sun; Park, Rae-Kil; Kim, Min-Sun; Park, Byung-Rim; Jeong, Sejin; Um, Jae-Young; Kim, Hyung-Min; Hong, Seung-Heon

    2007-03-01

    Cisplatin is a highly effective chemotherapeutic agent but with significant ototoxic side effects. Apoptosis is an important mechanism of cochlear hair cell loss following exposure to an ototoxic level of cisplatin. The present study investigated the effects of the cannabinoid receptor 2 (CB2) ligand JWH-015 on cisplatin-induced apoptosis. CB2 mRNA was constitutively expressed in the auditory cell line HEI-OC1. By using MTT assay, DNA fragmentation, and FACS analysis, we demonstrated that apoptosis induced by cisplatin was inhibited by treatment with JWH-015 in a dose-dependent manner. Activation of caspase-3, caspase-8, and caspase-9 was detected after treatment with cisplatin, and the cleavage of poly-(ADP)-ribose polymerase (PARP) was observed within cisplatin-treated HEI-OC1 cells. JWH-015 inhibited the activation of caspase-3, caspase-8, and caspase-9; cleavage of PARP; and release of cytochrome c. JWH-015 also inhibited the apoptosis through activation of the extracellular signal-regulated kinase pathway. Finally, JWH-015 inhibited cisplatin-induced reactive oxygen species and tumor necrosis factor-alpha production. Collectively, these findings show that blocking a critical step in apoptosis by using JWH-015 may be a useful strategy to prevent harmful side effects of cisplatin ototoxicity in patients having to undergo chemotherapy.

  1. Salinomycin enhances cisplatin-induced cytotoxicity in human lung cancer cells via down-regulation of AKT-dependent thymidylate synthase expression.

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    Ko, Jen-Chung; Zheng, Hao-Yu; Chen, Wen-Ching; Peng, Yi-Shuan; Wu, Chia-Hung; Wei, Chia-Li; Chen, Jyh-Cheng; Lin, Yun-Wei

    2016-12-15

    Salinomycin, a polyether antibiotic, acts as a highly selective potassium ionophore and has anticancer activity on various cancer cell lines. Cisplatin has been proved as chemotherapy drug for advanced human non-small cell lung cancer (NSCLC). Thymidylate synthase (TS) is a key enzyme in the pyrimidine salvage pathway, and increased expression of TS is thought to be associated with resistance to cisplatin. In this study, we showed that salinomycin (0.5-2μg/mL) treatment down-regulating of TS expression in an AKT inactivation manner in two NSCLC cell lines, human lung adenocarcinoma A549 and squamous cell carcinoma H1703 cells. Knockdown of TS using small interfering RNA (siRNA) or inhibiting AKT activity with PI3K inhibitor LY294002 enhanced the cytotoxicity and cell growth inhibition of salinomycin. A combination of cisplatin and salinomycin resulted in synergistic enhancement of cytotoxicity and cell growth inhibition in NSCLC cells, accompanied with reduced activation of phospho-AKT, and TS expression. Overexpression of a constitutive active AKT (AKT-CA) expression vector reversed the salinomycin and cisplatin-induced synergistic cytotoxicity. In contrast, pretreatment with LY294002 further decreased the cell viability in salinomycin and cisplatin cotreated cells. Our findings suggested that the down-regulation of AKT-mediated TS expression by salinomycin enhanced the cisplatin-induced cytotoxicity in NSCLC cells. These results may provide a rationale to combine salinomycin with cisplatin for lung cancer treatment.

  2. Improved Protective Effect of Umbilical Cord Stem Cell Transplantation on Cisplatin-Induced Kidney Injury in Mice Pretreated with Antithymocyte Globulin

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    Željka Večerić-Haler

    2016-01-01

    Full Text Available Mesenchymal stem cells (MSCs are recognised as a promising tool to improve renal recovery in experimental models of cisplatin-induced acute kidney injury. However, these preclinical studies were performed on severely immunodeficient animals. Here, we investigated whether human umbilical cord derived MSC treatment could equally ameliorate acute kidney injury induced by cisplatin and prolong survival in mice with a normal immune system and those with a suppressed immune system by polyclonal antithymocyte globulin (ATG. We demonstrated that ATG pretreatment, when followed by MSC transplantation, significantly improved injured renal function parameters, as evidenced by decreased blood urea nitrogen and serum creatinine concentration, as well as improved renal morphology. This tissue restoration was also supported by increased survival of mice. The beneficial effects of ATG were associated with reduced level of inflammatory protein serum amyloid A3 and induced antioxidative expression of superoxide dismutase-1 (SOD-1, glutathione peroxidase (GPx, and hem oxygenase-1 (HO-1. Infused MSCs became localised predominantly in peritubular areas and acted to reduce renal cell death. In conclusion, these results show that ATG diminished in situ inflammation and oxidative stress associated with cisplatin-induced acute kidney injury, the effects that may provide more favourable microenvironment for MSC action, with consequential synergistic improvements in renal injury and animal survival as compared to MSC treatment alone.

  3. Total Coumarins from Hydrangea paniculata Protect against Cisplatin-Induced Acute Kidney Damage in Mice by Suppressing Renal Inflammation and Apoptosis

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    Jie, Ma; Jingzhi, Yang; Dongjie, Wang; Dongming, Zhang

    2017-01-01

    Aim. Hydrangea paniculata (HP) Sieb. is a medical herb which is widely distributed in southern China, and current study is to evaluate renal protective effect of aqueous extract of HP by cisplatin-induced acute kidney injury (AKI) in animal model and its underlying mechanisms. Materials and Methods. HP extract was prepared and the major ingredients were coumarin glycosides. AKI mouse models were established by single i.p. injection of 20 mg/kg cisplatin, and HP was orally administrated for total five times. The renal biochemical functions, pathological staining, kidney oxidative stress, and inflammatory status were measured. Apoptosis of tubular cells and infiltration of macrophages and neutrophils were also tested. Results. HP administration could improve the renal function by decreasing concentration of blood urea nitrogen (BUN) and creatinine and attenuates renal oxidative stress and tubular pathological injury and apoptosis; further research demonstrated that HP could inhibit the overproduction of proinflammatory cytokines and regulate caspase and BCL-2 family proteins. HP also reduced renal infiltration of macrophages and neutrophils, and its effect might be by downregulating phosphorylation of ERK1/2 and stat3 signaling pathway. Conclusions. This present study suggests that HP could ameliorate cisplatin induced kidney damage by antioxidation and suppressing renal inflammation and tubular cell apoptosis.

  4. MiR-182-5p protects inner ear hair cells from cisplatin-induced apoptosis by inhibiting FOXO3a

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    Li, Yimeng; Li, Ao; Wu, Jingfang; He, Yingzi; Yu, Huiqian; Chai, Renjie; Li, Huawei

    2016-01-01

    Cisplatin is widely used for chemotherapy of a variety of malignancies. However, the clinical application of cisplatin is hampered by the resultant irreversible hearing loss due to hair cell apoptosis. To date, no practical regimen to resolve this has been developed. Meanwhile, the role of microRNA in protecting hair cells from cisplatin-induced apoptosis in the inner ear has not been extensively investigated. In this study, we monitored miR-183, -96, and -182 turnover in the cochlea during cisplatin treatment in vitro. We found that overexpression of miR-182, but not miR-183 and -96, improved hair cell survival after 3 μM cisplatin treatment in vitro. We demonstrated that overexpression of miR-182 repressed the intrinsic apoptotic pathway by inhibiting the translation of FOXO3a. Our study offers a new therapeutic target for alleviating cisplatin-induced hair cell apoptosis in a rapid and tissue-specific manner. PMID:27607577

  5. The Flavonoid Apigenin Ameliorates Cisplatin-Induced Nephrotoxicity through Reduction of p53 Activation and Promotion of PI3K/Akt Pathway in Human Renal Proximal Tubular Epithelial Cells

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    Sung Min Ju

    2015-01-01

    Full Text Available Apigenin is a member of the flavone subclass of flavonoids present in fruits and vegetables. Apigenin has long been considered to have various biological activities, such as antioxidant, anti-inflammatory, and antitumorigenic properties, in various cell types. Cisplatin was known to exhibit cytotoxic effect to renal cells by inducing apoptosis through activation of p53. The present study investigated the antiapoptotic effects of apigenin on the cisplatin-treated human renal proximal tubular epithelial (HK-2 cells. HK-2 cells were pretreated with apigenin (5, 10, 20 μM for 1 h and then treated with 40 μM cisplatin for various times. Apigenin inhibited the cisplatin-induced apoptosis of HK-2 cells. Interestingly, apigenin itself exerted cytostatic activity because of its ability to induce cell cycle arrest. Apigenin inhibited caspase-3 activity and PARP cleavage in cisplatin-treated cells. Apigenin reduced cisplatin-induced phosphorylation and expression of p53, with no significant influence on production of ROS that is known to induce p53 activation. Furthermore, apigenin promoted cisplatin-induced Akt phosphorylation, suggesting that enhanced Akt activation may be involved in cytoprotection. Taken together, these results suggest that apigenin ameliorates cisplatin-induced apoptosis through reduction of p53 activation and promotion of PI3K/Akt pathway in HK-2 cells.

  6. Opioid-induced hyperalgesia and burn pain.

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    Holtman, Joseph R; Jellish, W Scott

    2012-01-01

    The treatment of pain produced during the management of burn injury has been an ongoing problem for physicians caring for these patients. The main therapeutic option for analgesia has been the repeated and prolonged use of opioids. The adverse effects of opioids are well known but the long term use of opioids which produces tolerance with accompanying dose escalation and dependence is most problematic. Another potentially important consequence of opioid exposure that sometimes masks as tolerance is that of opioid induced hyperalgesia. This syndrome is manifest as enhanced pain, sensitivity and loss of analgesic efficacy in patients treated with opioids who actually become sensitized to painful stimuli. This article focuses on the treatment of burn pain and how current analgesic therapies with opioids may cause hyperalgesia and affect the adequacy of treatment for burn pain. This article also provides possible modalities to help therapeutically manage these patients and considers future analgesic strategies which may help to improve pain management in this complicated patient population.

  7. EVALUATION OF CISPLATIN-INDUCED PICA BEHAVIOUR IN RATS BY MEASURING FAECAL CARMINE-DYE EXCRETION: AN IMPROVED EXPERIMENTAL MODEL TO SCREEN SAMPLES WITH ANTI-EMETIC PROPERTIES

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    Rajesh S.

    2012-02-01

    Full Text Available The objective of the present study is to evaluate the Cisplatin-induced pica behaviour in rats by measuring faecal carmine dye excretion and to evaluate the anti-emetic effect of drugs on Cisplatin-induced pica behaviour in rats. Thirty-two rats were divided into 4 groups of 8 animals each. Rats from group I and II received DM water (10ml/kg p.o. Rats from group III and IV received Himalaya Anti-emetic Tablets (HAT 250 mg/kg p.o. and ondansetron 4mg/kg p.o, respectively. After one hour of the assigned treatment, all the animals except in group I were injected with Cisplatin 3mg/kg i.p. Rats in group I were injected with saline (1ml/kg i.p.. All the animals were fed with normal as well as kaolin pellets (impregnated with carmine dye. The faeces of each rat was collected after 72 hrs of drug administration and analysed for the carmine content.Cisplatin injection (3mg/kg caused a significant increase in kaolin consumption, which was indicated by increased carmine dye excretion in faeces compared to control. Pre-treatment with HAT and ondansetron significantly suppressed kaolin consumption induced by Cisplatin. The present findings showed that the exact kaolin consumption can be quantified by measuring the faecal excretion of carmine, which was added in kaolin pellets and this can be a sensitive model to study the anti-emetic potential of drugs, overcoming the inherent disadvantages of measuring direct kaolin intake. Pre-treatment with ondansetron and HAT significantly decreased kaolin consumption in rats-induced by Cisplatin injection, which was further shown by decrease in faecal excretion of carmine, indicating anti-emetic potential of tested drugs.

  8. Downregulation of ATG14 by EGR1-MIR152 sensitizes ovarian cancer cells to cisplatin-induced apoptosis by inhibiting cyto-protective autophagy.

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    He, Jun; Yu, Jing-Jie; Xu, Qing; Wang, Lin; Zheng, Jenny Z; Liu, Ling-Zhi; Jiang, Bing-Hua

    2015-01-01

    Cisplatin is commonly used in ovarian cancer treatment by inducing apoptosis in cancer cells as a result of lethal DNA damage. However, the intrinsic and acquired resistance to cisplatin in cancer cells remains a big challenge for improving overall survival. The cyto-protective functions of autophagy in cancer cells have been suggested as a potential mechanism for chemoresistance. Here, we reported MIR152 as a new autophagy-regulating miRNA that plays a role in cisplatin-resistance. We showed that MIR152 expression was dramatically downregulated in the cisplatin-resistant cell lines A2780/CP70, SKOV3/DDP compared with their respective parental cells, and in ovarian cancer tissues associated with cisplatin-resistance. Overexpression of MIR152 sensitized cisplatin-resistant ovarian cancer cells by reducing cisplatin-induced autophagy, enhancing cisplatin-induced apoptosis and inhibition of cell proliferation. A mouse subcutaneous xenograft tumor model using A2780/CP70 cells with overexpressing MIR152 was established and displayed decreased tumor growth in response to cisplatin. We also identified that ATG14 is a functional target of MIR152 in regulating autophagy inhibition. Furthermore, we found that EGR1 (early growth response 1) regulated the MIR152 gene at the transcriptional level. Ectopic expression of EGR1 enhanced efficacy of chemotherapy in A2780/CP70 cells. More importantly, these findings were relevant to clinical cases. Both EGR1 and MIR152 expression levels were significantly lower in ovarian cancer tissues with high levels of ERCC1 (excision repair cross-complementation group 1), a marker for cisplatin-resistance. Collectively, these data provide insights into novel mechanisms for acquired cisplatin-resistance. Activation of EGR1 and MIR152 may be a useful therapeutic strategy to overcome cisplatin-resistance by preventing cyto-protective autophagy in ovarian cancer.

  9. Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell

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    Xu, Ning; Zhang, Jianjun; Shen, Conghuan; Luo, Yi; Xia, Lei; Xue, Feng [Department of Transplantation and Hepatic Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, People' s Republic of China (China); Xia, Qiang, E-mail: xiaqiang1@yahoo.com.cn [Department of Transplantation and Hepatic Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, People' s Republic of China (China)

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer miR-199a-5p levels were significantly decreased after cisplatin treatment. Black-Right-Pointing-Pointer Cisplatin treatment induced autophagy activation. Black-Right-Pointing-Pointer Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell. -- Abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Systemic chemotherapy plays an important role in the treatment of patients with advanced liver cancer. However, chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic, and the underlying mechanism of such resistance is not fully understood. In the study, we found that miR-199a-5p levels were significantly reduced in HCC patients treated with cisplatin-based chemotherapy. Cisplatin treatment also resulted in decreased miR-199a-5p levels in human HCC cell lines. Forced expression of miR-199a-5p promoted cisplatin-induced inhibition of cell proliferation. Cisplatin treatment activated autophagy in Huh7 and HepG2 cells, which increased cell proliferation. We further demonstrated that downregulated miR-199a-5p enhanced autophagy activation by targeting autophagy-associated gene 7 (ATG7). More important, autophagy inhibition abrogated miR-199a-5p downregulation-induced cell proliferation. These data demonstrated that miR-199a-5p/autophagy signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC.

  10. Long-term aerobic exercise protects against cisplatin-induced nephrotoxicity by modulating the expression of IL-6 and HO-1.

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    Mariana Yasue Saito Miyagi

    Full Text Available Nephrotoxicity is substantial side effect for 30% of patients undergoing cancer therapy with cisplatin and may force them to change or even abandon the treatment. Studies regarding aerobic exercise have shown its efficacy for the treatment of many types of diseases and its capacity to reduce tumors. However, little is known about the impact of physical exercise on cisplatin-induced acute kidney injury (AKI. In the present study, our aim was to investigate the role of physical exercise in AKI induced by cisplatin. We submitted C57Bl6 male mice to seven weeks of chronic exercise on a training treadmill and treated them with single i.p. injection of cisplatin (20 mg/kg in the last week. Exercise efficacy was confirmed by an increased capillary-to-fiber ratio in the gastrocnemius muscle of exercised groups (EX and CIS-EX. The group submitted to exercise before cisplatin administration (CIS-EX exhibited less weight loss and decreased serum urea levels compared to the cisplatin group (CIS. Exercise also showed a protective role against cisplatin-induced cell death in the kidney. The CIS-EX group showed a lower inflammatory response, with less TNF and IL-10 expression in the kidney and serum. In the same group, we observed an increase of IL-6 and HO-1 expression in the kidney. Taken together, our results indicate that chronic aerobic exercise is able to attenuate AKI by inducing IL-6 and HO-1 production, which results in lower inflammatory and apoptotic profiles in the kidney.

  11. Abrogation of cisplatin-induced nephrotoxicity in mice by alpha lipoic acid through ameliorating oxidative stress and enhancing gene expression of antioxidant enzymes.

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    El-Beshbishy, Hesham A; Bahashwan, Saleh A; Aly, Hamdy A A; Fakher, Hesham A

    2011-10-01

    Cisplatin is chemotherapeutic drug used in treatment of malignancies. However, its clinical utility is limited by nephrotoxicity. The purpose of present study is to investigate biochemical and molecular effects of alpha lipoic acid (ALA) to protect against cisplatin-induced nephrotoxicity in mice. Cisplatin (12 mg/kg/day) was administered i.p. for 4 days. Group of mice were given ALA (20 mg/kg/day) for 18 days. Another set were administered ALA for 4 days before and 14 days after cisplatin intoxication. The results obtained revealed that kidney/body weight ratio of cisplatin-treated mice was increased by +40%. ALA intake declined the ratio by -19%. Serum creatinine and urea levels were increased in cisplatin-treated mice by +375% and +69%, respectively. These changes were moved to normalcy upon ALA intake. Cisplatin treatment elevated malondialdehyde (MDA) by 27 fold and declined reduced glutathione (GSH) by -49%. Cisplatin decreased catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymes by -47%, -49% and -59%, respectively. ALA decreased the MDA by -286% and increased the GSH, catalase, SOD and GPx levels by +60%, +81%, +90% and +38%, respectively. ALA increased mRNA expression of catalase, CuZn SOD and GPx genes near to normalcy compared to cisplatin-treated mice. Cisplatin-treated mice increased caspase-3-activity by +223%, nitric oxide (NO) by +74% and inducible nitric oxide synthase (iNOS) by 10 fold. ALA intake declined these changes by -43%, -45% and -73%, respectively. ALA may play renoprotective role on cisplatin-induced nephrotoxicity through antioxidant and antiapoptotic mechanisms combined with initiation of mRNA expression of antioxidant genes.

  12. IL-17 induces hyperalgesia via TNF-dependent neutrophil infiltration.

    Science.gov (United States)

    McNamee, Kay E; Alzabin, Saba; Hughes, Jane P; Anand, Praveen; Feldmann, Marc; Williams, Richard O; Inglis, Julia J

    2011-08-01

    Interleukin-17 (IL-17) and tumour necrosis factor-α (TNF) are critical in the pathogenesis of arthritis but their relationship during inflammatory pain has received limited attention. We aimed to establish whether IL-17 can induce hyperalgesia in acute conditions, and investigated the role of TNF in mediating the pain response. Hyperalgesia was elicited in C57BL/6 mice by injection of recombinant IL-17, TNF or vehicle into the plantar tissue. Elevated pain was measured by the Hargreaves test for thermal hyperalgesia and Linton incapacitance tester for weight-bearing change. Cellular infiltration during hyperalgesia was determined by histological analysis and myeloperoxidase assay. IL-17 was found to induce hyperalgesia, but this was dependent on neutrophil migration and TNF binding to TNF receptor 1 (TNFR1). Because TNF-induced hyperalgesia was also dependent on neutrophil migration, the relationship between the resident fibroblasts, the cytokines and the migrating neutrophils was further investigated. By means of an air pouch model of cell migration, it was established that IL-17-induced neutrophil infiltration was dependent of TNF/TNFR1 as this interaction was required for the induction of the chemokine keratinocyte chemoattractant. These findings suggest that IL-17 causes acute hyperalgesia indirectly by inducing TNF from resident cells. The subsequent production of keratinocyte chemoattractant then triggers neutrophil chemotaxis to the plantar tissue, releasing algesic mediators locally to sensitise the nerve.

  13. Fentanyl-induced hyperalgesia in acute pain management.

    Science.gov (United States)

    Lyons, Pamela J; Rivosecchi, Ryan M; Nery, Jose P; Kane-Gill, Sandra L

    2015-06-01

    There are safety concerns with the use of fentanyl, including respiratory depression, nausea, constipation, and possibly opioid-induced hyperalgesia (OIH). The purpose of this review is to evaluate the occurrence and significance of opioid-induced hyperalgesia (OIH) after acute fentanyl exposure. A literature search was conducted from October 1995 through January 2015 using MEDLINE, Embase, and Scopus with the terms hyperalgesia, fentanyl, pronociceptive, acute tolerance, and acute. Published articles evaluating the adverse effects of fentanyl during acute pain management (≤96 hours) in humans were included. Opioid-induced hyperalgesia is a phenomenon defined by increasing pain after opioid exposure with the worsening of pain occurring when opioid doses are increased. Hyperalgesia has been described following remifentanil and morphine use, but the question remains about the associated risk with acute fentanyl exposure. Six randomized, controlled trials evaluating the effect of fentanyl on pain in the acute setting have been conducted. Two trials oppose whereas four trials support the occurrence of fentanyl-induced hyperalgesia. The data on OIH after acute fentanyl exposure are limited and conflicting. Hyperalgesia should be considered in patients with uncontrolled pain despite escalating fentanyl doses, since the possibility of fentanyl-induced OIH exists in the acute setting. Well-designed trials are needed to determine the clinical significance of this phenomenon.

  14. Failure of intrathecal ketorolac to reduce remifentanil-induced postinfusion hyperalgesia in humans.

    Science.gov (United States)

    Eisenach, James C; Tong, Chuanyao; Curry, Regina S

    2015-01-01

    In rodents, acute exposure to opioids results in transient antinociception followed by longer lasting hypersensitivity to tactile or thermal stimuli, a phenomenon termed opioid-induced hyperalgesia. This hypersensitivity can be blocked or reversed by intrathecally administered cyclooxygenase inhibitors, including ketorolac, suggesting a role for spinal prostaglandins. In surgical patients, the dose of intraoperative opioid, particularly the short-acting drug, remifentanil, is directly related to increased pain and opioid requirements for many hours postoperatively. In addition, experimentally induced tactile hypersensitivity in humans is exaggerated after cessation of remifentanil infusions. The degree of this experimental opioid-induced hyperalgesia is reduced by systemic treatment with cyclooxygenase inhibitors, and investigators have speculated that this reduction reflects the actions in the central nervous system, most likely in the spinal cord. To test this hypothesis, we measured cerebrospinal fluid prostaglandin E2 concentrations during and after remifentanil infusion in 30 volunteers. These volunteers received intrathecal ketorolac or saline in a random, blinded manner during intravenous remifentanil infusion after generation of hypersensitivity by topical capsaicin. Remifentanil reduced pain to noxious heat stimuli and reduced areas of capsaicin-induced hypersensitivity similarly in those receiving intrathecal ketorolac or saline. The primary outcome measure, area of capsaicin-induced hypersensitivity after stopping remifentanil, showed a similar increase in those receiving ketorolac as in those receiving saline. Cerebrospinal fluid prostaglandin E2 concentrations did not increase during postinfusion hyperalgesia compared with those during infusion, and they were not increased during infusion compared with those in historical controls. These data fail to support the hypothesis that acute opioid-induced hyperalgesia reflects spinal cyclooxygenase activation

  15. The major brain endocannabinoid 2-AG controls neuropathic pain and mechanical hyperalgesia in patients with neuromyelitis optica.

    Directory of Open Access Journals (Sweden)

    Hannah L Pellkofer

    Full Text Available Recurrent myelitis is one of the predominant characteristics in patients with neuromyelitis optica (NMO. While paresis, visual loss, sensory deficits, and bladder dysfunction are well known symptoms in NMO patients, pain has been recognized only recently as another key symptom of the disease. Although spinal cord inflammation is a defining aspect of neuromyelitis, there is an almost complete lack of data on altered somatosensory function, including pain. Therefore, eleven consecutive patients with NMO were investigated regarding the presence and clinical characteristics of pain. All patients were examined clinically as well as by Quantitative Sensory Testing (QST following the protocol of the German Research Network on Neuropathic Pain (DFNS. Additionally, plasma endocannabinoid levels and signs of chronic stress and depression were determined. Almost all patients (10/11 suffered from NMO-associated neuropathic pain for the last three months, and 8 out of 11 patients indicated relevant pain at the time of examination. Symptoms of neuropathic pain were reported in the vast majority of patients with NMO. Psychological testing revealed signs of marked depression. Compared to age and gender-matched healthy controls, QST revealed pronounced mechanical and thermal sensory loss, strongly correlated to ongoing pain suggesting the presence of deafferentation-induced neuropathic pain. Thermal hyperalgesia correlated to MRI-verified signs of spinal cord lesion. Heat hyperalgesia was highly correlated to the time since last relapse of NMO. Patients with NMO exhibited significant mechanical and thermal dysesthesia, namely dynamic mechanical allodynia and paradoxical heat sensation. Moreover, they presented frequently with either abnormal mechanical hypoalgesia or hyperalgesia, which depended significantly on plasma levels of the endogenous cannabinoid 2-arachidonoylglycerole (2-AG. These data emphasize the high prevalence of neuropathic pain and hyperalgesia

  16. Opioid induced hyperalgesia in anesthetic settings.

    Science.gov (United States)

    Lee, Hyeon Jeong; Yeomans, David C

    2014-11-01

    Pain is difficult to investigate and difficult to treat, in part, because of problems in quantification and assessment. The use of opioids, combined with classic anesthetics to maintain hemodynamic stability by controlling responses to intraoperative painful events has gained significant popularity in the anesthetic field. However, several side effects profiles concerning perioperative use of opioid have been published. Over the past two decades, many concerns have arisen with respect to opioid-induced hyperalgesia (OIH), which is the paradoxical effect wherein opioid usage may decrease pain thresholds and increase atypical pain unrelated to the original, preexisting pain. This brief review focuses on the evidence, mechanisms, and modulatory and pharmacologic management of OIH in order to elaborate on the clinical implication of OIH.

  17. Bilateral mechanical and thermal hyperalgesia and tactile allodynia after chronic compression of dorsal root ganglion in mice.

    Science.gov (United States)

    Chen, Rong-Gui; Kong, Wei-Wei; Ge, Da-Long; Luo, Ceng; Hu, San-Jue

    2011-08-01

    OBJECTIVE Low back pain is one of the most inextricable problems encountered in clinics. Animal models that imitate symptoms in humans are valuable tools for investigating low back pain mechanisms and the possible therapeutic applications. With the development of genetic technology in pain field, the possibility of mutating specific genes in mice has provided a potent tool for investigating the specific mechanisms of pain. The aim of the present study was to develop a mouse model of chronic compression of dorsal root ganglion (CCD), in which gene mutation can be applied to facilitate the studies of chronic pain. METHODS Chronic compression of L4 and L5 dorsal root ganglia was conducted in mice by inserting fine stainless steel rods into the intervertebral foramina, one at L4 and the other at L5. Mechanical allodynia and thermal hyperalgesia were examined with von Frey filaments and radiating heat stimulator, respectively. RESULTS The CCD mice displayed dramatic mechanical and thermal hyperalgesia as well as tactile allodynia in the hindpaw ipsilateral to CCD. In addition, this mechanical and thermal hyperalgesia as well as tactile allodynia was also found to spread to the contralateral hindpaw. CONCLUSION This model, combined with the possible genetic modification, will strengthen our knowledge of the underlying mechanisms of low back pain. It also favors the development of new treatment strategies for pain and hyperalgesia after spinal injury and other disorders which affect the dorsal root ganglion in humans.

  18. Phosphorylation of TRPV1 by cyclin-dependent kinase 5 promotes TRPV1 surface localization, leading to inflammatory thermal hyperalgesia.

    Science.gov (United States)

    Liu, Jiao; Du, Junxie; Yang, Yanrui; Wang, Yun

    2015-11-01

    Cyclin-dependent kinase 5 (Cdk5) is an important serine/threonine kinase that plays critical roles in many physiological processes. Recently, Cdk5 has been reported to phosphorylate TRPV1 at threonine 407 (Thr-407) in humans (Thr-406 in rats), which enhances the function of TRPV1 channel and promotes thermal hyperalgesia in the complete Freund's adjuvant (CFA)-induced inflammatory pain rats. However, the underlying mechanisms are still unknown. Here, we demonstrate that Cdk5 phosphorylates TRPV1 at Threonine 406 and promotes the surface localization of TRPV1, leading to inflammatory thermal hyperalgesia. The mutation of Thr-406 of TRPV1 to alanine reduced the interaction of TRPV1 with the cytoskeletal elements and decreased the binding of TRPV1 with the motor protein KIF13B, which led to reduced surface distribution of TRPV1. Disrupting the phosphorylation of TRPV1 at Thr-406 dramatically reduced the surface level of TRPV1 in HEK 293 cells after transient expression and the channel function in cultured dorsal root ganglion (DRG) neurons. Notably, intrathecal administration of the interfering peptide against the phosphorylation of Thr-406 alleviated heat hyperalgesia and reduced the surface level of TRPV1 in inflammatory pain rats. Together, these results demonstrate that Cdk5-mediated phosphorylation of TRPV1 at Thr-406 increases the surface level and the function of TRPV1, while the TAT-T406 peptide can effectively attenuate thermal hyperalgesia. Our studies provide a potential therapy for inflammatory pain.

  19. Pharmacology of intracisternal or intrathecal glycine, muscimol, and baclofen in strychnine-induced thermal hyperalgesia of mice.

    Science.gov (United States)

    Lee, Il Ok; Son, Jin Kook; Lim, Eui-Sung; Kim, Yeon-Soo

    2011-10-01

    Glycine and γ-aminobutyric acid (GABA) are localized and released by the same interneurons in the spinal cord. Although the effects of glycine and GABA on analgesia are well known, little is known about the effect of GABA in strychnine-induced hyperalgesia. To investigate the effect of GABA and the role of the glycine receptor in thermal hyperalgesia, we designed an experiment involving the injection of muscimol (a GABA(A) receptor agonist), baclofen (a GABA(B) receptor agonist) or glycine with strychnine (strychnine sensitive glycine receptor antagonist). Glycine, muscimol, or baclofen with strychnine was injected into the cisterna magna or lumbar subarachnoidal spaces of mice. The effects of treatment on strychnine-induced heat hyperalgesia were observed using the pain threshold index via the hot plate test. The dosages of experimental drugs and strychnine we chose had no effects on motor behavior in conscious mice. Intracisternal or intrathecal administration of strychnine produced thermal hyperalgesia in mice. Glycine antagonize the effects of strychnine, whereas, muscimol or baclofen does not. Our results indicate that glycine has anti-thermal hyperalgesic properties in vivo; and GABA receptor agonists may lack the binding abilities of glycine receptor antagonists with their sites in the central nervous system.

  20. PHARMACOLOGIC TREATMENT OF HYPERALGESIA EXPERIMENTALLY INDUCED BY NUCLEUS PULPOSUS

    OpenAIRE

    de Souza Grava, André Luiz; Ferrari,Luiz Fernando; Parada, Carlos Amílcar; Defino, Helton Luiz Aparecido

    2015-01-01

    Objective: To evaluate the effect of anti-inflammatory drugs (dexamethasone, indomethacin, atenolol and indomethacin plus atenolol) and analgesic drugs (morphine) on hyperalgesia experimentally induced by the nucleus pulposus (NP) in contact with the L5 dorsal root ganglion (DRG). Methods: Thirty male Wistar rats of weights ranging from 220 to 250 g were used in the study. Hyperalgesia was induced by means of a fragment of NP removed from the sacrococcygeal region that was placed in contact w...

  1. 5-hydroxyindolacetic acid (5-HIAA, a main metabolite of serotonin, is responsible for complete Freund's adjuvant-induced thermal hyperalgesia in mice

    Directory of Open Access Journals (Sweden)

    Moessner Rainald

    2011-03-01

    Full Text Available Abstract Background The role of serotonin (5-hydroxytrptamine, 5-HT in the modulation of pain has been widely studied. Previous work led to the hypothesis that 5-hydroxyindolacetic acid (5-HIAA, a main metabolite of serotonin, might by itself influence pain thresholds. Results In the present study, we investigated the role of 5-HIAA in inflammatory pain induced by intraplantar injection of complete Freund's adjuvant (CFA into the hind paw of mice. Wild-type mice were compared to mice deficient of the 5-HT transporter (5-HTT-/- mice using behavioral tests for hyperalgesia and high-performance liquid chromatography (HPLC to determine tissue levels of 5-HIAA. Wild-type mice reproducibly developed thermal hyperalgesia and paw edema for 5 days after CFA injection. 5-HTT-/- mice treated with CFA had reduced thermal hyperalgesia on day 1 after CFA injection and normal responses to heat thereafter. The 5-HIAA levels in spinal cord and sciatic nerve as measured with HPLC were lower in 5-HTT-/- mice than in wild-type mice after CFA injection. Pretreatment of wild-type mice with intraperitoneal injection of para-chlorophenylalanine (p-CPA, a serotonin synthesis inhibitor, resulted in depletion of the 5-HIAA content in spinal cord and sciatic nerve and decrease in thermal hyperalgesia in CFA injected mice. The application of exogenous 5-HIAA resulted in potentiation of thermal hyperalgesia induced by CFA in 5-HTT-/- mice and in wild-type mice pretreated with p-CPA, but not in wild-type mice without p-CPA pretreatment. Further, methysergide, a broad-spectrum serotonin receptor antagonist, had no effect on 5-HIAA-induced potentiation of thermal hyperalgesia in CFA-treated wild-type mice. Conclusion Taken together, the present results suggest that 5-HIAA plays an important role in modulating peripheral thermal hyperalgesia in CFA induced inflammation, probably via a non-serotonin receptor mechanism.

  2. Assessment of sup 99m Tc-DMSA renoscintigraphy and uptake compared with creatinine clearance in rats with drug-induced nephrotoxicity, 2; Cisplatin-induced nephrotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Yamada, Masafumi (Ehime Univ., Shigenobu (Japan). School of Medicine)

    1991-04-01

    For evaluation of technetium-99m dimercaptosuccinic acid ({sup 99m}Tc-DMSA) renal uptake as an absolute renal function, {sup 99m}Tc-DMSA uptake was compared with endogenous creatinine clearance (Ccr) in cisplatin-induced nephrotoxicity. At first, male Wistar rats were given intraperitoneally 1.8 mg/kg/day of cisplatin for periods of 3, 5, 7 and 9 days. On the next day, {sup 99m}Tc-DMSA uptake and Ccr were measured. Ccr of 5-day treated group was significantly lower than that of control (0.13+-0.10 vs 0.34+-0.05 ml/min/100 g; p<0.01) but {sup 99m}Tc-DMSA uptake did not change. {sup 99m}Tc-DMSA uptake of 7-day treated group was significantly lower than that of control (28.57+-7.23 vs 39.84+-2.23%; p<0.01). As the second experiment, cisplatin (3.6 mg/kg/day) was given intraperitoneally on the 1st, 2nd, 15th and 16th day. On the 5th, 8th, 11th, 15th, 20th, 23rd, 26th and 30th day, the same measurements were done as the first one. Ccr was lower in cisplatin treated rats on the 5th day than that in control (0.10+-0.03 vs 0.34+-0.05 ml/min/100 g; p<0.01), thereafter tended to be recovered to the control level. On the other hand, {sup 99m}Tc-DMSA uptake was lower than that of control on the 8th, 11th and 15th day (32.40+-3.86, 32.56+-1.19, 35.21+-2.97 vs 39.84+-2.23%, respectively; p<0.01). The discrepancy between {sup 99m}Tc-DMSA uptake and Ccr was observed in the cisplatin-induced nephrotoxicity. {sup 99m}Tc-DMSA uptake was suggested to be a reliable indicator of a renal function in a different way from Ccr. (author).

  3. Cisplatin-induced apoptosis in non-small-cell lung cancer cells is dependent on Bax- and Bak-induction pathway and synergistically activated by BH3-mimetic ABT-263 in p53 wild-type and mutant cells.

    Science.gov (United States)

    Matsumoto, Masaru; Nakajima, Wataru; Seike, Masahiro; Gemma, Akihiko; Tanaka, Nobuyuki

    2016-04-29

    Cisplatin is a highly effective anticancer drug for treatment of various tumors including non-small-cell lung cancer (NSCLC), and is especially useful in cases nonresponsive to molecular-targeted drugs. Accumulating evidence has shown that cisplatin activates the p53-dependent apoptotic pathway, but it also induces apoptosis in p53-mutated cancer cells. Here we demonstrated that DNA-damage inducible proapoptotic BH3 (Bcl-2 homology region 3)-only Bcl-2 family members, Noxa, Puma, Bim and Bid, are not involved in cisplatin-induced apoptosis in human NSCLC cell lines. In contrast, the expression of proapoptotic multidomain Bcl-2-family members, Bak and Bax, was induced by cisplatin in p53-dependent and -independent manners, respectively. Moreover, in wild-type p53-expressing cells, cisplatin mainly used the Bak-dependent apoptotic pathway, but this apoptotic pathway shifted to the Bax-dependent pathway by loss-of-function of p53. Furthermore, both Bak- and Bax-induced apoptosis was enhanced by the antiapoptotic Bcl-2 family member, Bcl-XL knockdown, but not by Mcl-1 knockdown. From this result, we tested the effect of ABT-263 (Navitoclax), the specific inhibitor of Bcl-2 and Bcl-XL, but not Mcl-1, and found that ABT-263 synergistically enhanced cisplatin-induced apoptosis in NSCLC cells in the presence or absence of p53. These results indicate a novel regulatory system in cisplatin-induced NSCLC cell apoptosis, and a candidate efficient combination chemotherapy method against lung cancers.

  4. Sip-jeon-dea-bo-tang, a traditional herbal medicine, ameliorates cisplatin-induced anorexia via the activation of JAK1/STAT3-mediated leptin and IL-6 production in the fat tissue of mice.

    Science.gov (United States)

    Woo, Sang-Mi; Choi, Youn Kyung; Kim, Ah-Jeong; Yun, Yee Jin; Shin, Yong Cheol; Cho, Sung-Gook; Ko, Seong Gyu

    2016-04-01

    Despite its therapeutic advantages, chemotherapy can also cause adverse effects, including anorexia and loss of appetite. Although numerous patients with cancer have been reported to suffer from anorexia during or following chemotherapy, treatment options for anorexia remain to be determined. In Asian countries, traditional medicines are widely used to treat problems with appetite; sip-jeon-dea-bo-tang (SJDBT) is one of those medicines used for the treatment of anorexia. The present study demonstrated that SJDBT ameliorated cisplatin-induced anorexia. In a mouse model of chemotherapy-induced anorexia, oral administration of SJDBT prevented the cisplatin-induced reduction of food intake, inhibiting weight loss. The results of multiplex assays showed that SJDBT only altered the levels of interleukin (IL)-6 and leptin in the serum and fat tissue. In addition, SJDBT maintained the serum leptin level and increased the serum IL-6 level, whereas cisplatin reduced the levels of both serum leptin and IL‑6. Furthermore, SJDBT was revealed to increase the levels of leptin and IL-6 in the fat tissue by activating the JAK1/STAT3 signaling pathway. In conclusion, the present results revealed that SJDBT ameliorated cisplatin-induced anorexia, suggesting its usefulness in the prevention of anorexia during chemotherapy.

  5. 5-Azacytidine prevents cisplatin induced nephrotoxicity and potentiates anticancer activity of cisplatin by involving inhibition of metallothionein, pAKT and DNMT1 expression in chemical induced cancer rats.

    Science.gov (United States)

    Tikoo, Kulbhushan; Ali, Idrish Yunus; Gupta, Jeena; Gupta, Chanchal

    2009-12-15

    5-Azactydine inhibits cell growth by direct cytotoxic action as well as by inhibition of DNA methyl transferase enzyme. Inhibitors of DNMT have been reported to potentiate the therapeutic activity of cisplatin in vitro. Dose dependent bone marrow toxicity, neurotoxicity and nephrotoxicity are the major side effects of cisplatin, limiting its use as an effective chemotherapeutic agent. The present study was aimed to reduce the nephrotoxic potential of cisplatin without compensating its potency. To best of our knowledge, this is the first report which shows that the combination of 5-azacytidine with cisplatin leads to remarkable reduction in nephrotoxicity, by involving inhibition of cisplatin induced metallothionein expression. 5-Azacytidine treatment with cisplatin leads to maximum reduction in tumor size in DMH induced colon cancer and tumor volume in DMBA induced breast cancer bearing SD rats. This combination regimen prevents phosphorylation and acetylation of histone H3 which may be involved in inhibition of aberrant gene expression in colon tumors. Further, 5-azacytidine potentiated cisplatin induced antitumor activity by involving decreased expression of pAKT, DNMT1 and an increased expression of p38 in colon tumors. Thus, combination of 5-azactydine with cisplatin attenuates the cisplatin induced nephrotoxicity and potentiates the anti-cancer activity which can have profound clinical implications.

  6. Serotonergic signaling inhibits hyperalgesia induced by spinal cord damage.

    Science.gov (United States)

    Horiuchi, Hideki; Ogata, Tadanori; Morino, Tadao; Takeba, Jun; Yamamoto, Haruyasu

    2003-02-14

    Although dysesthesia is one of the most serious problems in patients with spinal cord injury, most of them being unresponsive to conventional treatments. In this study, we established a rat thoracic spinal cord mild-compression model that revealed thermal hyperalgesia in the hind limb. The thoracic spinal cord was compressed gently, using a 20 g weight for 20 min. The withdrawal latency of the thermal stimulation of the bilateral hind-limb was monitored using Hargreaves' Plantar test apparatus. In this model, thermal-hyperalgesia was observed for 1 week after the injury. The spinal cord injury-induced thermal-hyperalgesia was mimicked by the intrathecal application of metergoline, a non-selective 5-HT antagonist, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido) butyl]-piperazine hydrobromide (NAN190), a selective 5-HT1 antagonist, and 3-tropanyl-3,5-dichlorobenzoate (MDL72222), a selective 5-HT3 antagonist. Intraperitoneal application of fluvoxamine maleate, a selective serotonin reuptake inhibitor, reduced the intensity of hyperalgesia induced by spinal cord injury. The inhibitory effect of fluvoxamine maleate on thermal hyperalgesia was prevented by the application of the aforementioned nonselective or selective 5-HT receptor antagonists. Intrathecal application of fluvoxamine maleate and selective 5-HT receptor agonists, i.e., 8-hydroxy-2-(di-n-proplyamino)-tetralin hydrobromide (8-OH-DPAT: 5HT-1 selective) and 2-methyl-5-hydroxytryptamine maleate (2-m-5-HT: 5HT-3 selective), inhibited the spinal cord injury-induced hyperalgesia. These results suggest that the change in the descending serotonergic signal plays an important role in hyperalgesia after the spinal cord injury, and that the application of selective serotonin reuptake inhibitors will be one of the candidates for new therapeutic methods against post-spinal cord injury dysesthesia.

  7. Opioid-Induced Hyperalgesia: A Diagnostic Dilemma.

    Science.gov (United States)

    Carullo, Veronica; Fitz-James, Ingrid; Delphin, Ellise

    2015-01-01

    Opioids are utilized frequently for the treatment of moderate to severe acute pain in the perioperative setting, as well as in the treatment of cancer-related pain. When prescribing chronic opioid therapy to patients with chronic pain, it is crucial for the practitioner to be aware not only of the issues of tolerance and withdrawal, but also to have knowledge of the possibility for opioid-induced hyperalgesia (OIH). An understanding of the differences between tolerance and OIH when escalating opioid therapy allows the titration of opioid as well as nonopioid analgesics in order to obtain maximum control of both chronic and acute pain. A case study is described to highlight the importance of judicious utilization of opioids in the treatment of cancer-related pain. In this case, high-dose opioid therapy did not improve chronic pain and contributed to a hyperalgesic state in which a young man experienced severe intractable pain postoperatively after two routine thoracotomies, despite aggressive pharmacologic measures to manage his perioperative pain. Furthermore, it illustrates the potential advantages of opioid rotation to methadone when OIH is suspected.

  8. Knockdown of miR-221 promotes the cisplatin-inducing apoptosis by targeting the BIM-Bax/Bak axis in breast cancer.

    Science.gov (United States)

    Ye, Zhiqiang; Hao, Rutian; Cai, Yefeng; Wang, Xiaobo; Huang, Guanli

    2016-04-01

    Accumulating evidence shows that microRNAs (miRNAs) have a critical role in the initiation and progression of types of human cancer, including breast cancer. Recent research indicated that miRNAs are also related with the chemotherapy on cancers. In this study, the expression of miR-221 in breast cancer (BC) patients' serum and cancer tissues was found to be significantly up-regulated. The results of in vitro MTT assay indicated that although the anti-miR-221 oligonucleotide alone did not influence the viability of BC cell lines markedly, it significantly promoted the cytotoxicity of cisplatin (DDP) to BC cells. Mechanistic studies demonstrated that the gene of BIM (Bcl-2 interacting mediator of cell death), a pro-apoptotic Bcl-2 family protein, was up-regulated by the knockdown of miR-221. We found that the synergetic effect of anti-miR-221 on increasing the sensitivity of MDA-MB-231 was BIM dependant. Furthermore, results of immunoprecipitation showed the up-regulated BIM directly combined with the Bax and Bak, leading to mitochondrial dysfunction. Our results suggest the anti-miR-221 could promote the cisplatin-inducing apoptosis by targeting the Bim-Bax/Bak axis in breast cancer.

  9. Constitutively active ErbB2 regulates cisplatin-induced cell death in breast cancer cells via pro- and antiapoptotic mechanisms

    DEFF Research Database (Denmark)

    Sigurðsson, Haraldur H; Olesen, Christina Wilkens; Dybboe, Rie

    2015-01-01

    UNLABELLED: Despite the frequent expression of N-terminally truncated ErbB2 (ΔNErbB2/p95HER2) in breast cancer and its association with Herceptin resistance and poor prognosis, it remains poorly understood how ΔNErbB2 affects chemotherapy-induced cell death. Previously it was shown that ΔNErbB2...... upregulates acid extrusion from MCF-7 breast cancer cells and that inhibition of the Na(+)/H(+) exchanger (SLC9A1/NHE1) strongly sensitizes ΔNErbB2-expressing MCF-7 cells to cisplatin chemotherapy. The aim of this study was to identify the mechanism through which ΔNErbB2 regulates cisplatin-induced breast...... cancer cell death, and determine how NHE1 regulates this process. Cisplatin treatment elicited apoptosis, ATM phosphorylation, upregulation of p53, Noxa (PMAIP1), and PUMA (BBC3), and cleavage of caspase-9, -7, fodrin, and PARP-1 in MCF-7 cells. Inducible ΔNErbB2 expression strongly reduced cisplatin...

  10. Spinal processing of bee venom-induced pain and hyperalgesia

    Institute of Scientific and Technical Information of China (English)

    Jun CHEN

    2008-01-01

    Subcutaneous injection of bee venom causes long-term neural activation and hypersensitization in the dorsal horn of the spinal cord, which contributes to the development and maintenance of various pain-related behaviors. The unique behavioral 'pheno-types' of nociception and hypersensitivity identified in the rodent bee venom test are believed to reflect a complex pathological state of inflammatory pain and might be appropriate to the study of phenotype-based mechanisms of pain and hyperalgesia. In this review, the spinal processing of the bee venom-induced different 'phenotypes' of pain and hyperalgesia will be described. The accumulative electrophysiological, pharmacological, and behavioral data strongly suggest that different 'phenotypes' of pain and hyperalgesia are mediated by different spinal signaling pathways. Unraveling the phenotype-based mechanisms of pain might be useful in development of novel therapeutic drugs against complex clinic pathological pain.

  11. Electroacupuncture Reduces Hyperalgesia after Injections of Acidic Saline in Rats

    Directory of Open Access Journals (Sweden)

    Leonardo Yung dos Santos Maciel

    2014-01-01

    Full Text Available Background. Injections of acidic saline into the gastrocnemius muscle in rats produce a bilateral long-lasting hyperalgesia similar to fibromyalgia in humans. No previous study investigated the effect of electroacupuncture (EA on this acidic saline model. This study aimed to identify the effects of EA in the hyperalgesia produced by repeated intramuscular injections of acidic saline. Methods. Rats were divided into four groups (n=6, each group: control, acupuncture, EA 15 Hz, and 100 Hz. Left gastrocnemius muscle was injected with 100 μL of pH 4.0 sterile saline twice five days apart. EA, acupuncture, or control therapy was daily administered (20 min for 5 consecutive days under anesthesia. Needles were placed in the St36 and Sp6 acupoints. The assessment of secondary mechanical hyperalgesia, thermal hyperalgesia, and motor performance was performed before injections and before and after the treatment performed on each day. The paw withdrawal threshold was tested using the nonparametric Kruskal-Wallis test and differences within the group Wilcoxon Matched Pairs. The latency and motor performance were tested for ANOVA parametric test for independent measures, and for differences in the group, we used t-test for paired samples. Post hoc Tukey test was used for multiple corrections. P values ​​less than 0.05 were considered statistically significant. Results. Indicate that there was a significant reduction of mechanical withdrawal threshold and paw withdrawal latency 24 hours following the second injection. Moreover, mechanical and thermal hyperalgesia were significantly reversed by EA 15, 100 Hz, and acupuncture. Conclusions. The results suggest that EA high and low frequency as well as acupuncture are effective in reducing hyperalgesia in chronic muscle pain model.

  12. Anti-hyperalgesic effects of anti-serotonergic compounds on serotonin- and capsaicin-evoked thermal hyperalgesia in the rat.

    Science.gov (United States)

    Loyd, D R; Chen, P B; Hargreaves, K M

    2012-02-17

    The peripheral serotonergic system has been implicated in the modulation of an array of pain states, from migraine to fibromyalgia; however, the mechanism by which serotonin (5HT) induces pain is unclear. Peripherally released 5HT induces thermal hyperalgesia, possibly via modulation of the transient receptor potential V1 (TRPV1) channel, which is gated by various noxious stimuli, including capsaicin. We previously reported in vitro that 5HT increases calcium accumulation in the capsaicin-sensitive population of sensory neurons with a corresponding increase in proinflammatory neuropeptide release, and both are antagonized by pretreatment with 5HT(2A) and 5HT(3) antagonists, as well as the anti-migraine drug sumatriptan. In the current study, we extended these findings in vivo using the rat hind paw thermal assay to test the hypothesis that peripheral 5HT enhances TRPV1-evoked thermal hyperalgesia that can be attenuated with 5HT(2A) and 5HT(3) receptor antagonists, as well as sumatriptan. Thermal hyperalgesia and edema were established by 5HT injection (0.1-10 nmol/100 μl) into the rat hind paw, and the latency to paw withdrawal (PWL) from noxious heat was determined. Rats were then pretreated with either 5HT before capsaicin (3 nmol/10 μl), the 5HT(2A) receptor antagonist ketanserin or the 5HT(3) receptor antagonist granisetron (0.0001-0.1 nmol/100 μl) before 5HT and/or capsaicin, or the 5HT(1B/1D) receptor agonist sumatriptan (0.01-1 nmol/100 μl) before capsaicin, and PWL was determined. We report that 5HT pretreatment enhances TRPV1-evoked thermal hyperalgesia, which is attenuated with local pretreatment with ketanserin, granisetron, or sumatriptan. We also report that peripheral 5HT induced a similar magnitude of thermal hyperalgesia in male and female rats. Overall, our results provide in vivo evidence supporting an enhancing role of 5HT on TRPV1-evoked thermal hyperalgesia, which can be attenuated by peripheral serotonergic intervention.

  13. The pain pathway in the rat following noxious thermal stimulation: effect of morphine on pERK1/2 and TRPV1 at the dorsal horn level, and on hyperalgesia.

    Science.gov (United States)

    Donnerer, Josef; Liebmann, Ingrid

    2013-01-01

    The aim of the present study was to investigate the phosphorylation of ERK1/2 in the lumbar dorsal horn of the rat by fluorescence immunohistochemistry following a noxious thermal stimulation of the hind paw. The protein level of TRPV1 in the dorsal spinal cord and the development of a heat hyperalgesia after the acute noxious thermal stimulation were also measured. The protein content of TRPV1 was determined by Western blot and heat hyperalgesia by the plantar test. At 2 and 10 min after the thermal stimulation a 4-fold increase in pERK1/2 immunoreactivity was observed in cells of lamina I/II of the L3-L5 dorsal horn. A pretreatment with the opioid analgesic morphine markedly attenuated ERK1/2 phosphorylation. The protein content of TRPV1 in the lumbar dorsal spinal cord was not significantly altered at 1 and 4 h after the thermal hind paw stimulation and by the morphine pretreatment. Heat hyperalgesia in the plantar test was observed at 8 h, but not at 24 h after the noxious stimulation. This temporary hyperalgesia was prevented by the morphine pretreatment. The present findings indicate that ERK1/2 activation in dorsal horn nociceptive neurons may be linked to the development of hyperalgesia, and that opioid analgesics are effective agents to prevent sensitization in the pain pathway at spinal level.

  14. 沙利度胺对顺铂诱发大鼠异食癖的影响%Effect of thalidomide on cisplatin-induced pica in rats

    Institute of Scientific and Technical Information of China (English)

    马剑; 韩正祥; 高向阳

    2012-01-01

    目的 观察沙利度胺对顺铂引起的大鼠异食癖的作用,探讨其抗化疗呕吐的实验基础.方法 健康大鼠24只,随机分为对照组、模型组、低剂量沙利度胺组、高剂量沙利度胺组,观察72 h内大鼠摄取高岭土所占总进食量的比值;另取大鼠48只,分组同前,分别于实验开始后5、33 h,取大鼠延髓及胃窦组织,放免法测定P物质,免疫组化法测定神经激肽1受体(NK-1R).结果 顺铂10 mg/kg可以引起大鼠异食癖,沙利度胺10 mg/kg在顺铂应用24 h后可以减轻这种异食癖(P<0.05),同时伴有延髓及胃窦P物质的减少(P<0.05),而NK-1R未出现明显变化.结论 沙利度胺可以减轻顺铂引起的大鼠异食癖,提示在抗呕吐治疗中沙利度胺可能有一定的应用前景.%Objective To observe the effect of thalidomide on cisplatin - induced pica in rats , and to explore the experimental basis of thalidomide resistant to chemotherapy - induced nausea and vomiting. Methods 24 healthy rats were randomly devided into 4 groups: control group , model group , thalidomide group (low dose) and thalidomide group (high dose). The ratio of intake of kaolin total food intake within 72 h was observed. Another 48 rats were randomly devided into 4 groups which were the same as stated above , medullar tissue and gastric antrum were taken out at 5 , 33 hours after the start of the experiment, the substance P (SP) were measured by radioimmunoassay and the neurokinin 1 receptor (NK -1R) determined by immunohistochemistry method. Results Cisplatin 10 mg/kg induced pica,which could be decreased by thalidomide at 10 mg/kg 24 h after the application of cisplatin (P < 0.05) , while accompanied with reduced SP level (P < 0. 05) , but NK - 1R did not have significant changes. Conclusion Thalidomide can reduce cisplatin - induced pica in rats, which suggests that thalidomide may have some prospect in the treatment of anti -chemotherapy vomiting.

  15. Changes in expression of renal Oat1, Oat3 and Mrp2 in cisplatin-induced acute renal failure after treatment of JBP485 in rats

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Tao, E-mail: liutaomedical@qq.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Meng, Qiang, E-mail: mengq531@yahoo.cn [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University (China); Wang, Changyuan, E-mail: wangcyuan@163.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University (China); Liu, Qi, E-mail: llaqii@yahoo.com.cn [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University (China); Guo, Xinjin, E-mail: guo.xinjin@163.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Sun, Huijun, E-mail: sunhuijun@hotmail.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University (China); Peng, Jinyong, E-mail: jinyongpeng2005@163.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University (China); and others

    2012-11-01

    The purpose of this study is to investigate whether the effect of cyclo-trans-4-L-hydroxyprolyl-L-serine (JBP485) on acute renal failure (ARF) induced by cisplatin is related to change in expression of renal Oat1, Oat3 and Mrp2 in rats. JBP485 reduced creatinine, blood urea nitrogen (BUN) and indoxyl sulfate (IS) in plasma and malondialdehyde (MDA) in kidney, and recovered the glomerular filtration rate (GFR) and the activity of superoxide dismutase (SOD) in cisplatin-treated rats. The plasma concentration of PAH (para-aminohippurate) determined by LC–MS/MS was increased markedly after intravenous administration of cisplatin, whereas cumulative urinary excretion of PAH and the uptake of PAH in kidney slices were significantly decreased. qRT-PCR and Western-blot showed a decrease in mRNA and protein of Oat1 and Oat3, an increase in mRNA and protein of Mrp2 in cisplatin-treated rats, and an increase in IS (a uremic toxin) after co-treatment with JBP485. It indicated that JBP485 promoted urinary excretion of toxins by upregulating renal Mrp2. This therefore gives in part the explanation about the mechanism by which JBP485 improves ARF induced by cisplatin in rats. -- Highlights: ► Cisplatin induces acute renal failure (ARF). ► The expression of Oat1, Oat3 and Mrp2 were changed during ARF. ► The regulated expression of Oat1, Oat3 and Mrp2 is an adaptive protected response. ► JBP485 could facilitate the adaptive protective action.

  16. Betaine supplementation mitigates cisplatin-induced nephrotoxicity by abrogation of oxidative/nitrosative stress and suppression of inflammation and apoptosis in rats.

    Science.gov (United States)

    Hagar, Hanan; Medany, Azza El; Salam, Reem; Medany, Gamila El; Nayal, Omina A

    2015-02-01

    Cisplatin is one of the most potent chemotherapeutic antitumor drugs used in the treatment of a wide range of solid tumors. Its primary dose-limiting side effect is nephrotoxicity. This study aims to investigate the effect of betaine supplementation on cisplatin-induced nephrotoxicity. A single intraperitoneal injection of cisplatin (5mg/kg) deteriorated the kidney functions as reflected by elevated blood urea nitrogen and serum creatinine levels. Oxidative/nitrosative stress was evident in cisplatin group by increased renal thiobarbituric acid-reactive substances (TBARS), an indicator of lipid peroxidation, reduced renal total antioxidant status and increased renal nitrite concentration. Cisplatin resulted in a decline in the concentrations of reduced glutathione, glutathione peroxidase, catalase, and superoxide dismutase in renal tissues. Renal tumor necrosis factor-α (TNF-α) was also elevated. Expressions of nuclear factor-kappa B (NF-κB) and caspase-3 were up-regulated in renal tissues as indicated by immunohistochemical analysis. Histopathological changes were observed in cisplatin group. Betaine supplementation (250 mg/kg/day) orally via gavage for 21 days prior to cisplatin injection was able to protect against deterioration in kidney function, abrogate the decline in antioxidants enzymes and suppressed the increase in TBARS, nitrite and TNF-α concentrations. Moreover, betaine inhibited NF-κB and caspase-3 activation and improved the histological changes induced by cisplatin. Thus, the present study demonstrated the renoprotective nature of betaine by attenuating the pro-inflammatory and apoptotic mediators and improving antioxidant competence in kidney tissues of cisplatin treated rats. Betaine could be a beneficial dietary supplement to attenuate cisplatin nephrotoxicity.

  17. 5-Aminolevulinic acid protects against cisplatin-induced nephrotoxicity without compromising the anticancer efficiency of cisplatin in rats in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Yoshio Terada

    Full Text Available BACKGROUND/AIMS: Nephrotoxicity is a frequent and major limitation in cisplatin (CDDP-based chemotherapy. 5-Aminolevulinic acid (ALA is widely distributed in animal cells, and it is a precursor of tetrapyrole compounds such as heme that is fundamentally important in aerobic energy metabolism. The aim of this study is to evaluate the protective role of ALA in CDDP-induced acute kidney injury (AKI. METHOD: We used CDDP-induced AKI rat model and cultured renal tubular cells (NRK-52E. We divided four groups of rats: control, CDDP only, CDDP + ALA(post;(ALA 10 mg/kg + Fe in drinking water after CDDP, CDDP + ALA(pre & post. RESULT: CDDP increased Cr up to 6.5 mg/dl, BUN up to 230 mg/dl, and ALA significantly reduced these changes. ALA ameliorates CDDP-induced morphological renal damages, and reduced tubular apoptosis evaluated by TUNEL staining and cleaved caspase 3. Protein and mRNA levels of ATP5α, complex(COX IV, UCP2, PGC-1α in renal tissue were significantly decreased by CDDP, and ALA ameliorates reduction of these enzymes. In contrast, Heme Oxigenase (HO-1 level is induced by CDDP treatment, and ALA treatment further up-regulates HO-1 levels. In NRK-52E cells, the CDDP-induced reduction of protein and mRNA levels of mitochondrial enzymes was significantly recovered by ALA + Fe. CDDP-induced apoptosis were ameliorated by ALA + Fe treatment. Furthermore, we evaluated the size of transplantated bladder carcinoma to the rat skin, and ALA did not change the anti cancer effects of CDDP. CONCLUSION: These data suggested that the protective role of ALA in cisplatin-induced AKI is via protection of mitochondrial viability and prevents tubular apoptosis. Also there are no significant effects of ALA on anticancer efficiency of CDDP in rats. Thus, ALA has the potential to prevent CDDP nephrotoxicity without compromising its anticancer efficacy.

  18. Protective efficacy of antioxidants on cisplatin-induced tissue damage caused in Leishmania donovani infected BALB/c mice against murine visceral leishmaniasis

    Directory of Open Access Journals (Sweden)

    Meenakshi Sharma

    2013-06-01

    Full Text Available Objective: Therapeutic interventions against visceral leishmaniasis (VL are limited and facing serious concerns of toxicity, high cost and emerging resistance, there is a greater interest in new drug developments which are cost effective, efficient and easily available to people suffering from leishmaniasis. Cisplatin (cis-diamminedichloroplatinum II; CDDP has been found to have antileishmanial activity in vitro and in vivo which lead towards an apoptosis like cell death of both promastigotes and amastigotes and a significant reduction in parasite load and enhanced DTH responses which suggested the generation of protective cell-mediated immune responses. But, at higher doses it causes nephrotoxicity-a major side effect. The present study was designed to evaluate the protective efficacy of antioxidants on cisplatin induced tissue damage in Leishmania donovani infected BALB/c mice. Materials and methods: L. donovani infected and uninfected animals were treated with higher doses (5 and 2.5 mg/kg body weight of cisplatin alone and in combination with antioxidants (vitamin C, vitamin E and silibinin for 5 days. Mice were examined for the protective effects of antioxidants on cisplatin indiced tissue damage by DNA fragmentation and histological studies of kidneys, liver and spleen. Results: The damage caused by cisplatin was ameliorated after the supplementation of antioxidants showing a marked reduction in the extent of tubular damage, the focal reaction changes in liver were reversed and no signs of toxicity in the spleen were reported. Moreover, no DNA damage was observed in animals treated with cisplatin along with various antioxidants. Conclusion: The present results showed that antioxidants helped in the amelioration of drug induced toxic effects against murine visceral leishmaniasis, making the combination a potential anti-leishmanial therapy. [J Interdiscipl Histopathol 2013; 1(3.000: 121-136

  19. Inhibition of p38-MAPK potentiates cisplatin-induced apoptosis via GSH depletion and increases intracellular drug accumulation in growth-arrested kidney tubular epithelial cells.

    Science.gov (United States)

    Rodríguez-García, Maria Elena; Quiroga, Adoración G; Castro, José; Ortiz, Alberto; Aller, Patricio; Mata, Felicísima

    2009-10-01

    We were interested in analyzing the regulation by mitogen-activated protein kinases (MAPKs) of cisplatin-provoked toxicity in epithelial renal tubule cell lines, when assayed under culture conditions (cell confluence plus serum deprivation), which mimic the characteristics of a nonproliferating epithelium. Under these restrictive growth conditions, cisplatin induced apoptosis with lower efficacy than in exponentially growing cells, and decreased p38-MAPK phosphorylation in NRK-52E and other (LLC-PK1, MDCK, HK2) cell lines. Moreover, cisplatin-provoked apoptosis was potentiated by cotreatment with p38-MAPK-specific inhibitors (SB203580, SB220025) or transfection with a kinase-negative mutant of MKK6, whereas c-Jun NH2-terminal kinase or extracellular signal-regulated kinase/MAPK and ERK Kinase inhibitors were ineffective. By contrast, when applied to exponentially growing cells, cisplatin stimulated p38-MAPK phosphorylation and apoptosis, was attenuated by kinase inhibitors. Treatment of confluent/serum-deprived cells with cisplatin caused mitochondrial transmembrane potential disruption and activated the mitochondrial apoptotic pathway, as indicated by the decrease in Bcl-X(L) expression, increase in Bax expression and cytochrome c release, and these effects were potentiated by cotreatment with SB203580. Treatment of confluent/serum-deprived cells with cisplatin plus SB203580 decreased the intracellular reduced glutathione (GSH) content, and increased intracellular cisplatin accumulation as well as cisplatin binding to DNA. Cotreatment with the GSH-depleting agent D,L-buthionine-R,S-sulfoximine also potentiated cisplatin-provoked apoptosis. In summary, p38-MAPK inhibition potentiates cisplatin-provoked apoptosis in growth-arrested epithelial renal tubule cells, a result that may be explained at least in part by GSH depletion and drug transport alteration.

  20. Short-term exposure to 50 Hz ELF-EMF alters the cisplatin-induced oxidative response in AT478 murine squamous cell carcinoma cells.

    Science.gov (United States)

    Bułdak, Rafał Jakub; Polaniak, Renata; Bułdak, Lukasz; Zwirska-Korczala, Krystyna; Skonieczna, Magdalena; Monsiol, Aleksandra; Kukla, Michał; Duława-Bułdak, Anna; Birkner, Ewa

    2012-12-01

    The aim of this study was to assess the influence of cisplatin and an extremely low frequency electromagnetic field (ELF-EMF) on antioxidant enzyme activity and the lipid peroxidation ratio, as well as the level of DNA damage and reactive oxygen species (ROS) production in AT478 carcinoma cells. Cells were cultured for 24 and 72 h in culture medium with cisplatin. Additionally, the cells were irradiated with 50 Hz/1 mT ELF-EMF for 16 min using a solenoid as a source of the ELF-EMF. The amount of ROS, superoxide dismutase (SOD) isoenzyme activity, glutathione peroxidase (GSH-Px) activity, DNA damage, and malondialdehyde (MDA) levels were assessed. Cells that were exposed to cisplatin exhibited a significant increase in ROS and antioxidant enzyme activity. The addition of ELF-EMF exposure to cisplatin treatment resulted in decreased ROS levels and antioxidant enzyme activity. A significant reduction in MDA concentrations was observed in all of the study groups, with the greatest decrease associated with treatment by both cisplatin and ELF-EMF. Cisplatin induced the most severe DNA damage; however, when cells were also irradiated with ELF-EMF, less DNA damage occurred. Exposure to ELF-EMF alone resulted in an increase in DNA damage compared to control cells. ELF-EMF lessened the effects of oxidative stress and DNA damage that were induced by cisplatin; however, ELF-EMF alone was a mild oxidative stressor and DNA damage inducer. We speculate that ELF-EMF exerts differential effects depending on the exogenous conditions. This information may be of value for appraising the pathophysiologic consequences of exposure to ELF-EMF.

  1. Peripheral Receptor Mechanisms Underlying Orofacial Muscle Pain and Hyperalgesia

    Science.gov (United States)

    Saloman, Jami L.

    Musculoskeletal pain conditions, particularly those associated with temporomandibular joint and muscle disorders (TMD) are severely debilitating and affect approximately 12% of the population. Identifying peripheral nociceptive mechanisms underlying mechanical hyperalgesia, a prominent feature of persistent muscle pain, could contribute to the development of new treatment strategies for the management of TMD and other muscle pain conditions. This study provides evidence of functional interactions between ligand-gated channels, P2X3 and TRPV1/TRPA1, in trigeminal sensory neurons, and proposes that these interactions underlie the development of mechanical hyperalgesia. In the masseter muscle, direct P2X3 activation, via the selective agonist αβmeATP, induced a dose- and time-dependent hyperalgesia. Importantly, the αβmeATP-induced hyperalgesia was prevented by pretreatment of the muscle with a TRPV1 antagonist, AMG9810, or the TRPA1 antagonist, AP18. P2X3 was co-expressed with both TRPV1 and TRPA1 in masseter muscle afferents confirming the possibility for intracellular interactions. Moreover, in a subpopulation of P2X3 /TRPV1 positive neurons, capsaicin-induced Ca2+ transients were significantly potentiated following P2X3 activation. Inhibition of Ca2+-dependent kinases, PKC and CaMKII, prevented P2X3-mechanical hyperalgesia whereas blockade of Ca2+-independent PKA did not. Finally, activation of P2X3 induced phosphorylation of serine, but not threonine, residues in TRPV1 in trigeminal sensory neurons. Significant phosphorylation was observed at 15 minutes, the time point at which behavioral hyperalgesia was prominent. Similar data were obtained regarding another nonselective cation channel, the NMDA receptor (NMDAR). Our data propose P2X3 and NMDARs interact with TRPV1 in a facilitatory manner, which could contribute to the peripheral sensitization underlying masseter hyperalgesia. This study offers novel mechanisms by which individual pro-nociceptive ligand

  2. The terminal basal mitosis of chicken retinal Lim1 horizontal cells is not sensitive to cisplatin-induced cell cycle arrest.

    Science.gov (United States)

    Shirazi Fard, Shahrzad; Thyselius, Malin; All-Ericsson, Charlotta; Hallböök, Finn

    2014-01-01

    For proper development, cells need to coordinate proliferation and cell cycle-exit. This is mediated by a cascade of proteins making sure that each phase of the cell cycle is controlled before the initiation of the next. Retinal progenitor cells divide during the process of interkinetic nuclear migration, where they undergo S-phase on the basal side, followed by mitoses on the apical side of the neuroepithelium. The final cell cycle of chicken retinal horizontal cells (HCs) is an exception to this general cell cycle behavior. Lim1 expressing (+) horizontal progenitor cells (HPCs) have a heterogenic final cell cycle, with some cells undergoing a terminal mitosis on the basal side of the retina. The results in this study show that this terminal basal mitosis of Lim1+ HPCs is not dependent on Chk1/2 for its regulation compared to retinal cells undergoing interkinetic nuclear migration. Neither activating nor blocking Chk1 had an effect on the basal mitosis of Lim1+ HPCs. Furthermore, the Lim1+ HPCs were not sensitive to cisplatin-induced DNA damage and were able to continue into mitosis in the presence of γ-H2AX without activation of caspase-3. However, Nutlin3a-induced expression of p21 did reduce the mitoses, suggesting the presence of a functional p53/p21 response in HPCs. In contrast, the apical mitoses were blocked upon activation of either Chk1/2 or p21, indicating the importance of these proteins during the process of interkinetic nuclear migration. Inhibiting Cdk1 blocked M-phase transition both for apical and basal mitoses. This confirmed that the cyclin B1-Cdk1 complex was active and functional during the basal mitosis of Lim1+ HPCs. The regulation of the final cell cycle of Lim1+ HPCs is of particular interest since it has been shown that the HCs are able to sustain persistent DNA damage, remain in the cell cycle for an extended period of time and, consequently, survive for months.

  3. Opioid-induced hyperalgesia (OIH): a real clinical problem or just an experimental phenomenon?

    Science.gov (United States)

    Eisenberg, Elon; Suzan, Erica; Pud, Dorit

    2015-03-01

    Although opioid-induced hyperalgesia (OIH) is mentioned as a potential cause of opioid dose escalation without adequate analgesia, true evidence in support of this notion is relatively limited. Most studies conducted in the context of acute and experimental pain, which seemingly demonstrated evidence for OIH, actually might have measured other phenomena such as acute opioid withdrawal or tolerance. OIH studies in patients with chronic pain have used various experimental pain models (such as cold pain tolerance or heat pain intensity). Therefore, the fact that they have yielded inconsistent results is hard to interpret. Thus far, with the exception of a few clinical case reports on OIH in patients with cancer pain and one prospective study in patients with chronic neuropathic pain, evidence for OIH in patients with chronic or cancer-related pain is lacking. Whether experimental pain models are necessary for establishing the clinical diagnosis of OIH, and which specific model is preferred, are yet to be determined.

  4. Co-culture of bone marrow-derived mesenchymal stem cells overexpressing lipocalin 2 with HK-2 and HEK293 cells protects the kidney cells against cisplatin-induced injury.

    Science.gov (United States)

    Halabian, Raheleh; Roudkenar, Mehryar Habibi; Jahanian-Najafabadi, Ali; Hosseini, Kamran Mousavi; Tehrani, Hossein Abdul

    2015-02-01

    Conditioned medium of mesenchymal stem cells (MSCs) is now being used for its cytoprotective effects, especially when the cells are equipped with cytoprotective factors to strengthen them against unfavorable microenvironments. Overexpression of Lcn2 in MSCs mimics in vivo kidney injury. Hence, unraveling how Lcn2-engineered MSCs affect kidney cells has been investigated. Cisplatin treated HK-2 or HEK293 kidney cells were co-cultivated with Lcn2 overexpressing MSCs in upper and lower chambers of transwell plates. Proliferation, apoptosis, and expression of growth factors and cytokines were assessed in the kidney cells. Co-cultivation with the MSCs-Lcn2 not only inhibited cisplatin-induced cytotoxicity in the HK-2 and HEK293 cells, but increased proliferation rate, prevented cisplatin-induced apoptosis, and increased expression of growth factors and the amount of antioxidants in the kidney cells. Thus Lcn2-engineered MSCs can ameliorate and repair injured kidney cells in vitro, which strongly suggests there are beneficial effects of the MSCs-Lcn2 in cell therapy of kidney injury.

  5. Suspected opioid-induced hyperalgesia in an infant.

    Science.gov (United States)

    Hallett, B R; Chalkiadis, G A

    2012-01-01

    One explanation for diminished opioid analgesic efficacy is opioid-induced hyperalgesia (OIH). We report a case of OIH in an infant with gastroschisis, requiring multiple surgical interventions and prolonged sedation for ventilation. This is the first report of OIH in an infant. On day 41 of life after nine separate surgical interventions, the patient's pain scores increased and remained elevated, despite increasing opioid administration. The patient also developed hyperalgesia, allodynia, and photophobia and became extremely irritable upon handling. Other possible causes were excluded, including interruption to opioid delivery, sepsis, acid-base and electrolyte disturbance, and ongoing surgical pathology. An opioid rotation to hydromorphone was initiated and ketamine was commenced. Sedation for ventilation was achieved with dexmedetomidine and midazolam infusions. Over a period of 24 h after opioid de-escalation, pain scores reduced rapidly and the patient became significantly less irritable with handling. All infusions were gradually weaned and eventually ceased.

  6. When medications make pain worse: opioid-induced hyperalgesia.

    Science.gov (United States)

    Martin, Caren McHenry

    2011-08-01

    Opioid medications are commonly used to treat moderate-to-severe pain. While these medications are generally an effective means of pain control, they can, in rare cases, actually exacerbate the pain. This paradoxical reaction is called opioid-induced hyperalgesia (OIH). Patients experiencing OIH may benefit from decreasing or discontinuing the opioid, switching to an alternative opioid, and/or using a nonopioid medication for pain.

  7. [Opioid-induced hyperalgesia. Pathophysiology and clinical relevance].

    Science.gov (United States)

    Koppert, W

    2004-05-01

    Opioids are the drugs of choice for the treatment of moderate to severe acute and chronic pain. However, clinical evidence suggests that opioids can elicit increased sensitivity to noxious stimuli suggesting that administration of opioids can activate both pain inhibitory and pain facilitatory systems. Acute receptor desensitization via uncoupling of the receptor from G-proteins, up-regulation of the cAMP pathway, activation of the N-methyl-D-aspartate (NMDA) receptor system, as well as descending facilitation, have been proposed as potential mechanisms underlying opioid-induced hyperalgesia. Numerous reports exist demonstrating that opioid-induced hyperalgesia is observed both in animal and human experimental models. Brief exposures to micro-receptor agonists induce long-lasting hyperalgesic effects for days, which might by reflected by clinical observations that large doses of intraoperative micro-receptor agonists increased postoperative pain and morphine consumption. Furthermore, the prolonged use of opioids in patients often requires increasing doses and may be accompanied by the development of abnormal pain. Successful strategies that may decrease or prevent opioid-induced hyperalgesia include the concomitant administration of drugs like NMDA-antagonists, alpha(2)-agonists, or non-steroidal anti-inflammatory drugs (NSAIDs), opioid rotation or combinations of opioids with different receptor selectivity.

  8. Carbamazepine Withdrawal-induced Hyperalgesia in Chronic Neuropathic Pain.

    Science.gov (United States)

    Ren, Zhenyu; Yang, Bing; Yang, Bin; Shi, Le; Sun, Qing-Li; Sun, A-Ping; Lu, Lin; Liu, Xiaoguang; Zhao, Rongsheng; Zhai, Suodi

    2015-11-01

    Combined pharmacological treatments are the most used approach for neuropathic pain. Carbamazepine, an antiepileptic agent, is generally used as a third-line treatment for neuropathic pain and can be considered an option only when patients have not responded to the first- and second-line medications. In the case presented herein, a patient with neuropathic pain was treated using a combined pharmacological regimen. The patient's pain deteriorated, despite increasing the doses of opioids, when carbamazepine was discontinued, potentially because carbamazepine withdrawal disrupted the balance that was achieved by the multifaceted pharmacological regimen, thus inducing hyperalgesia. Interestingly, when carbamazepine was prescribed again, the patient's pain was successfully managed. Animal research has reported that carbamazepine can potentiate the analgesic effectiveness of morphine in rodent models of neuropathic pain and postoperative pain. This clinical case demonstrates that carbamazepine may have a synergistic effect on the analgesic effectiveness of morphine and may inhibit or postpone opioid-induced hyperalgesia. We postulate that a probable mechanism of action of carbamazepine may involve -aminobutyric acid-ergic potentiation and the interruption of glutamatergic function via N-methyl-D-aspartate receptors. Further research is warranted to clarify the analgesic action of carbamazepine and its potential use for the prevention of opioid-induced hyperalgesia in chronic neuropathic pain patients.

  9. The impact of opioid-induced hyperalgesia for postoperative pain.

    Science.gov (United States)

    Koppert, Wolfgang; Schmelz, Martin

    2007-03-01

    Clinical evidence suggests that--besides their well known analgesic activity - opioids can increase rather than decrease sensitivity to noxious stimuli. Based on the observation that opioids can activate pain inhibitory and pain facilitatory systems, this pain hypersensitivity has been attributed to a relative predominance of pronociceptive mechanisms. Acute receptor desensitization via uncoupling of the receptor from G-proteins, upregulation of the cAMP pathway, activation of the N-methyl-D-aspartate (NMDA)-receptor system, as well as descending facilitation, have been proposed as potential mechanisms underlying opioid-induced hyperalgesia. Numerous reports exist demonstrating that opioid-induced hyperalgesia is observed both in animal and human experimental models. Brief exposures to micro-receptor agonists induce long-lasting hyperalgesic effects for days in rodents, and also in humans large-doses of intraoperative micro-receptor agonists were found to increase postoperative pain and morphine consumption. Furthermore, the prolonged use of opioids in patients is often associated with a requirement for increasing doses and the development of abnormal pain. Successful strategies that may decrease or prevent opioid-induced hyperalgesia include the concomitant administration of drugs like NMDA-antagonists, alpha2-agonists, or non-steroidal anti-inflammatory drugs (NSAIDs), opioid rotation or combinations of opioids with different receptor/selectivity.

  10. Trigeminal-Rostral Ventromedial Medulla circuitry is involved in orofacial hyperalgesia contralateral to tissue injury

    Directory of Open Access Journals (Sweden)

    Chai Bryan

    2012-10-01

    Full Text Available Abstract Background Our previous studies have shown that complete Freund’s adjuvant (CFA-induced masseter inflammation and microinjection of the pro-inflammatory cytokine interleukin-1β (IL-1β into the subnucleus interpolaris/subnucleus caudalis transition zone of the spinal trigeminal nucleus (Vi/Vc can induce contralateral orofacial hyperalgesia in rat models. We have also shown that contralateral hyperalgesia is attenuated with a lesion of the rostral ventromedial medulla (RVM, a critical site of descending pain modulation. Here we investigated the involvement of the RVM-Vi/Vc circuitry in mediating contralateral orofacial hyperalgesia after an injection of CFA into the masseter muscle. Results Microinjection of the IL-1 receptor antagonist (5 nmol, n=6 into the ipsilateral Vi/Vc attenuated the CFA-induced contralateral hyperalgesia but not the ipsilateral hyperalgesia. Intra-RVM post-treatment injection of the NK1 receptor antagonists, RP67580 (0.5-11.4 nmol and L-733,060 (0.5-11.4 nmol, attenuated CFA-induced bilateral hyperalgesia and IL-1β induced bilateral hyperalgesia. Serotonin depletion in RVM neurons prior to intra-masseter CFA injection prevented the development of contralateral hyperalgesia 1–3 days after CFA injection. Inhibition of 5-HT3 receptors in the contralateral Vi/Vc with direct microinjection of the select 5-HT3 receptor antagonist, Y-25130 (2.6-12.9 nmol, attenuated CFA-induced contralateral hyperalgesia. Lesions to the ipsilateral Vc prevented the development of ipsilateral hyperalgesia but did not prevent the development of contralateral hyperalgesia. Conclusions These results suggest that the development of CFA-induced contralateral orofacial hyperalgesia is mediated through descending facilitatory mechanisms of the RVM-Vi/Vc circuitry.

  11. Effects of intrathecal administration of nitric oxide synthase inhibitors on carrageenan-induced thermal hyperalgesia

    OpenAIRE

    Osborne, Michael G; Coderre, Terence J

    1999-01-01

    We examined the effects of various nitric oxide synthase (NOS) inhibitors on carrageenan-induced thermal hyperalgesia.First, we determined the time point at which a subcutaneous plantar injection of carrageenan into the rat hindpaw produced maximum thermal hyperalgesia. Subsequently, we demonstrated that intrathecal administration of the non-selective NOS inhibitor L-NG-nitro-arginine methyl ester (L-NAME) produces a dose-dependent reduction of carrageenan-induced thermal hyperalgesia.Four re...

  12. Cisplatin induced paroxysmal supraventricular tachycardia

    Directory of Open Access Journals (Sweden)

    Waseem Raja

    2013-01-01

    Full Text Available Cisplatin or cis-diamminedichloroplatinum (CDDP is the first member of a class of platinum-containing anti-cancer drugs that act by binding to and causing cross-linking of deoxyribonucleic acid, which ultimately triggers apoptosis. Cisplatin has a broad-spectrum antineoplastic activity against various types of human tumors. Unfortunately, the optimal usefulness of Cisplatin is limited secondary to its dose related toxicity especially nephrotoxicity. Cisplatin chemotherapy is also associated with cardiotoxic effects that may range from silent arrhythmias to heart failure and even sudden cardiac death. These effects are more pronounced when cisplatin is combined with other cardiotoxic drugs. Here, we report a case of patient of cancer lung who developed paroxysmal supraventricular tachycardia following administration of Cisplatin. A brief review of the literature follows.

  13. Cisplatin induced paroxysmal supraventricular tachycardia.

    Science.gov (United States)

    Raja, Waseem; Mir, M Hussain; Dar, Imtiyaz; Banday, Muzamil Ahmad; Ahmad, Irfan

    2013-10-01

    Cisplatin or cis-diamminedichloroplatinum (CDDP) is the first member of a class of platinum-containing anti-cancer drugs that act by binding to and causing cross-linking of deoxyribonucleic acid, which ultimately triggers apoptosis. Cisplatin has a broad-spectrum antineoplastic activity against various types of human tumors. Unfortunately, the optimal usefulness of Cisplatin is limited secondary to its dose related toxicity especially nephrotoxicity. Cisplatin chemotherapy is also associated with cardiotoxic effects that may range from silent arrhythmias to heart failure and even sudden cardiac death. These effects are more pronounced when cisplatin is combined with other cardiotoxic drugs. Here, we report a case of patient of cancer lung who developed paroxysmal supraventricular tachycardia following administration of Cisplatin. A brief review of the literature follows.

  14. Opioid-induced hyperalgesia and rapid opioid detoxification after tacrolimus administration.

    Science.gov (United States)

    Siniscalchi, Antonio; Piraccini, Emanuele; Miklosova, Zuzana; Taddei, Stefania; Faenza, Stefano; Martinelli, Gerardo

    2008-02-01

    Opioids can induce central sensitization and hyperalgesia, referred to as "opioid-induced hyperalgesia." Our report describes a patient who underwent intestinal transplant followed by immunosuppressant-related neuropathic pain. Her pain was treated with limited success over the course of 3 yr with different therapies, including i.v. morphine. She developed opioid-induced hyperalgesia, which was successfully treated with rapid detoxification under general anesthesia. Detoxification improved her quality of life, including the ability to resume physiotherapy. Six months after treatment, she remained opioid free. Our experience suggests that rapid detoxification under general anesthesia may be an effective treatment for opioid-induced hyperalgesia and merits comparison to traditional detoxification methods.

  15. NMDA and AMPA receptors contribute to the maintenance of substance P-induced thermal hyperalgesia.

    Science.gov (United States)

    Nakayama, Tomohiro; Naono, Rumi; Ikeda, Tetsuya; Nishimori, Toshikazu

    2010-05-01

    It is well known that intrathecal administration of substance P (SP) induces thermal hyperalgesia, but the mechanisms underlying the maintenance of SP-induced thermal hyperalgesia remain to be clarified. Thus, to clarify the receptors involved in the maintenance of SP-induced thermal hyperalgesia, the effect of administering SP or glutamate receptor agonists, NMDA or AMPA, under SP-induced thermal hyperalgesia was investigated. Also, the effect of pretreatment with protein kinase inhibitors on scratching behavior by NMDA or AMPA under SP-induced thermal hyperalgesia was examined. Under SP-induced thermal hyperalgesia, the number of scratchings following SP administration was time-dependently suppressed, whereas the number of scratchings after NMDA or AMPA administration was markedly enhanced and SP-induced thermal hyperalgesia was attenuated by pretreatment with NMDA or AMPA receptor antagonist. Furthermore, pretreatment with kinase inhibitors significantly attenuated the enhancement of scratching behavior by NMDA or AMPA under SP-induced thermal hyperalgesia. These findings indicate that SP-induced thermal hyperalgesia may be maintained through the enhanced responsiveness of NMDA or AMPA receptors, but not the receptor of SP, mediated by kinases.

  16. Galanin-Mediated Behavioural Hyperalgesia from the Dorsomedial Nucleus of the Hypothalamus Involves Two Independent Descending Pronociceptive Pathways.

    Directory of Open Access Journals (Sweden)

    Diana Amorim

    Full Text Available Activation of the dorsomedial nucleus of the hypothalamus (DMH by galanin (GAL induces behavioural hyperalgesia. Since DMH neurones do not project directly to the spinal cord, we hypothesized that the medullary dorsal reticular nucleus (DRt, a pronociceptive region projecting to the spinal dorsal horn (SDH and/or the serotoninergic raphe-spinal pathway acting on the spinal 5-HT3 receptor (5HT3R could relay descending nociceptive facilitation induced by GAL in the DMH. Heat-evoked paw-withdrawal latency (PWL and activity of SDH neurones were assessed in monoarthritic (ARTH and control (SHAM animals after pharmacological manipulations of the DMH, DRt and spinal cord. The results showed that GAL in the DMH and glutamate in the DRt lead to behavioural hyperalgesia in both SHAM and ARTH animals, which is accompanied particularly by an increase in heat-evoked responses of wide-dynamic range neurons, a group of nociceptive SDH neurones. Facilitation of pain behaviour induced by GAL in the DMH was reversed by lidocaine in the DRt and by ondansetron, a 5HT3R antagonist, in the spinal cord. However, the hyperalgesia induced by glutamate in the DRt was not blocked by spinal ondansetron. In addition, in ARTH but not SHAM animals PWL was increased after lidocaine in the DRt and ondansetron in the spinal cord. Our data demonstrate that GAL in the DMH activates two independent descending facilitatory pathways: (i one relays in the DRt and (ii the other one involves 5-HT neurones acting on spinal 5HT3Rs. In experimental ARTH, the tonic pain-facilitatory action is increased in both of these descending pathways.

  17. Comparison of pain models to detect opioid-induced hyperalgesia

    Directory of Open Access Journals (Sweden)

    Krishnan S

    2012-04-01

    Full Text Available Sumithra Krishnan1, Amy Salter2, Thomas Sullivan2, Melanie Gentgall3, Jason White4, Paul Rolan11Discipline of Pharmacology, School of Medical Sciences, The University of Adelaide, 2Discipline of Public Health, The University of Adelaide, 3Pain and Anesthesia Research Clinic, Royal Adelaide Hospital, 4Pharmacy School, University of South Australia, Adelaide, South Australia, AustraliaObjective: Chronic opioid therapy may be associated with hyperalgesia. Our objective was to determine if opioid-induced hyperalgesia detection sensitivity is dependent on the stimulus used to detect it.Methods: This open design study compared the detection of hyperalgesia in opioid-dependent subjects (n = 16 and healthy control subjects (n = 16 using the following pain stimuli: cold pain, electrical stimulation, mechanical pressure, and ischemic pain. The opioid-dependent subjects were maintained on either methadone (n = 8 or buprenorphine (n = 8 for at least 3 months. None of the controls was dependent on opioids or other drugs of abuse.Results: The opioid-dependent subjects were markedly more sensitive than controls to the cold pain test. Compared with the control group, the hazard ratio for ceasing the test due to intolerable pain was 7.7 (95% confidence interval [CI] 2.6–23.3 in the buprenorphine group and 4.5 (95% CI 1.7–15.6 in the methadone group, with similar data for the cold pain threshold. Of the remaining tests, there were differences only for the electrical pain threshold between treatment groups, with the geometric mean threshold in the buprenorphine group being 1.5 (95% CI 1.1–1.9-fold higher (ie, less sensitive than that of the controls; the geometric mean for the methadone group was 1.3 (95% CI 1.04–1.7-fold higher than that of the controls. There were no significant differences between buprenorphine and methadone patients in test responses. Women were more sensitive to the cold pain (hazard ratio for tolerance, 3.1 [95% CI 1.4–7.3] and

  18. Mechanical and thermal hyperalgesia and ectopic neuronal discharge after chronic compression of dorsal root ganglia.

    Science.gov (United States)

    Song, X J; Hu, S J; Greenquist, K W; Zhang, J M; LaMotte, R H

    1999-12-01

    Chronic compression of the dorsal root ganglion (CCD) was produced in adult rats by implanting a stainless steel rod unilaterally into the intervertebral foramen, one rod at L(4) and another at L(5). Two additional groups of rats received either a sham surgery or an acute injury consisting of a transient compression of the ganglion. Withdrawal of the hindpaw was used as evidence of a nocifensive response to mechanical and thermal stimulation of the plantar surface. In addition, extracellular electrophysiological recordings of spontaneous discharges were obtained from dorsal root fibers of formerly compressed ganglia using an in vitro nerve-DRG-dorsal root preparation. The mean threshold force of punctate indentation and the mean threshold temperature of heating required to elicit a 50% incidence of foot withdrawal ipsilateral to the CCD were significantly lower than preoperative values throughout the 35 days of postoperative testing. The number of foot withdrawals ipsilateral to the CCD during a 20-min contact with a temperature-controlled floor was significantly increased over preoperative values throughout postoperative testing when the floor was 4 degrees C (hyperalgesia) and, to a lesser extent, when it was 30 degrees C (spontaneous pain). Stroking the foot with a cotton wisp never elicited a reflex withdrawal before surgery but did so in most rats tested ipsilateral to the CCD during the first 2 postoperative weeks. In contrast, the CCD produced no changes in responses to mechanical or thermal stimuli on the contralateral foot. The sham operation and acute injury produced no change in behavior other than slight, mechanical hyperalgesia for approximately 1 day, ipsilateral to the acute injury. Ectopic spontaneous discharges generated within the chronically compressed ganglion and, occurring in the absence of blood-borne chemicals and without an intact sympathetic nervous system, were recorded from neurons with intact, conducting, myelinated or unmyelinated

  19. Tetrodotoxin suppresses thermal hyperalgesia and mechanical allodynia in a rat full thickness thermal injury pain model.

    Science.gov (United States)

    Salas, Margaux M; McIntyre, Matthew K; Petz, Lawrence N; Korz, Walter; Wong, Donald; Clifford, John L

    2015-10-21

    Burn injuries have been identified as the primary cause of injury in 5% of U.S. military personnel evacuated from Operations Iraqi Freedom and Enduring Freedom. Severe burn-associated pain is typically treated with opioids such as fentanyl, morphine, and methadone. Side effects of opioids include respiratory depression, cardiac depression, decrease in motor and cognitive function, as well as the development of hyperalgesia, tolerance and dependence. These effects have led us to search for novel analgesics for the treatment of burn-associated pain in wounded combat service members. Tetrodotoxin (TTX) is a selective voltage-gated sodium channel blocker currently in clinical trials as an analgesic. A phase 3 clinical trial for cancer-related pain has been completed and phase 3 clinical trials on chemotherapy-induced neuropathic pain are planned. It has also been shown in mice to inhibit the development of chemotherapy-induced neuropathic pain. TTX was originally identified as a neurotoxin in marine animals but has now been shown to be safe in humans at therapeutic doses. The antinociceptive effects of TTX are thought to be due to inhibition of Na(+) ion influx required for initiation and conduction of nociceptive impulses. One TTX sensitive sodium channel, Nav1.7, has been shown to be essential in lowering the heat pain threshold after burn injuries. To date, the analgesic effect of TTX has not been tested in burn-associated pain. Male Sprague-Dawley rats were subjected to a full thickness thermal injury on the right hind paw. TTX (8 μg/kg) was administered once a day systemically by subcutaneous injection beginning 3 days post thermal injury and continued through 7 days post thermal injury. Thermal hyperalgesia and mechanical allodynia were assessed 60 and 120 min post injection on each day of TTX treatment. TTX significantly reduced thermal hyperalgesia at all days tested and had a less robust, but statistically significant suppressive effect on mechanical

  20. Effect of transient receptor potential vanilloid 1 (TRPV1) receptor antagonist compounds SB705498, BCTC and AMG9810 in rat models of thermal hyperalgesia measured with an increasing-temperature water bath.

    Science.gov (United States)

    Tékus, Valéria; Bölcskei, Kata; Kis-Varga, Agnes; Dézsi, László; Szentirmay, Eva; Visegrády, András; Horváth, Csilla; Szolcsányi, János; Petho, Gábor

    2010-09-01

    The transient receptor potential vanilloid 1 (TRPV1) receptor is activated by noxious heat, various endogenous mediators and exogenous irritants. The aim of the present study was to compare three TRPV1 receptor antagonists (SB705498, BCTC and AMG9810) in rat models of heat hyperalgesia. The behavioural noxious heat threshold, defined as the lowest temperature evoking nocifensive reaction, was measured with an increasing-temperature water bath. The effects of TRPV1 receptor antagonists were assessed in thermal hyperalgesia induced by the TRPV1 agonist resiniferatoxin (RTX), mild heat injury (51 degrees C, 20s) or plantar incision in rats. The control heat threshold was 43.2+/-0.4 degrees C. RTX induced an 8-10 degrees C decrease in heat threshold which was dose-dependently inhibited by oral pre-treatment with any of the TRPV1 receptor antagonists with a minimum effective dose of 1mg/kg. The mild heat injury-evoked 7-8 degrees C heat threshold drop was significantly reversed by all three antagonists injected i.p. as post-treatment. The minimum effective doses were as follows: SB705498 10, BCTC 3 and AMG9810 1mg/kg. Plantar incision-induced heat threshold drop (7-8 degrees C) was dose-dependently diminished by an oral post-treatment with any of the antagonists with minimum effective doses of 10, 3 and 3mg/kg, respectively. Assessment of RTX hyperalgesia by measurement of the paw withdrawal latency with a plantar test apparatus yielded 30 mg/kg minimum effective dose for each antagonist. In conclusion, measurement of the noxious heat threshold with the increasing-temperature water bath is suitable to sensitively detect the effects of TRPV1 receptor antagonists in thermal hyperalgesia models.

  1. Endogenous prolactin generated during peripheral inflammation contributes to thermal hyperalgesia.

    Science.gov (United States)

    Scotland, Phoebe E; Patil, Mayur; Belugin, Sergei; Henry, Michael A; Goffin, Vincent; Hargreaves, Kenneth M; Akopian, Armen N

    2011-09-01

    Prolactin (PRL) is a hormone and a neuromodulator. It sensitizes TRPV1 (transient receptor potential cation channel subfamily V member 1) responses in sensory neurons, but it is not clear whether peripheral inflammation results in the release of endogenous PRL, or whether endogenous PRL is capable of acting as an inflammatory mediator in a sex-dependent manner. To address these questions, we examined inflammation-induced release of endogenous PRL, and its regulation of thermal hyperalgesia in female and male rats. PRL is expressed in several types of peripheral neuronal and non-neuronal cells, including TRPV1-positive nerve fibers, preadipocytes and activated macrophages/monocytes localized in the vicinity of nerves. Evaluation of PRL levels in hindpaws and plasma indicated that complete Freund's adjuvant (CFA) stimulates release of peripheral, but not systemic, PRL within 6-48 h in both ovariectomized females with estradiol replacement (OVX-E) and intact male rats. The time course of release varies in OVX-E and intact male rats. We next employed the prolactin receptor (PRL-R) antagonist Δ1-9-G129R-hPRL to assess the role of locally produced PRL in nociception. Applied at a ratio of 1 : 1 (PRL:Δ1-9-G129R-hPRL; 40 nm each), this antagonist was able to nearly (≈ 80%) reverse PRL-induced sensitization of capsaicin responses in rat sensory neurons. CFA-induced inflammatory thermal hyperalgesia in OVX-E rat hindpaws was significantly reduced in a dose-dependent manner by the PRL-R antagonist at 6 h but not at 24 h. In contrast, PRL contributed to inflammatory thermal hyperalgesia in intact male rats at 24, but not at 6 h. These findings indicate that inflammation leads to accumulation of endogenous PRL in female and male rats. Furthermore, PRL acts as an inflammatory mediator at different time points for female and intact male rats.

  2. Impaired nocifensive behaviours and mechanical hyperalgesia, but enhanced thermal allodynia in pituitary adenylate cyclase-activating polypeptide deficient mice.

    Science.gov (United States)

    Sándor, K; Kormos, V; Botz, B; Imreh, A; Bölcskei, K; Gaszner, B; Markovics, A; Szolcsányi, J; Shintani, N; Hashimoto, H; Baba, A; Reglodi, D; Helyes, Z

    2010-10-01

    Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) and its receptors (PAC1 and VPAC) have been shown in the spinal dorsal horn, dorsal root ganglia and sensory nerve terminals. Data concerning the role of PACAP in central pain transmission are controversial and we have recently published its divergent peripheral effects on nociceptive processes. The aim of the present study was to investigate acute somatic and visceral nocifensive behaviours, partial sciatic nerve ligation-evoked chronic neuropathic, as well as resiniferatoxin-induced inflammatory thermal and mechanical hyperalgesia in PACAP deficient (PACAP(-/-)) mice to elucidate its overall function in pain transmission. Neuronal activation was investigated with c-Fos immunohistochemistry. Paw lickings in the early (0-5 min) and late (20-45 min) phases of the formalin test were markedly reduced in PACAP(-/-) mice. Acetic acid-evoked abdominal contractions referring to acute visceral chemonociception was also significantly attenuated in PACAP knockout animals. In both models, the excitatory role of PACAP was supported by markedly greater c-Fos expression in the periaqueductal grey and the somatosensory cortex. In PACAP-deficient animals neuropathic mechanical hyperalgesia was absent, while c-Fos immunopositivity 20 days after the operation was significantly higher. In this chronic model, these neurons are likely to indicate the activation of secondary inhibitory pathways. Intraplantarly injected resiniferatoxin-evoked mechanical hyperalgesia involving both peripheral and central processes was decreased, but thermal allodynia mediated by only peripheral mechanisms was increased in PACAP(-/-) mice. These data clearly demonstrate an overall excitatory role of PACAP in pain transmission originating from both exteroceptive and interoceptive areas, it is also involved in central sensitization. This can be explained by the signal transduction mechanisms of its identified receptors, both PAC1 and VPAC

  3. [The clinical relevance of opioid-induced hyperalgesia remains unresolved].

    Science.gov (United States)

    Sørensen, Jakob; Sjøgren, Per

    2011-03-28

    Opioids are widely used as analgesics in chronic pain of malignant as well as non-malignant origin. During opioid treatment, pain is occasionally worsened. This could be due to progression of the disease or tolerance or opioid-induced hyperalgesia (OIH). The present article summarizes the preclinical and clinical data in support of the existence of OIH. Further, possible mechanisms and potential treatments are outlined. We conclude that only a few clinical studies on OIH are available. However, a growing body of experimental data supports the presence of OIH in clinical settings. Diagnostic tools for assessment of OIH have yet to be developed.

  4. Does naloxone reinstate secondary hyperalgesia in humans after resolution of a burn injury?

    DEFF Research Database (Denmark)

    Pereira, Manuel P; Werner, Mads U; Ringsted, Thomas K;

    2013-01-01

    Development of secondary hyperalgesia following a cutaneous injury is a centrally mediated, robust phenomenon. The pathophysiological role of endogenous opioid signalling to the development of hyperalgesia is unclear. Recent animal studies, carried out after the resolution of inflammatory pain, h......, have demonstrated reinstatement of tactile hypersensitivity following administration of μ-opioid-receptor-antagonists. In the present study in humans, we analyzed the effect of naloxone when given after the resolution of secondary hyperalgesia following a first-degree burn injury.......Development of secondary hyperalgesia following a cutaneous injury is a centrally mediated, robust phenomenon. The pathophysiological role of endogenous opioid signalling to the development of hyperalgesia is unclear. Recent animal studies, carried out after the resolution of inflammatory pain...

  5. Opioid-induced hyperalgesia: is it clinically relevant for the treatment of pain patients?

    Science.gov (United States)

    Raffa, Robert B; Pergolizzi, Joseph V

    2013-09-01

    There is a curious and paradoxic phenomenon, reliably demonstrated in animal models, that consists of an increased sensitivity to pain that is apparently induced by the very opioid drugs used to ameliorate the pain. This phenomenon is termed "opioid-induced hyperalgesia." Whether opioid-induced hyperalgesia occurs in humans, and, if so, to what extent and consequence, is far less established. This is a critical question for attempting to treat pain. If opioid-induced hyperalgesia develops in a patient, it would masquerade as tolerance (because the clinical effectiveness of the opioid would be diminished), yet the appropriate clinical adjustment would be precisely the opposite to that of tolerance. It would be to decrease, rather than increase, the dose of opioid. We review the evidence, particularly the clinical evidence, about opioid-induced hyperalgesia and the postulated mechanisms. We conclude that given the clinical ramifications, opioid-induced hyperalgesia is one of the most understudied important aspects of opioid research.

  6. 乙咪酯全身及鞘内用药对蜜蜂毒诱致大鼠热和机械性痛敏的抑制作用%Effects of intravenous and/or intrathecal etomidate on thermal and mechanical hyperalgesia induced by intraplantar injection of bee venum in rats

    Institute of Scientific and Technical Information of China (English)

    孙焱芫; 熊利泽; 曾祥龙; 陈军; 李会莉

    2001-01-01

    Objective To investigate whether etomidate (E) has any suppressive effects on hyperalgesia induced by intraplantar subcutaneous injection of bee venum (BV). Methods BV was injected into the plantar surface of one hind paw to produce hyperalgesia. Pain was estimated by measuring withdrawal response latency of the hindpaw to radiant heat and withdrawal threshold to von Frey filament of different stimulation intensity (40-580mN). Both injected and contralateral hind paw were tested. 36 adult male and female SD rats weighing 180-250g were randomly divided into 6 groups of 6 rats each:group C1 :normal control; group C2: hyperalgesia induced by BV; group V: intravenous E 1.28mg/kg before BV-induced hyperalgesia; group T: intrathecal E 20μg/10μl before BV-induced hyperalgesia; group TT: intrathecal E 20μg/10μl before induced hyperalgesia + intrathecal E 20μg/10μl 4h after induced hyperalgesia; group TV: intrathecal E 20μg/10μl before induced hyperalgesia + intravenous E 1.28mg/kg 4h after induced hyperalgesia. Intrathecal E was given through an implanted spinal cannulae. Pain response was measured 2 h after BV-induced hyperalgesia in group C2, V and T and 4 h after BV-induced latency of the injected hindpaw to heat stimulation drop by 86 % and withdrawal threshold to mechanical stimulation drop by 89% but also reduced the withdrawal latency of the contralateral hindpaw to heat prolonged the withdrawal latency to heat stimulation after intraplantar BV injection. Withdrawal latency to heat stimulation was further prolonged by intravenous or intrathecal etomidate given after BV-induced hyperalgesia. Withdrawal threshold to mechanical von Frey filament stimulation was increased significantly only by intrathecal etomidate pretreatment combined with intravenous etomidate given after BV-induced hyperalgesia. Conclusions Etomidate has suppressive effects on the primary and secondary BV-induced thermal hyperalgesia in a dose accumulative manner. The mechanism of

  7. Effects of COX inhibition on experimental pain and hyperalgesia during and after remifentanil infusion in humans.

    Science.gov (United States)

    Lenz, Harald; Raeder, Johan; Draegni, Tomas; Heyerdahl, Fridtjof; Schmelz, Martin; Stubhaug, Audun

    2011-06-01

    Opioids may enhance pain sensitivity resulting in opioid-induced hyperalgesia (OIH). Activation of spinal cyclooxygenase may play a role in the development of OIH. The aim of this study was to demonstrate remifentanil-induced postinfusion hyperalgesia in an electrical pain and a cold pain model, and to investigate whether COX-2 (parecoxib) or COX-1 (ketorolac) inhibition could prevent hyperalgesia after remifentanil infusion. Sixteen healthy males were enrolled in this randomized, double-blind, placebo-controlled crossover study. Each subject went through 4 sessions: control, remifentanil, parecoxib+remifentanil, and ketorolac+remifentanil. Transcutaneous electrical stimulation induced acute pain and areas of pinprick hyperalgesia. The areas of pinprick hyperalgesia were assessed before, during, and after a 30-minute infusion of either remifentanil or saline. The cold-pressor test (CPT) was performed before, at the end of, and 1 hour after the infusions. The subjects received a bolus of either saline, 40 mg parecoxib, or 30 mg ketorolac intravenously after the first CPT. The areas of pinprick hyperalgesia and CPT pain after the end of remifentanil infusion increased significantly compared to control (P pain and cold-pressor pain. Both parecoxib and ketorolac prevented hyperalgesia in the electrical model, parecoxib to a larger extent.

  8. TDAG8 involved in initiating inflammatory hyperalgesia and establishing hyperalgesic priming in mice

    Science.gov (United States)

    Dai, Shih-Ping; Huang, Ya-Han; Chang, Chung-Jen; Huang, Yu-Fen; Hsieh, Wei-Shan; Tabata, Yasuhiko; Ishii, Satoshii; Sun, Wei-Hsin

    2017-01-01

    Chronic pain, resulting from injury, arthritis, and cancer, is often accompanied by inflammation. High concentrations of protons found in inflamed tissues results in tissue acidosis, a major cause of pain and hyperalgesia. Acidosis signals may mediate a transition from acute to chronic hyperalgesia (hyperalgesic priming) via proton-sensing G-protein-coupled receptors (GPCRs). The expression of T-cell death-associated gene 8 (TDAG8), a proton-sensing GPCR, is increased during inflammatory hyperalgesia. Attenuating TDAG8 expression in the spinal cord inhibits bone cancer pain, but whether TDAG8 is involved in inflammatory hyperalgesia or hyperalgesic priming remains unclear. In this study, we used TDAG8-knockout or -knockdown to explore the role of TDAG8 in pain. Suppressed TDAG8 expression delayed the onset of inflammatory hyperalgesia and shortened hyperalgesic time in mice. In a dual acid-injection model (acid [pH 5.0] injected twice, 5 days apart), shRNA inhibition of TDAG8 shortened the duration of the second hyperalgesia. Similar results were found in TDAG8-deficient mice. The dual administration of TDAG8 agonist also confirmed that TDAG8 is involved in hyperalgsic priming. Accordingly, TDAG8 may mediate acidosis signals to initiate inflammatory hyperalgesia and establish hyperalgesic priming. PMID:28145512

  9. Opioid-induced hyperalgesia: when pain killers make pain worse.

    Science.gov (United States)

    Kaneria, Anshuni

    2014-06-04

    A 44-year-old woman had a temporal glioma and was admitted to the hospice with pain that was not controlled despite escalating opioids. Her pain levels rose after every dose increase resulting now in continuous pain, making her very low in mood. Her short-term memory had also declined in a stepwise fashion with each increase in opioids. Additionally, her poor health had had a detrimental effect on family life. Physical examination was difficult due to allodynia but no major abnormality was found. The team suspected opioid-induced hyperalgesia and decided to cut the patient's opioids by one-third initially. This immediately improved the overall pain. The opioids continued to be decreased incrementally every 1-2 days until the pain had disappeared completely. She was stabilised on a dose almost one-seventh of her original regime. Mood and memory also improved as opioids decreased and she was discharged home after 8 days.

  10. Opioid-induced hyperalgesia: clinically relevant or extraneous research phenomenon?

    Science.gov (United States)

    Tompkins, D Andrew; Campbell, Claudia M

    2011-04-01

    Opioids have become the unequivocal therapy of choice in treating many varieties of chronic pain. With the increased prescription of opioids, some unintended consequences have occurred. After prolonged opioid exposure, opioid-induced hyperalgesia (OIH), the paradoxical effect that opioid therapy may in fact enhance or aggravate preexisting pain, may occur. Over the past several decades, an increasing number of laboratory and clinical reports have suggested lowered pain thresholds and heightened atypical pain unrelated to the original perceived pain sensations as hallmarks of OIH. However, not all evidence supports the clinical importance of OIH, and some question whether the phenomenon exists at all. Here, we present a nonexhaustive, brief review of the recent literature. OIH will be reviewed in terms of preclinical and clinical evidence for and against its existence; recommendations for clinical evaluation and intervention also will be discussed.

  11. Classical conditioning and pain: conditioned analgesia and hyperalgesia.

    Science.gov (United States)

    Miguez, Gonzalo; Laborda, Mario A; Miller, Ralph R

    2014-01-01

    This article reviews situations in which stimuli produce an increase or a decrease in nociceptive responses through basic associative processes and provides an associative account of such changes. Specifically, the literature suggests that cues associated with stress can produce conditioned analgesia or conditioned hyperalgesia, depending on the properties of the conditioned stimulus (e.g., contextual cues and audiovisual cues vs. gustatory and olfactory cues, respectively) and the proprieties of the unconditioned stimulus (e.g., appetitive, aversive, or analgesic, respectively). When such cues are associated with reducers of exogenous pain (e.g., opiates), they typically increase sensitivity to pain. Overall, the evidence concerning conditioned stress-induced analgesia, conditioned hyperalagesia, conditioned tolerance to morphine, and conditioned reduction of morphine analgesia suggests that selective associations between stimuli underlie changes in pain sensitivity.

  12. The Effect of Vitamin E on Cisplatin Induced Nephrotoxicity in Mice and its Mechanism%维生素E对顺铂所致的小鼠肾毒性的影响及其机制研究

    Institute of Scientific and Technical Information of China (English)

    张林; 刘伏友; 彭佑铭; 李大伟; 曾妮; 武蓉; 刘沧桑

    2012-01-01

      目的观察维生素E对抗癌药物顺铂致小鼠肾毒性的影响及其可能机制.方法采用10 mg·kg-1顺铂腹腔注射诱导小鼠肾脏损伤,48小时后分别予维生素E 250 mg·kg-1和500 mg·kg-1口服灌胃,顺铂诱导72小时后通过检测小鼠血清尿素氮和肌酐水平评价肾功能的变化,检测肾组织中丙二醛(malonaldehyde,MDA)含量,过氧化物歧化酶(superoxide dismutase,SOD)、过氧化氢酶(catalase,CAT)、还原型谷胱甘肽(reduced glutathione,GSH)和谷胱甘肽过氧化物酶(glutathion peroxidase,GPX)活性的变化,以评价小鼠肾组织氧化应激水平.结果与正常小鼠相比,10 mg·kg-1顺铂诱导的小鼠血清尿素氮、肌酐水平和肾组织MDA水平均显著升高(P0.05).结论高剂量的维生素E可以有效改善顺铂诱导的小鼠肾功能,可能与其降低肾组织的氧化应激有关.%  Objective To investigate the effects of vitamin E on cisplatin induced nephrotoxicity in mice and its mechanism. Methods 10 mg·kg-1 cisplatin was used to induce nephrotoxicity in mice by intraperitoneal injection, and 48 h later, 250 mg·kg-1 and 500 mg·kg-1 vitamin E were respectively used. Then at 72 h after cisplatin treatment, the serum level of urea nitrogen and creatinine were detected to evaluate the change of renal function, and the activities of malonaldehyde (MDA), superoxide dis-mutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathion peroxidase (GPX) in renal tissue were detected to evaluate the change of oxidative stress. Results Compared with normal mice, the serum level of urea nitrogen and creatinine as well as MDA in renal tissue significantly increased in 10 mg·kg-1 cisplatin-induced mice (P0.05). Conclusions High dose of vitamin E was effective to improve the renal function of cisplatin induced mice, and the decrease of oxidative stress may be involved.

  13. Protective effect of Heliotropium eichwaldi against cisplatin-induced nephrotoxicity in mice%艾氏天芥菜对顺铂引起的小鼠肾损伤的保护作用

    Institute of Scientific and Technical Information of China (English)

    Surendra Kr.Sharma; Naveen Goyal

    2012-01-01

    目的:该研究旨在评估紫草科药材艾氏天芥菜的甲醇提取物对于顺铂导致小鼠急性肾损伤的保护作用.方法:用腹膜内注射顺铂(16 mg/kg)诱导小鼠肾损伤.将瑞士白化小鼠分为正常对照组、顺铂模型对照组、艾氏天芥菜的甲醇提取物治疗组(200和400mg/kg),并给予相应药物.于顺铂注射前4 d开始每天予两组治疗组小鼠分别口服艾氏天芥菜的甲醇提取物200及400 mg/kg,共服用7d.治疗结束后3d处死小鼠,并取血及肾脏组织,检测分析血尿素氮、血清肌酐和丙二醛水平以及过氧化氢酶和过氧化物歧化酶活性.结果:艾氏天芥菜的甲醇提取物能够显著降低因注射顺铂而引起的小鼠血尿素氮及血清肌酐升高(P<0.05),并且能降低顺铂引起的高丙二醛水平,同时升高降低的过氧化氢酶和过氧化物歧化酶活性(P<0.05).此外,组织病理学检测显示艾氏天芥菜的甲醇提取物能够明显改善顺铂导致的肾小管坏死.结论:艾氏天芥菜的甲醇提取物可用于缓解顺铂的肾毒性.%OBJECTIVE:The aim of the present study was to evaluate the nephroprotective effect of methanolic extract of Heliotropium eichwaldii (MHE) in mice with cisplatin-induced acute renal damage.METHODS:Nephrotoxicity was induced by a single intraperitoneal injection of cisplatin (16 mg/kg).Swiss albino mice were injected with vehicle,cisplatin,cisplatin plus MHE 200 mg/kg and cisplatin plus MHE 400 mg/kg,respectively.MHE was administered for 7 d at a dose of 200 and 400 mg/kg per day orally starting 4 d before cisplatin injsetion.Animals were sacrificed 3 d after treatment and blood as well as kidney tissue was isolated and analyzed.The various parameters such as blood urea nitrogen (BUN),serum creatinine (CRE),malondialdehyde (MDA),and catalase (CAT) and superoxide dismutase (SOD) activities were analyzed.RESULTS:MHE treatment significantly reduced BUN and serum CRE levels elevated by cisplatin

  14. 左卡尼汀缓解顺铂造成急性肾损伤的血清代谢组学研究%L-carnitine alleviating cisplatin induced acute kidney injury through serum metabolomics analysis

    Institute of Scientific and Technical Information of China (English)

    纪松岗; 吴琼; 朱臻宇; 董昕; 洪战英; 柴逸峰

    2015-01-01

    目的:利用血清代谢组学探究顺铂诱导小鼠急性肾损伤的特异性变量,同时评价左卡尼汀的干预作用。方法将19只小鼠分为正常对照组、模型组和干预组,适应3 d后,对干预组给予左卡尼汀(400 mg/kg ,ip)干预,2 d后给予模型组和干预组顺铂(20 mg/kg ,ip)造模,每天称量各组小鼠的体质量,2 d后取小鼠血清进行LC-MS分析,结合模式识别分析各组间代谢组差异,并评价左卡尼汀的干预作用。结果代谢组学分析共鉴别28个差异代谢物,顺铂诱导的急性肾损伤主要涉及磷脂类、氨基酸类和脂肪酸类代谢途径的改变,而左卡尼汀有改善作用。结论左卡尼汀可改善顺铂诱导的急性肾损伤,其机制可能是通过调控色氨酸代谢、谷氨酸代谢和能量代谢,从而减缓急性肾损伤的疾病进程。%Objective To explore specific variables related to cisplatin induced acute kidney injury ,serum metabonomics techniques were applied and simultaneously the value of intervention effects of L-carnitine were appraised .Methods 19 mice were divided into the normal control group ,model group ,and intervention group ,After a three day accommodation period ,the intervention group was given L-carnitine (400 mg/kg ,ip) .Two days later ,cisplatin (20 mg/kg ,ip) was given to the model and intervention groups .The body weight of every mouse in each group was measured daily .Two days after the serum sample of each mice was collected and analyzed by LC-MS ,pattern recognition analysis of metabolomics differences among the groups , and the effectiveness of L-carnitine intervention were evaluated .Results A total of 28 metabolites were identified through ser-um metabolomics analysis .Our data shows that there is a possible mechanism that cisplatin induced AKI was mainly involved in changing phospholipids ,amino acid and fatty acid metabolic pathways and L-carnitine mitigates the damage of acute

  15. Spatial and temporal aspects of muscle hyperalgesia induced by nerve growth factor in humans

    DEFF Research Database (Denmark)

    Andersen, H.; Arendt-Nielsen, L.; Svensson, P.

    2008-01-01

    scale were used to assess soreness during muscle function. An area of hyperalgesia was observed locally at the injected site 3 h after injection of NGF, which expanded both proximally and distally on day 1; this effect subsided on day 4. Decreased PPT was also found between 1st and 2nd metatarsal on day...... 1. Hypertonic saline evoked more pain in men when injected in the NGF treated TA compared to the control leg. Injection of NGF increased muscle soreness during muscle activity for 7 days. In this material there was no gender effect of NGF-induced muscle hyperalgesia. The expansion of muscle...... distribution of muscle hyperalgesia over time (immediately after, 3 h, 1, 4, 7 and 21 days) after injecting NGF (5 mu g) into the tibialis anterior (TA) muscle, to explore possibly involved central pain mechanisms and to investigate the effect of gender on development of hyperalgesia. Totally 20 healthy...

  16. Is the Volume of the Caudate Nuclei Associated With Area of Secondary Hyperalgesia?

    DEFF Research Database (Denmark)

    Hansen, Morten Sejer; Asghar, Mohammad Sohail; Wetterslev, Jørn

    2016-01-01

    volunteers with differences in size of the area of secondary hyperalgesia following a standardized burn injury. OBJECTIVE: We aim to investigate the degree of association between the volume of pain-relevant structures in the brain and the size of the area of secondary hyperalgesia following brief thermal...... participants will undergo experimental pain testing in a parallel study (Clinicaltrials.gov Identifier: NCT02527395). Results from this experimental pain testing, as well as the size of the area of secondary hyperalgesia from the included participants, will be extracted from this parallel study. RESULTS......: The association between the volume of pain-relevant structures in the brain and the area of secondary hyperalgesia will be investigated by linear regression of the estimated best linear unbiased predictors on the individual volumes of the pain relevant brain structures. CONCLUSIONS: We plan to investigate...

  17. Lipopolysaccharide-induced hyperalgesia of intracranial capsaicin sensitive afferents in conscious rats

    NARCIS (Netherlands)

    Kemper, RHA; Spoelstra, MB; Meijler, WJ; Ter Horst, GJ

    1998-01-01

    Migraineous and non-migraineous headache is reported to be at highest intensity after an infection. This study investigated whether activation of the immune system can induce hyperalgesia in intracranial capsaicin sensitive afferents. The effects of intraperitoneal injected lipopolysaccharides (LPS)

  18. The amino-terminal region of hemokinin-1 regulates the induction of thermal hyperalgesia in rats.

    Science.gov (United States)

    Sunakawa, N; Naono, R; Ikeda, T; Matsushima, O; Sakoda, S; Nishimori, T

    2010-06-01

    It is known that intrathecal administration of substance P (SP) induces thermal hyperalgesia, whereas hemokinin-1 (HK-1), a member of the same tachykinin family as SP, hardly induces thermal hyperalgesia; however, the underlying mechanism remains to be elucidated. Therefore, we aimed to clarify which amino acid of these peptides contributes to the induction of thermal hyperalgesia. When two chimera peptides between the N-terminal region of SP and the C-terminal region of HK-1, and vice versa, SP (1-5)/HK-1 and HK-1 (1-5)/SP, were intrathecally administered, SP (1-5)/HK-1 induced thermal hyperalgesia whereas HK-1 (1-5)/SP had hardly any effect; furthermore, thermal hyperalgesia was induced by only C-terminal fragments of HK-1 and SP. These findings indicate that the N-terminal region of HK-1 is involved in the non-induction of thermal hyperalgesia. Next, we synthesized and intrathecally administered these chimera peptides in which part of the N-terminal region of HK-1 was replaced with that of SP, and vice versa, and all synthesized peptides induced thermal hyperalgesia. Both SP (1-2)/HK-1 and HK-1 (1-4)/SP certainly induced thermal hyperalgesia, although HK-1 and HK-1 (1-5)/SP had hardly any effect; therefore, it is probable that Ser at the 2nd position and Arg at the 5th position of HK-1 may be involved in the non-induction of thermal hyperalgesia. Furthermore, peptides in which amino acid at the 3rd and/or 4th positions of HK-1 was replaced with that of SP were synthesized. Intrathecal administration of HK-1 (1-2,4-5)/SP, but not HK-1 (1-2,5)/SP and HK-1 (1-3,5)/SP, hardly induced thermal hyperalgesia. These findings indicate that three amino acids, Ser, Thr and Arg at the 2nd, 4th and 5th positions of HK-1, respectively, regulate the induction of thermal hyperalgesia by HK-1.

  19. Cisplatin-induced zebrafish lateral line hair cell loss and regeneration%顺铂诱导斑马鱼侧线毛细胞损伤及再生模型的建立

    Institute of Scientific and Technical Information of China (English)

    芈肖肖; 严健; 李圆; 施军平

    2016-01-01

    Objective To establish a model of cisplatin-induced hair cell loss and regeneration in zebrafish. Methods Zebrafish larval were incubated in cisplatin solution. Using antibody staining, transgenic fish live imaging and in situ hybrid-ization, hair cell numbers before and after cisplatin treatment were characterized. Results Higher concentration cisplatin in-cubation caused more hair cell loss than lower concentration cisplatin when incubated for the same duration. Hair cells re-generation after lower concentration cisplatin incubation was also faster (P<0.001). Conclusion Cisplatin induced zebrafish lateral line hair cell loss and regeneration show dose and time-dependent patterns.%目的:建立顺铂诱导斑马鱼侧线毛细胞损伤及再生模型。方法采用顺铂溶液直接孵育斑马鱼方法,通过免疫组化、荧光特异性标记侧线细胞的转基因鱼活体成像、原位杂交等方法统计分析顺铂处理前后斑马鱼侧线毛细胞剩余情况以及药物撤除后毛细胞再生情况。结果顺铂引起斑马鱼侧线毛细胞丢失具有剂量依赖效应,相同的孵育时间较高浓度的顺铂孵育后几乎可杀死全部侧线毛细胞;毛细胞再生与顺铂的毒性积累程度有关,较低浓度孵育较短时间毛细胞再生速度较快。毛细胞再生数目随着时间的延长不断增加,72小时后可再生原有数目的90%以上。结论斑马鱼侧线毛细胞经不同浓度顺铂孵育不同时间后,其毛细胞丢失与再生具有剂量和时间依赖效应。

  20. Cyclosporin inhibits hyperalgesia and edema in arthritic rats: role of the central nervous system

    Directory of Open Access Journals (Sweden)

    J.N. Francischi

    1997-01-01

    Full Text Available Since arthritis induced by Mycobacterium products (adjuvant in rats is considered to be immunologically driven, the objective of the present study was to determine if the immunosuppressor drug cyclosporin could affect hindpaw edema and joint hyperalgesia simultaneously. Female Holtzman rats (140-170 g presented hyperalgesia and edema on the 8th and 12th day following adjuvant injection. Daily systemic (oral or intramuscular administration of cyclosporin (0.5-5.0 mg kg-1 day-1 or dexamethasone (0.01-0.1 mg kg-1 day-1 for 15 days starting on day zero dose-dependently inhibited the hindpaw edema and hyperalgesia in arthritic rats. However, hyperalgesia but not edema could be detected two days after cyclosporin withdrawal. We concluded that a the continuous presence of cyclosporin is essential to reduce the development of joint hyperalgesia and that b different mechanisms underlie the appearance of hyperalgesia and edema in this model. The intracerebroventricular (icv administration of 5-50-fold smaller doses of cyclosporin (1.5-150 µg/day or dexamethasone (15 µg/day also reduced the arthritic hindpaw edema and hyperalgesia. Peripheral blood from animals injected with effective systemic cyclosporin doses showed detectable levels of the drug, whereas peripheral blood from those injected with icv cyclosporin did not, as measured by specific RIA. Our results indicate that cyclosporin administered by the central route is as effective as by the systemic route to reduce joint hyperalgesia and hindpaw edema in arthritic rats. The antiarthritic effect induced by low doses of cyclosporin in the central nervous system (CNS could be explored to avoid its often associated systemic side effects during chronic therapy. However, the mechanism(s involved in the antiarthritic response to cyclosporin in the CNS remain to be elucidated

  1. Attenuation of reperfusion hyperalgesia in the rat by systemic administration of benzodiazepines.

    OpenAIRE

    1993-01-01

    1. An investigation into whether reperfusion hyperalgesia is modulated by prior systemic administration of two benzodiazepine agonists (diazepam and chlordiazepoxide), and an antagonist (flumazenil) was conducted. 2. Transient ischaemia was induced in conscious rats by applying an inflatable tourniquet to the base of the tail; when the rats exhibited a co-ordinated escape response, the tourniquet was deflated and reperfusion of the tail was allowed. Reperfusion hyperalgesia manifested as a de...

  2. The nitroxyl donor, Angeli’s salt, inhibits inflammatory hyperalgesia in rats

    OpenAIRE

    2013-01-01

    Nitric oxide modulates pain development. However, there is no evidence on the effect of nitroxyl (HNO/NO−) in nociception. Therefore, we addressed whether nitroxyl inhibits inflammatory hyperalgesia and its mechanism using the nitroxyl donor Angeli’s salt (AS; Na2N2O3). Mechanical hyperalgesia was evaluated using a modified Randall and Selitto method in rats, cytokine production by ELISA and nitroxyl was determined by confocal microscopy in DAF (a cell permeable reagent that is converted into...

  3. Mechanisms mediating nitroglycerin-induced delayed-onset hyperalgesia in the rat.

    Science.gov (United States)

    Ferrari, L F; Levine, J D; Green, P G

    2016-03-11

    Nitroglycerin (glycerol trinitrate, GTN) induces headache in migraineurs, an effect that has been used both diagnostically and in the study of the pathophysiology of this neurovascular pain syndrome. An important feature of this headache is a delay from the administration of GTN to headache onset that, because of GTN's very rapid metabolism, cannot be due to its pharmacokinetic profile. It has recently been suggested that activation of perivascular mast cells, which has been implicated in the pathophysiology of migraine, may contribute to this delay. We reported that hyperalgesia induced by intradermal GTN has a delay to onset of ∼ 30 min in male and ∼ 45 min in female rats. This hyperalgesia was greater in females, was prevented by pretreatment with the anti-migraine drug, sumatriptan, as well as by chronic pretreatment with the mast cell degranulator, compound 48/80. The acute administration of GTN and compound 48/80 both induced hyperalgesia that was prevented by pretreatment with octoxynol-9, which attenuates endothelial function, suggesting that GTN and mast cell-mediated hyperalgesia are endothelial cell-dependent. Furthermore, A-317491, a P2X3 antagonist, which inhibits endothelial cell-dependent hyperalgesia, also prevents GTN and mast cell-mediated hyperalgesia. We conclude that delayed-onset mechanical hyperalgesia induced by GTN is mediated by activation of mast cells, which in turn release mediators that stimulate endothelial cells to release ATP, to act on P2X3, a ligand-gated ion channel, in perivascular nociceptors. A role of the mast and endothelial cell in GTN-induced hyperalgesia suggests potential novel risk factors and targets for the treatment of migraine.

  4. Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia.

    Directory of Open Access Journals (Sweden)

    Folabomi A Oladosu

    Full Text Available A subset of the population receiving opioids for the treatment of acute and chronic clinical pain develops a paradoxical increase in pain sensitivity known as opioid-induced hyperalgesia. Given that opioid analgesics are one of few treatments available against clinical pain, it is critical to determine the key molecular mechanisms that drive opioid-induced hyperalgesia in order to reduce its prevalence. Recent evidence implicates a splice variant of the mu opioid receptor known as MOR-1K in the emergence of opioid-induced hyperalgesia. Results from human genetic association and cell signaling studies demonstrate that MOR-1K contributes to decreased opioid analgesic responses and produces increased cellular activity via Gs signaling. Here, we conducted the first study to directly test the role of MOR-1K in opioid-induced hyperalgesia.In order to examine the role of MOR-1K in opioid-induced hyperalgesia, we first assessed pain responses to mechanical and thermal stimuli prior to, during, and following chronic morphine administration. Results show that genetically diverse mouse strains (C57BL/6J, 129S6, and CXB7/ByJ exhibited different morphine response profiles with corresponding changes in MOR-1K gene expression patterns. The 129S6 mice exhibited an analgesic response correlating to a measured decrease in MOR-1K gene expression levels, while CXB7/ByJ mice exhibited a hyperalgesic response correlating to a measured increase in MOR-1K gene expression levels. Furthermore, knockdown of MOR-1K in CXB7/ByJ mice via chronic intrathecal siRNA administration not only prevented the development of opioid-induced hyperalgesia, but also unmasked morphine analgesia.These findings suggest that MOR-1K is likely a necessary contributor to the development of opioid-induced hyperalgesia. With further research, MOR-1K could be exploited as a target for antagonists that reduce or prevent opioid-induced hyperalgesia.

  5. Differential regulation of peripheral IL-1β-induced mechanical allodynia and thermal hyperalgesia in rats.

    Science.gov (United States)

    Kim, Min J; Lee, Sang Y; Yang, Kui Y; Nam, Soon H; Kim, Hyun J; Kim, Young J; Bae, Yong C; Ahn, Dong K

    2014-04-01

    This study examined the differential mechanisms of mechanical allodynia and thermal hyperalgesia after injection of interleukin (IL) 1β into the orofacial area of male Sprague-Dawley rats. The subcutaneous administration of IL-1β produced both mechanical allodynia and thermal hyperalgesia. Although a pretreatment with iodoresiniferatoxin (IRTX), a transient receptor potential vanilloid 1 (TRPV1) antagonist, did not affect IL-1β-induced mechanical allodynia, it significantly abolished IL-1β-induced thermal hyperalgesia. On the other hand, a pretreatment with D-AP5, an N-methyl-d-aspartate (NMDA) receptor antagonist, and NBQX, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, blocked IL-1β-induced mechanical allodynia. Pretreatment with H89, a protein kinase A (PKA) inhibitor, blocked IL-1β-induced mechanical allodynia but not thermal hyperalgesia. In contrast, pretreatment with chelerythrine, a protein kinase C (PKC) inhibitor, inhibited IL-1β-induced thermal hyperalgesia. Subcutaneous injections of 2% lidocaine, a local anesthetic agent, blocked IL-1β-induced thermal hyperalgesia but not IL-1β-induced mechanical allodynia. In the resiniferatoxin (RTX)-pretreated rats, a subcutaneous injection of IL-1β did not produce thermal hyperalgesia due to the depletion of TRPV1 in the primary afferent fibers. Double immunofluorescence revealed the colocalization of PKA with neurofilament 200 (NF200) and of PKC with the calcitonin gene-related peptide (CGRP) in the trigeminal ganglion. Furthermore, NMDA receptor 1 (NR1) and TRPV1 predominantly colocalize with PKA and PKC, respectively, in the trigeminal ganglion. These results suggest that IL-1β-induced mechanical allodynia is mediated by sensitized peripheral NMDA/AMPA receptors through PKA-mediated signaling in the large-diameter primary afferent nerve fibers, whereas IL-1β-induced thermal hyperalgesia is mediated by sensitized peripheral TRPV1 receptors through PKC

  6. Endometriosis-induced vaginal hyperalgesia in the rat: role of the ectopic growths and their innervation.

    Science.gov (United States)

    McAllister, Stacy L; McGinty, Kristina A; Resuehr, David; Berkley, Karen J

    2009-12-15

    Endometriosis is a painful disorder defined by extrauteral endometrial growths whose contribution to pain symptoms is poorly understood. Endometriosis is created in rats by autotransplanting on abdominal arteries pieces of either uterus (ENDO), which form cysts, or fat (shamENDO), which do not form cysts. ENDO, but not shamENDO induces vaginal hyperalgesia. We tested the hypothesis that the cysts are necessary to maintain vaginal hyperalgesia by assessing the effect of surgically removing them. Complete-cyst-removal eliminated ENDO-induced vaginal hyperalgesia up to 4 months post-operatively. Sham-cyst-removal in ENDO rats, in which cysts were not removed, or partial cyst-removal increased the ENDO-induced hyperalgesia. The decreases and increases both took 3-6 weeks to develop. Changes in ENDO-induced hyperalgesia did not occur in a control group of ENDO rats who had no surgery after ENDO. In a double-surgery control group, neither shamENDO surgery nor a subsequent sham surgery that mimicked "removal" of non-existent cysts influenced vaginal nociception. In a no-surgery control group, vaginal nociception remained stable for >6 months. The increases in ENDO-induced hyperalgesia produced by the sham-cyst-removal surgery were smaller in proestrus than in other estrous stages. During the other stages (but not during proestrus), sympathetic innervation of the cysts increased. These results suggest that maintenance of ENDO-induced vaginal hyperalgesia requires continued presence of at least some ectopic endometrial tissue, and that surgical treatment that fails to remove ectopic endometrial tissue can exacerbate the hyperalgesia, possibly due in part to an increase in the cysts' sympathetic innervation.

  7. Endometriosis-Induced Vaginal Hyperalgesia in the Rat: Role of the Ectopic Growths and their Innervation

    OpenAIRE

    McAllister, Stacy L.; McGinty, Kristina A.; Resuehr, David; Berkley, Karen J

    2009-01-01

    Endometriosis is a painful disorder defined by extrauteral endometrial growths whose contribution to pain symptoms is poorly understood. Endometriosis is created in rats by autotransplanting on abdominal arteries pieces of either uterus (ENDO), which form cysts, or fat (shamENDO), which do not form cysts. ENDO, but not shamENDO induces vaginal hyperalgesia. We tested the hypothesis that the cysts are necessary to maintain vaginal hyperalgesia by assessing the effect of surgically removing the...

  8. Acute phenobarbital administration induces hyperalgesia: pharmacological evidence for the involvement of supraspinal GABA-A receptors

    Directory of Open Access Journals (Sweden)

    C.M. Yokoro

    2001-03-01

    Full Text Available The aim of the present study was to determine if phenobarbital affects the nociception threshold. Systemic (1-20 mg/kg phenobarbital administration dose dependently induced hyperalgesia in the tail-flick, hot-plate and formalin tests in rats and in the abdominal constriction test in mice. Formalin and abdominal constriction tests were the most sensitive procedures for the detection of hyperalgesia in response to phenobarbital compared with the tail-flick and hot-plate tests. The hyperalgesia induced by systemic phenobarbital was blocked by previous administration of 1 mg/kg ip picrotoxin or either 1-2 mg/kg sc or 10 ng icv bicuculline. Intracerebroventricular phenobarbital administration (5 µg induced hyperalgesia in the tail-flick test. In contrast, intrathecal phenobarbital administration (5 µg induced antinociception and blocked systemic-induced hyperalgesia in this test. We suggest that phenobarbital may mediate hyperalgesia through GABA-A receptors at supraspinal levels and antinociception through the same kind of receptors at spinal levels.

  9. Contributions of spinal D-amino acid oxidase to chronic morphine-induced hyperalgesia.

    Science.gov (United States)

    Ma, Shuai; Li, Xin-Yan; Gong, Nian; Wang, Yong-Xiang

    2015-12-10

    Spinal D-amino acid oxidase (DAAO) is an FAD-dependent peroxisomal flavoenzyme which mediates the conversion of neutral and polar D-amino acids (including D-serine) to the corresponding α-keto acids, and simultaneously produces hydrogen peroxide and ammonia. This study has aimed to explore the potential contributions of spinal DAAO and its mediated hydrogen peroxide/D-serine metabolism to the development of morphine-induced hyperalgesia. Bi-daily subcutaneous injections of morphine to mice over 7 days induced thermal hyperalgesia as measured by both the hot-plate and tail-immersion tests, and spinal astroglial activation with increased spinal gene expression of DAAO, glial fibrillary acidic protein (GFAP) and pro-inflammatory cytokines (interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)). Subcutaneous injections of the potent DAAO inhibitor CBIO (5-chloro-benzo[D]isoxazol-3-ol) prevented and reversed the chronic morphine-induced hyperalgesia. CBIO also inhibited both astrocyte activation and the expression of pro-inflammatory cytokines. Intrathecal injection of the hydrogen peroxide scavenger PBN (phenyl-N-tert-butylnitrone) and of catalase completely reversed established morphine hyperalgesia, whereas subcutaneous injections of exogenous D-serine failed to alter chronic morphine-induced hyperalgesia. These results provided evidence that spinal DAAO and its subsequent production of hydrogen peroxide rather than the D-serine metabolism contributed to the development of morphine-induced hyperalgesia.

  10. Cisplatin-induced renal toxicity via tumor necrosis factor-α, interleukin 6, tumor suppressor P53, DNA damage, xanthine oxidase, histological changes, oxidative stress and nitric oxide in rats: protective effect of ginseng.

    Science.gov (United States)

    Yousef, Mokhtar I; Hussien, Hend M

    2015-04-01

    Cisplatin is an effective chemotherapeutic agent successfully used in the treatment of a wide range of solid tumors, while its usage is limited due to its nephrotoxicity. The present study was undertaken to examine the effectiveness of ginseng to ameliorate the renal nephrotoxicity, damage in kidney genomic DNA, tumor necrosis factor-α, interleukin 6, tumor suppressor P53, histological changes and oxidative stress induced by cisplatin in rats. Cisplatin caused renal damage, including DNA fragmentation, upregulates gene expression of tumor suppressor protein p53 and tumor necrosis factor-α and IL-6. Cisplatin increased the levels of kidney TBARS, xanthine oxidase, nitric oxide, serum urea and creatinine. Cisplatin decreased the activities of antioxidant enzymes (GST, GPX, CAT and SOD), ATPase and the levels of GSH. A microscopic examination showed that cisplatin caused kidney damage including vacuolization, severe necrosis and degenerative changes. Ginseng co-treatment with cisplatin reduced its renal damage, oxidative stress, DNA fragmentation and induced DNA repair processes. Also, ginseng diminished p53 activation and improved renal cell apoptosis and nephrotoxicity. It can be concluded that, the protective effects of ginseng against cisplatin induced-renal damage was associated with the attenuation of oxidative stress and the preservation of antioxidant enzymes.

  11. Organic Anion Transporter 5 (Oat5) Urinary Excretion Is a Specific Biomarker of Kidney Injury: Evaluation of Urinary Excretion of Exosomal Oat5 after N-Acetylcysteine Prevention of Cisplatin Induced Nephrotoxicity.

    Science.gov (United States)

    Bulacio, Romina Paula; Anzai, Naohiko; Ouchi, Motoshi; Torres, Adriana Mónica

    2015-08-17

    Cisplatin is a commonly used chemotherapeutic agent. Its main side-effect is nephrotoxicity. It was reported that the organic anion transporter 5 (Oat5) urinary excretion is elevated, implying renal perturbation, when no modifications of traditional markers of renal damage are still observed in cisplatin-induced acute kidney injury (AKI). It was also demonstrated that Oat5 is excreted in urine by the exosomal pathway. This study was designated to demonstrate the specific response of the urinary excretion of exosomal Oat5 to kidney injury independently of other cisplatin toxic effects, in order to strengthen Oat5 urinary levels as a specific biomarker of AKI. To accomplish that aim, we evaluated if urinary excretion of exosomal Oat5 returns to its basal levels when cisplatin renal damage is prevented by the coadministration of the renoprotective compound N-acetylcysteine. Four days after cisplatin administration, AKI was induced in cisplatin-treated male Wistar rats (Cis group), as it was corroborated by increased urea and creatinine plasma levels. Tubular damage was also observed. In cotreated animals (Cis + NAC group), plasma urea and creatinine concentrations tended to return to their basal values, and tubular damage was improved. Urinary excretion of exosomal Oat5 was notably increased in the Cis group, but when renal injury was ameliorated by N-acetylcysteine coadministration, that increase was undetected. So, in this work we observed that urinary excretion of exosomal Oat5 was only increased if renal insult is produced, demonstrating its specificity as a renal injury biomarker.

  12. Opioid-induced hyperalgesia in community-dwelling adults with chronic pain.

    Science.gov (United States)

    Hooten, W Michael; Lamer, Tim J; Twyner, Channing

    2015-06-01

    The hyperalgesic effects of long-term opioid use in community-dwelling adults with chronic pain have not been widely reported. Therefore, the primary aim of this study was to determine the associations between opioid use and heat pain (HP) perception in a sample of community-dwelling adults with chronic pain. The study cohort involved 187 adults (85 opioid and 102 nonopioid) with chronic pain consecutively admitted to an outpatient interdisciplinary pain treatment program. Heat pain perception was assessed using a validated quantitative sensory test method of levels. An effect of opioid use was observed for nonstandardized (P = 0.004) and standardized (P = 0.005) values of HP 5-0.5 in which values of the opioid group were lower (more hyperalgesic) compared with those of the nonopioid group. HP 5-0.5 is a measure of the slope of the line connecting HP 0.5 (HP threshold) and HP 5 (intermediate measure of HP tolerance). In univariable (P = 0.019) and multiple variable (P = 0.003) linear regression analyses (adjusted for age, sex, body mass index, work status, pain diagnosis, pain severity, depression, and pain catastrophizing), opioid use was associated with lower (more hyperalgesic) nonstandardized values of HP 5-0.5. Similarly, in univariable (P = 0.004) and multiple variable (P = 0.011) linear regression analyses (adjusted for work status, pain diagnosis, pain severity, depression, and pain catastrophizing), opioid use was associated with lower standardized values of HP 5-0.5. In this sample of community-dwelling adults, these observations suggest that long-term opioid use was associated with hyperalgesia independent of other clinical factors known to influence HP perception.

  13. One night of total sleep deprivation promotes a state of generalized hyperalgesia: a surrogate pain model to study the relationship of insomnia and pain.

    Science.gov (United States)

    Schuh-Hofer, Sigrid; Wodarski, Rachel; Pfau, Doreen B; Caspani, Ombretta; Magerl, Walter; Kennedy, Jeffrey D; Treede, Rolf-Detlef

    2013-09-01

    Sleep disturbances are highly prevalent in chronic pain patients. Understanding their relationship has become an important research topic since poor sleep and pain are assumed to closely interact. To date, human experimental studies exploring the impact of sleep disruption/deprivation on pain perception have yielded conflicting results. This inconsistency may be due to the large heterogeneity of study populations and study protocols previously used. In addition, none of the previous studies investigated the entire spectrum of nociceptive modalities. To address these shortcomings, a standardized comprehensive quantitative sensory protocol was used in order to compare the somatosensory profile of 14 healthy subjects (6 female, 8 male, 23.5 ± 4.1 year; mean ± SD) after a night of total sleep deprivation (TSD) and a night of habitual sleep in a cross-over design. One night of TSD significantly increased the level of sleepiness (P<0.001) and resulted in higher scores of the State Anxiety Inventory (P<0.01). In addition to previously reported hyperalgesia to heat (P<0.05) and blunt pressure (P<0.05), study participants developed hyperalgesia to cold (P<0.01) and increased mechanical pain sensitivity to pinprick stimuli (P<0.05) but no changes in temporal summation. Paradoxical heat sensations or dynamic mechanical allodynia were absent. TSD selectively modulated nociception, since detection thresholds of non-nociceptive modalities remained unchanged. Our findings show that a single night of TSD is able to induce generalized hyperalgesia and to increase State Anxiety scores. In the future, TSD may serve as a translational pain model to elucidate the pathomechanisms underlying the hyperalgesic effect of sleep disturbances.

  14. Effect of selective inhibition of cyclooxygenase-2 on lipopolysaccharide-induced hyperalgesia.

    Science.gov (United States)

    Satyanarayana, Padi S V; Jain, Naveen K; Singh, Sukhjeet; Kulkarni, Shrinivas K

    2004-01-01

    Lipopolysaccharide (LPS) is known to increase the expression and release of various pro-inflammatory mediators, including cyclooxygenase-2 (COX-2) and produce hyperalgesia. It is also well known that prostaglandins (PGs), synthesised both in the periphery and centrally by COX isoforms, play a key role in sensitisation of nociceptors and nociceptive processing. To investigate the role of COX-2 in LPS-induced hyperalgesia, parecoxib, a selective COX-2-inhibiting pro-drug, was injected intravenously 30 min before assessing hyperalgesia induced by intraperitoneal or subcutaneous administration of LPS (50 microg/mouse or 25 microg/paw of rat, respectively). Acetic acid-induced writhing and tail immersion assay in mice and paw withdrawal response to thermal and mechanical stimuli in rats were used to assess the effect of inhibition of COX-2 on LPSinduced hyperalgesia. Animals showed significant hyperalgesic behavior 8 h after LPS injection. Parecoxib (up to 20 mg/kg, i.v.) had no effect in the two acute nociceptive assays but showed marked antinociceptive activity in writhing and tail immersion assay in LPS-pretreated mice. Similarly, parecoxib reversed the hyperalgesia in the LPS-injected paw but not in the contralateral paw of rats. Pre-treatment with dexamethasone, an inhibitor of COX-2 expression before LPS injection significantly affected the development of hyperalgesia in both mice and rats. These findings suggest that inducible COX-2 derived PGs are involved in central nociceptive processing, which resulted in hyperalgesic behavior following LPS administration and inhibition of COX-2 or its expression attenuated LPS-induced hyperalgesia.

  15. Intradermal glutamate and capsaicin injections: intra- and interindividual variability of provoked hyperalgesia and allodynia.

    Science.gov (United States)

    Nilsson, Matias; Lassen, Dorte; Andresen, Trine; Nielsen, Anders K; Arendt-Nielsen, Lars; Drewes, Asbjørn M

    2014-06-01

    Intradermal injections of glutamate and capsaicin are attractive to use in human experimental pain models because hyperalgesia and allodynia mimic isolated aspects of clinical pain disorders. The aim of the present study was to investigate the reproducibility of these models. Twenty healthy male volunteers (mean age 24 years; range 18-38 years) received intradermal injections of glutamate and capsaicin in the volar forearm. Magnitudes of secondary pinprick hyperalgesia and brush-evoked allodynia were investigated using von Frey filaments (gauges 10, 15, 60 and 100 g) and brush strokes. Areas of secondary hyperalgesia and allodynia were quantified immediately after injection and after 15, 30 and 60 min. Two identical experiments separated by at least 7 days were performed. Reproducibility across and within volunteers (inter- and intra-individual variation, respectively) was assessed using intraclass correlation coefficient (ICC) and coefficient of variation (CV). Secondary pinprick hyperalgesia was observed as a marked increase in the visual analogue scale (VAS) response to von Frey gauges 60 and 100 g (P capsaicin, secondary pinprick hyperalgesia was detected with all von Frey gauges (P  0.60) and brush strokes (ICC > 0.83). Capsaicin injection was reproducible for secondary hyperalgesia (ICC > 0.70) and allodynia (ICC > 0.71). Intra-individual variability was generally lower for the VAS response to von Frey and brush compared with areas of secondary hyperalgesia and allodynia. In conclusion, glutamate and capsaicin yield reproducible hyperalgesic and allodynic responses, and the present model is well suited for basic research, as well as for assessing the modulation of central phenomena.

  16. Chronic psychosocial stress induces visceral hyperalgesia in mice.

    Science.gov (United States)

    Tramullas, Mónica; Dinan, Timothy G; Cryan, John F

    2012-05-01

    Experimental and clinical evidence has shown that chronic stress plays an important role in the onset and/or exacerbation of symptoms of functional gastrointestinal disorders. Here, we aimed to investigate whether exposure to a chronic and temporally unpredictable psychosocial stressor alters visceral and somatic nociception as well as anxiety-related behaviour. In male C57BL/6J mice, chronic stress was induced by repeated exposure to social defeat (SD, 2 h) and overcrowding (OC, 24 h) during 19 consecutive days. Visceral and somatic nociception was evaluated by colorectal distension and a hot plate, respectively. The social interaction test was used to assess social anxiety. Mice exposed to psychosocial stress developed visceral hyperalgesia and somatic hypoalgesia 24 h following the last stress session. SD/OC mice also exhibited social anxiety-like behaviour. All these changes were also associated with physiological alterations, measured as a decreased faecal pellet output and hypothalamic-pituitary-adrenal (HPA) axis disruption. Taken together, these data confirm that this mouse model of chronic psychosocial stress may be useful for studies on the pathophysiological mechanisms underlying such stress-associated disorders and to further test potential therapies.

  17. Clinical interpretation of opioid tolerance versus opioid-induced hyperalgesia.

    Science.gov (United States)

    Chen, Lucy; Sein, Michael; Vo, Trang; Amhmed, Shihab; Zhang, Yi; Hilaire, Kristin St; Houghton, Mary; Mao, Jianren

    2014-01-01

    Opioid analgesics are commonly used to manage moderate to severe pain. However, the long-term use of opioids could lead to opioid tolerance (OT) and opioid-induced hyperalgesia (OIH). Distinguishing OIH from OT would impact the practice of opioid therapy because opioid dose adjustment may differentially influence OT and OIH. Currently, there are no standard criteria of OT versus OIH causing considerable ambiguity in clinical interpretation and management of these conditions. The authors designed a practitioner-based survey consisting of 20 targeted questions. Answering these questions would require responders' actual clinical experiences with opioid therapy. The survey was conducted between 2011 and 2012 through direct mails or e-mails to 1,408 physicians who are currently practicing in the United States. The authors find that certain clinical characteristics (eg, increased pain despite opioid dose escalation) are often used by practitioners to make differential diagnosis of OT and OIH despite some overlap in their clinical presentation. A key difference in clinical outcome is that OT and OIH could be improved and exacerbated by opioid dose escalation, respectively. Our survey results revealed a significant knowledge gap in some responders regarding differential diagnosis and management of OT and OIH. The results also identified several issues, such as opioid dose adjustment and clinical comorbidities related to OT and OIH, which require future patient-based studies.

  18. Effects of ginsenosides on opioid-induced hyperalgesia in mice.

    Science.gov (United States)

    Li, Peng; Tang, Minke; Li, Hui; Huang, Xinjie; Chen, Lei; Zhai, Haifeng

    2014-07-01

    Opioid-induced hyperalgesia (OIH) is characterized by nociceptive sensitization caused by the cessation of chronic opioid use. OIH can limit the clinical use of opioid analgesics and complicate withdrawal from opioid addiction. In this study, we investigated the effects of Re, Rg1, and Rb1 ginsenosides, the bioactive components of ginseng, on OIH. OIH was achieved in mice after subcutaneous administration of morphine for 7 consecutive days three times per day. During withdrawal (days 8 and 9), these mice were administered Re, Rg1, or Rb1 intragastrically two times per day. On the test day (day 10), mice were subjected to the thermal sensitivity test and the acetic acid-induced writhing test. Re (300 mg/kg) inhibited OIH in both the thermal sensitivity test and the acetic acid-induced writhing test. However, the Rg1 and Rb1 ginsenosides failed to prevent OIH in either test. Furthermore, Rg1 showed a tendency to aggravate OIH in the acetic acid-induced writhing test. Our data suggested that the ginsenoside Re, but not Rg1 or Rb1, may contribute toward reversal of OIH.

  19. Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations.

    Science.gov (United States)

    Arout, Caroline A; Edens, Ellen; Petrakis, Ismene L; Sofuoglu, Mehmet

    2015-06-01

    Opioid analgesics have become a cornerstone in the treatment of moderate to severe pain, resulting in a steady rise of opioid prescriptions. Subsequently, there has been a striking increase in the number of opioid-dependent individuals, opioid-related overdoses, and fatalities. Clinical use of opioids is further complicated by an increasingly deleterious profile of side effects beyond addiction, including tolerance and opioid-induced hyperalgesia (OIH), where OIH is defined as an increased sensitivity to already painful stimuli. This paradoxical state of increased nociception results from acute and long-term exposure to opioids, and appears to develop in a substantial subset of patients using opioids. Recently, there has been considerable interest in developing an efficacious treatment regimen for acute and chronic pain. However, there are currently no well-established treatments for OIH. Several substrates have emerged as potential modulators of OIH, including the N-methyl-D-aspartate and γ-aminobutyric acid receptors, and most notably, the innate neuroimmune system. This review summarizes the neurobiology of OIH in the context of clinical treatment; specifically, we review evidence for several pathways that show promise for the treatment of pain going forward, as prospective adjuvants to opioid analgesics. Overall, we suggest that this paradoxical state be considered an additional target of clinical treatment for chronic pain.

  20. Motor cortex stimulation reduces hyperalgesia in an animal model of central pain.

    Science.gov (United States)

    Lucas, Jessica M; Ji, Yadong; Masri, Radi

    2011-06-01

    Electrical stimulation of the primary motor cortex has been used since 1991 to treat chronic neuropathic pain. Since its inception, motor cortex stimulation (MCS) treatment has had varied clinical outcomes. Until this point, there has not been a systematic study of the stimulation parameters that most effectively treat chronic pain, or of the mechanisms by which MCS relieves pain. Here, using a rodent model of central pain, we perform a systematic study of stimulation parameters used for MCS and investigate the mechanisms by which MCS reduces hyperalgesia. Specifically, we study the role of the inhibitory nucleus zona incerta (ZI) in mediating the analgesic effects of MCS. In animals with mechanical and thermal hyperalgesia, we find that stimulation at 50 μA, 50 Hz, and 300 μs square pulses for 30 minutes is sufficient to reverse mechanical and thermal hyperalgesia. We also find that stimulation of the ZI mimics the effects of MCS and that reversible inactivation of ZI blocks the effects of MCS. These findings suggest that the reduction of hyperalgesia may be due to MCS effects on ZI. In an animal model of central pain syndrome, motor cortex stimulation reduces hyperalgesia by activating zona incerta and therefore restoring inhibition in the thalamus.

  1. Role of spinal GABAA receptor reduction induced by stress in rat thermal hyperalgesia.

    Science.gov (United States)

    Ma, Xuelian; Bao, Weiying; Wang, Xiujun; Wang, Zhilong; Liu, Qiaoran; Yao, Zhenyu; Zhang, Di; Jiang, Hong; Cui, Shuang

    2014-11-01

    The mechanisms underlying stress-induced hyperalgesia (SIH) remain poorly understood. Recent findings have provided strong evidence indicating that SIH could be related, at least in part, to alterations in spinal cord GABA activity. In the present study, we first investigated how acute restraint stress impacted pain responses as assessed using the tail flick immersion test. These results showed that rats developed hyperalgesia at 6 h after being subjected to 1-h acute restraint stress. Second, we measured the activation of spinal neurons and alterations in expression of GABAA receptor β2 and β3 subunits as related to stress-induced hyperalgesia. Results from Western blot and immunofluorescence assays showed that c-fos protein increased in the dorsal horn of the lumbar spinal cord and GABAA receptor β2 and β3 subunit proteins decreased significantly at 6 h after exposure to 1 h of acute restraint stress. Finally, the effects of spinal GABAA receptor alteration on SIH were evaluated. These results showed that intrathecal administration of muscimol inhibited hyperalgesia induced by stress while bicuculline enhanced hyperalgesia in the control groups. Taken together, the present data reveal that GABAA receptor β2 and β3 decrease following 1 h of acute restraint stress and may play a critical role in SIH.

  2. Interactions of estradiol and NSAIDS on carrageenan-induced hyperalgesia.

    Science.gov (United States)

    Hunter, Deirtra A; Barr, Gordon A; Shivers, Kai-Yvonne; Amador, Nicole; Jenab, Shirzad; Inturrisi, Charles; Quinones-Jenab, Vanya

    2011-03-25

    How exogenous estrogen affects inflammatory responses is poorly understood despite the large numbers of women receiving estrogen-alone hormone therapy. The aim of this study was to determine if estradiol alters injury- or inflammation-induced nociceptive responses after carrageenan administration in females and whether its effects are mediated through cyclo-oxygenase (COX) and prostaglandins (PG). To this end, paw withdrawal latencies and serum levels of PGE2 and PGD2 were measured in rats treated with estradiol (0, 10, 20, and 30%) and/or SC560 (COX-1 inhibitor) or NS398 (COX-2 inhibitor) after intraplantar carrageenan administration. Estradiol significantly increased withdrawal latencies before (baseline condition) and after carrageenan administration to one hindpaw. NS398 was anti-nociceptive only in carrageenan treated animals. SC560 increased withdrawal latencies in both paws at 1 and 5hours after carrageenan administration. Co-administration of estradiol and NS398, but not SC560, was additive except for a prolonged anti-nociceptive effects of estradiol combined with NS398. The anti-nociceptive effect extended beyond that observed with either drug or estradiol alone at the 5-hour time point. Estradiol had no significant effect on PGE2 serum levels, but both COX antagonists decreased them. Although neither estradiol nor the COX inhibitors alone had an effect on PGD2 serum levels, co-administration of NS398 and estradiol significantly elevated PGD2 levels. Taken together, our results suggest that estradiol is anti-nociceptive in the thermal test and reduces carrageenan-induced hyperalgesia. These effects are minimally altered through PG-mediated mechanisms.

  3. 塞来昔布抑制顺铂致大鼠迟发性呕吐的作用及机制研究%Mechanism of Antiemetic Effect of Celecoxib on Cisplatin-induced Delayed Emesis in Rats

    Institute of Scientific and Technical Information of China (English)

    鞠传霞; 岳旺; 孙福生; 平藤雅彦

    2009-01-01

    OBJECTIVE: To study the action mechanism and effect of eelecoxib on cisplatin-induced delayed emesis in rats. METHODS: The rats were divided into control group, eisplatin group, and eelecoxib group (cisplatin plus celecoxib) . Kaolin intake in the rats after administration of corresponding drugs was observed. Levels of 5-HT and its metabolite 5-HIAA in intestinal tissues, and the activities of tryptophan hydroxylase (TPH) and monoamine oxidase (MAP) were determined, and the morphological changes of the intestinal tissues were observed. RESULTS: In cisplatin group compared with control group, the Kaolin intake increased significantly (P<0.05), TPH activity in the intestine increased, MAP activity decreased while the content of 5-HT increased (P<0.05) . In celecoxib group compared with eisplatin group, kaolin intake decreased significantly, TPH activity and the content of 5-HT decreased as well (P<0.05), and the pathologic changes of intestinal tissue ameliorated. CONCLUSION: The inhibitory effect of celecoxib on cisplatin-induced chemotherapeutic allolriopagia suggests its preventive and curative effects on delayed nausea and emesis.%目的:研究选择性环氧合酶-2抑制剂塞来昔布对顺铂致大鼠迟发性呕吐的作用及机制.方法:将大鼠分为时照组、顺铂组和塞来昔布组(顺铂+塞来昔布),各组给予相应药物后观察大鼠摄食高岭土量;测定肠组织中5-羟色胺(5-HT)及其代谢产物5-羟基吲哚乙酸(5-HIAA)含量;测定色氨酸羟化酶(TPH)和单胺氧化酶(MAO)活性;观察小肠黏膜形态学改变.结果:与对照组比较,顺铂组摄食高岭土量明显增加(P<0.05),肠组织内TPH活性增强,MAO活性减弱,5-HT的含量增加(P<0.05).与顺铂组比较,塞来昔布组摄食高岭土量明显降低,TPH酶活性及5-HT的含量也均降低(P<0.05),且小肠组织病变减轻.结论:塞来昔布可以抑制顺铂所致化疗性异食癖,提示其可能具有防治迟发性恶心、呕吐的作用.

  4. 血栓通对顺铂肾损伤大鼠的肾功能和氧化指标的影响%Effect of Xueshuantong on Renal Function and Oxidation Indexes in Cisplatin-induced Nephroxicity Rats

    Institute of Scientific and Technical Information of China (English)

    席加喜; 刘晓霞; 杨玉芳; 张春花; 刘华钢

    2012-01-01

    目的:研究血栓通对顺铂肾损伤大鼠肾功能的保护作用和其对损伤大鼠氧化指标的影响.方法:采用顺铂(0.5 mg·kg-1)尾静脉注射的方法制造顺铂肾毒性模型.将72只大鼠随机分为6组,空白组、模型组、安磷汀阳性药物组、血栓通低剂、中、高剂量组(15.63,31.35,62.70 mg·kg-1).分别给药处理10d后,观察大鼠24 h尿蛋白量、尿N-乙酰β-D氨基葡萄糖苷酶NAG,血清中肌酐、尿素氮,肾组织匀浆中超氧化物歧化酶(SOD)活性、谷胱甘肽过氧化物酶(GSH-Px)活性、丙二醛(MAD)含量及肾组织的病理变化.结果:与模型组比较,各治疗组大鼠血肌酐、血清尿素氮,24h尿蛋白量、尿NAG的含量明显降低,肾组织匀浆中SOD活性、GSH-Px活性明显增高,MAD含量明显降低(P <0.01,P<0.05);肾脏的病理变化明显减轻.结论:血栓通能有效改善顺铂肾损伤大鼠肾功能,降低肾组织氧化水平,减轻肾脏的病理变化,对大鼠顺铂肾损伤有保护作用.%Objective: To study the protective effect of Xueshuantong against cisplatin-induced nephrotoxicity. Method; Female SD rats were randomly divided into six groups; normal saline (NS) group, model group, positive control group and the high dose group, middle dose group and low dose group of Xueshuantong, with 12 rats in each group. The model rats with nephrotoxicity were duplicated with injection of cisplatin by vena caudalis. Rats in model group, positive control group and the high dose group, middle dose group and low dose group of Xueshuantong were treated by amifostine, 0. 1 mg · kg-1, Xueshuantong, 15. 63 , 31. 35, 62.70 mg-kg-1 once a day. The changes of serum creatinine (SCr), blood urea nitrogen (BUN), W-acetyl-beta-D glucosa minidase (NAG), urine protein/24 h, the content of malondialdehyde ( MD A) and the activity of superoxide dismutase (SOD) , glutathione peroxidase (GSH-Px) were measured and renal structure was observed after 10 days of

  5. 鹿茸水提物减轻顺铂所致的小鼠肾损伤%Protective effect of aqueous extract of velvet antler on cisplatin-induced nephrotoxicity in mice

    Institute of Scientific and Technical Information of China (English)

    董思敏; 王海璐; 王全凯; 张晶

    2016-01-01

    AIM:To study the protective effect of aqueous extract of 2-branched and 3-branched velvet antler on cisplatin (CDDP)-induced nephrotoxicity in mice .METHODS:The mouse model of renal injury was induced by intra-gastric administration of CDDP at the dose of 15 mg/kg.After treatment, kidney index (KI), serum creatinine (SCr), blood urea nitrogen (BUN), the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and the content of malondialdehyde ( MDA) in the kidney were determined .The renal pathological changes were observed with HE staining.RESULTS:Aqueous extract of velvet antler at the tested dose markedly decreased BUN , SCr and the content of MDA, and elevated the activity of SOD and GSH-Px in the mice pretreated with CDDP ( P<0.05) .The pathological chan-ges of the renal tissues were improved obviously , and the injury of the epithelial cells of renal tubules was mitigated .The effect of the aqueous extract of 2-branched velvet antler on renal function and cisplatin-induced nephrotoxicity was better than that of 3-branched one at the same concentration .CONCLUSION: The aqueous extract of 2-branched and 3-branched velvet antler has a certain protective effect on cisplatin-induced nephrotoxicity , which may be associated with in-creasing the anti-oxidative capability of mouse renal tissue .%目的:探讨梅花鹿二杠茸和三岔茸水提物对顺铂( CDDP)所致小鼠肾损伤的影响。方法:采用灌胃给药方式,用顺铂(15 mg/kg)诱导小鼠肾损伤模型,测定小鼠肾脏指数(KI)、血清肌酐(SCr)、血尿素氮(BUN)、肾脏组织中超氧化物歧化酶( SOD)和谷胱甘肽过氧化物酶( GSH-Px)活性及丙二醛( MDA)含量,并对肾脏组织进行HE染色,观察肾脏病理学变化,研究梅花鹿二杠茸和三岔茸的水提物各剂量对小鼠肾损伤的影响。结果:与顺铂组相比,各剂量鹿茸水提物可显著降低CDDP诱导肾损伤小鼠SCr

  6. Protective Effects of Alcohol Extract of Okra Cisplatin Induced Acute Kidney Injury%黄秋葵醇提物对顺铂致急性肾损伤的保护作用

    Institute of Scientific and Technical Information of China (English)

    李莹; 高铭彤; 李婧毓; 刘一桐; 曾露露; 丁传波; 刘文丛; 郑毅男

    2016-01-01

    The study of okra tender fruit alcohol extract protective effects against cisplatin -induced acute kidney injury in mice.The 50 SPF ICR male mice were randomly divided into five groups:control (0.9% normal saline),model (0.9% normal saline),okra alcohol extraction from high,medium and low dose group(400、200、100 mg/kg).Respectively,7 d of intragastric administration.After 7 d,in addition to the control group, were given one hour after administration of gastric administration of cisplatin 20 mg/kg.And then intragastric administration 3 d,after eyeball plasma,serum centrifugal stay.We tested the content of serum blood urea nitrogen (BUN ), serum creatinine (CRE ),superoxide dismutase (SOD ), glutathione (GSH ) and malondialdehyde(MDA).Also measured SOD,GSH and MDA content in kidney homogenates;and inspected the changes of pathological by hematoxylin -eosin (HE).The experimental results show ,compared with the model, the okra alcohol extract high and middle dosage group,BUN,CRE content decreased and kidney tissues by GSH, SOD levels were increased (P <0.01,P <0.05).We discovered the okra alcohol extract better than the model could protectd renal pathological damage by HE.Therefore okra alcohol extract on cisplatin -induced acute kidney injury in mice has a protective effect.%为了探讨黄秋葵嫩果醇提物对顺铂致小鼠急性肾损伤是否具有保护作用,将50只 SPF级 ICR 雄性小鼠随机均分为空白对照组(0.9%生理盐水)、模型组(0.9%生理盐水)、黄秋葵醇提物(HQK)高中低剂量组(400、200、100 mg/kg),分别灌胃给药7 d,除空白对照组,于第7天给药1 h 后灌胃给顺铂20 mg/kg。再灌胃给药3 d 后,眼球取血,测定血清中尿素氮(BUN)、肌酐(CRE)、超氧化物歧化酶(SOD)、还原型谷胱甘肽(GSH)和丙二醛(MDA)的含量;测定肾脏匀浆中 SOD、GSH 和MDA 含量;并观察苏木精-伊红(HE)病理切片组织病理学变

  7. 铂类化疗药应用于持续腹腔热灌注治疗时的肾毒性评价%The evaluation of cisplatin-induced nephrotoxicity through hyperthermic intraperitoneal chemotherapy

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Objective: To investigate the incidence of cisplatin-induced nephrotoxicity through hyperthermic intraperitoneal chemotherapy (HIPEC) for gastrointestinal tumors.Methods: From January 2012 to July 2013, a consecutive series of 99 patients undergoing HIPEC were retrospectively reviewed. hTe patients were divided into cisplatin group and non-cisplatin group, and received HIPEC combined with cisplatin or not. Renal function parameters, nutritional status and immune function were compared between the two groups.Results: Based on the RIFLE classiifcation, four patients developed acute kidney injury and six slight renal insuffciency in the cisplatin group, and no patients had renal failure. The incidence of cisplatin-induced nephrotoxicity was 21.3%. The BUN and creatinine levels signiifcantly increased atfer perfusion therapy in the cisplatin group, were signiifcantly higher than those in the non-cisplatin group. However, there were no signiifcant differences in postoperative pain scaled with VAS score, albumin level and hospital stay between the two groups.Conclusion: Cisplatin-based HIPEC could increase the risk of postoperative nephrotoxicity. Renal function should be strictly monitored during cisplatin-based chemotherapy.%目的:了解顺铂等铂类药物应用于胃肠道肿瘤腹腔热灌注后短期肾毒性的发生情况。方法:从我科消化道肿瘤数据库中选择2012年1月至2013年7月期间行持续腹腔热灌注治疗的患者作为研究对象,根据治疗过程灌注液是否使用铂类药物分为观察组(铂类组)与对照组(无铂类组),观察两组患者治疗结束前后肾功能变化、疼痛评分、血清白蛋白水平及住院日。结果:99例患者纳入分析,47例接受铂类腹腔灌注治疗。铂类治疗组灌注后血尿素氮、肌酐水平明显升高,且显著高于对照组(P<0.05)。4例患者出现急性肾损害,6例出现轻微肾功能不全,肾毒性发生率为21.3%。两组患者术后疼

  8. Protective Effect of Breviscapine on Cisplatin-induced Nephrotoxicity in Mice%灯盏花素对小鼠顺铂肾损害的防治作用

    Institute of Scientific and Technical Information of China (English)

    任亮; 张印坡; 徐华; 马天江; 刘亚丽

    2012-01-01

    Objective: To observe the protective effect and mechanism of breviscapine on cisplatin-induced nephrotoxicity in mice. Method: The mice were randomly divided into four groups; control group, model group, breviscapine group treated by 25 mg·kg-1 (LBTG) and breviscapine group treated by 50 mg·kg-1 (HBTG). Other three groups were treated by a single injection of cisplatin(8 mg-kg-1 ) ip to establish model except control group, then the mice in LBTG and HBTG were given different dose of breviscapine (25, 50 mg-kg-1,ig) once a day for seven days. The renal tissue and change of BUN and SCr in their serum were observed. The change of SOD or MDA in there serum and renal cortex homogenate was also determined. Result: Serious damage in renal tissue was found, level of BUN and SCr was increased, and the content of MDA was increased, but the activity of SOD declined in serum and renal cortex homogenate in model group (P <0. 01 ). Change of renal tissue was improved in LBTG and HBTG compared with model group, level of BUN and Scr was significantly decreased in a dose-dependent manner(P <0. 05 ,P <0. 01 ) , the content of MDA was declined, but the activity of SOD was increased in serum and renal cortex homogenate ( P < 0. 05 ) . Conclusion: Breviscapine may reduce cisplatin-induced nephrotoxicity and its mechanism may be correlative with that breviscapine would inhibit blood and rencal cortex lipid peroxidation increasing%目的:观察灯盏花素对小鼠顺铂肾损害的防治作用及可能的作用机制.方法:将昆明小鼠随机分为空白组、模型对照组、灯盏花素25,50 mg· kg-1治疗组共4组.除空白组外,其余各组以顺铂8 mg·kg-1单次ip制备小鼠肾脏损害模型,两个治疗组随即分别给予25,50 mg· kg-1的灯盏花素ig,1次/d,连续给药7d.观察小鼠肾脏的改变及检测血清中肌酐(SCr)、尿素氮(BUN)的变化,检测血清及肾皮质中丙二醛(MDA)含量及超氧化物歧化酶(SOD)活性.结果:与空白

  9. Hydrogen sulfide protects human bone marrow mesesenchymal stem cells against cisplatin-induced damage%硫化氢抑制顺铂致人骨髓间充质干细胞的损伤

    Institute of Scientific and Technical Information of China (English)

    李敬春; 黄纲; 雍碧城; 徐名洪; 王姚斐; 张泷涓

    2011-01-01

    BACKGROUND: Due to serious myelosuppression caused by hemopoietic stem cell damage when using cisplatin chemo-treatment, there is no effective cytoprotective agent of chemo-treatment to lessen its adverse reaction.OBJECTIVE: To explore the protection of hydrogen sulfide (H2S) against cisplatin-induced human bone marrow mesesenchymal stem cells (hBMSCs) damage.METHODS: Sodium hydrosulfide (NaHS) as a H2S donor. hBMSCs treated with different concentrations of sodium hydrosulfide and cisplatin for 48 hours, the cell survival rate was measured by MTT assay; the morphological change of apoptotic cells was tested by using the chromatin dye Hoechst 33258; the proteins expression were detected with Western blot techniques.RESULTS AND CONCLUSION: MTT detection showed that cisplatin chould reduce the survival rate of BMSCs, and NaHS dose-dependently blocked the inhibition of hBMSCs cells growth induced by cisplatin. When hBMSCs cells were treated by both NaHS (0.5, 1 mmoUL) and cisplatin (20 mg/L) for 48 hours, the NF-κB (p65) was up-regulated, but the IκB-α was down-regulated.When hBMSCs cells were treated by both NaHS (1 mmol/L) and cisplatin (20 mg/L) for 6 hours, the level of phosphorylated protein kinase 1/2 was significantly ascended. The results showed that H2S chould protect hBMSCs against cisplatin-induced damage,which may be associated with the activation of protein kinase-NF-κB signaling pathway.%背景:在使用顺铂进行化疗时,常因造血干细胞损伤造成严重的骨髓抑制,而目前临床上还没有一种有效的化疗细胞保护剂来减轻其不良反应.目的:探讨硫化氢对顺铂致人骨髓间充质干细胞损伤的保护作用.方法:应用硫氢化钠作为硫化氢的供体,用不同浓度的硫氢化钠与顺铂同时作用于人骨髓间充质干细胞48 h后,甲氮甲唑蓝法(MTT)检测细胞存活率,Hoechst33258染色检测细胞凋亡,Western blot检测蛋白的表达.结果与结论:MTT检测发现顺铂可降低骨髓

  10. 连翘酯苷对顺铂致豚鼠耳毒性的影响及其机制探讨%Effect of forsythiaside on cisplatin-induced ototoxicity of guinea pigs

    Institute of Scientific and Technical Information of China (English)

    安宁; 侯学东; 时胜武

    2014-01-01

    目的:探讨连翘酯苷对顺铂致豚鼠耳毒性的影响及其机制。方法30只豚鼠随机分为对照组、顺铂组和连翘酯苷组,每组各10只。顺铂组豚鼠腹腔注射顺铂溶液8 mg/( kg· d),连续7 d;连翘酯苷组在每次注射顺铂溶液30 min前腹腔注射连翘酯苷25.0 mg/(kg· d),连续7 d;正常对照组以生理盐水代替顺铂溶液腹腔注射,连续7 d。实验动物被处死前,检测其畸变产物耳声发射( DPOAE)幅值变化;采用免疫组化SP法和Western blot法检测各组豚鼠耳蜗组织bcl-2蛋白的表达。结果1、2、4、6、8 kHz测试频率下,3组DPOAE幅值比较差异均有统计学意义(P均<0.05),即顺铂组<连翘酯苷组<对照组。3组豚鼠耳蜗组织bcl-2蛋白表达比较差异均有统计学意义(P<0.05或<0.01),即顺铂组<连翘酯苷组<对照组。结论连翘酯苷可减轻顺铂所致耳蜗损伤,上调耳蜗组织bcl-2蛋白表达可能是其作用机制之一。%Objective To study the effect of forsythiaside on cisplatin-induced ototoxicity of guinea pigs .Methods Thirty guinea pigs were randomly divided into the control group (n=10), cisplatin group (n=10) and forsythiaside group (n=10).The guinea pigs in the cisplatin group were induced by intraperitoneal injection of cisplatin solution (8 mg/kg per day) for 7 days, the guinea pigs in the forsythiaside group were given forsythiaside (25 mg/kg per day) at 30 min be-fore cisplatin solution for 7 consecutive days , and the normal saline instead of cisplatin was injected in the control group . The distortion product otoacoustic emission ( DPOAE) was detected before the experimental animals were killed , and the expression of bcl-2 in cochlea of guinea pigs was detected by immunohistochemistry and Western blotting .Results Statis-tical difference was found in the DPOAE amplitudes under 1, 2, 4, 6 and 8 kHz test frequencies among the three groups

  11. Acidosis Mediates the Switching of Gs-PKA and Gi-PKCε Dependence in Prolonged Hyperalgesia Induced by Inflammation.

    Science.gov (United States)

    Huang, Wei-Yu; Dai, Shih-Ping; Chang, Yan-Ching; Sun, Wei-Hsin

    2015-01-01

    Chronic inflammatory pain, when not effectively treated, is a costly health problem and has a harmful effect on all aspects of health-related quality of life. Previous studies suggested that in male Sprague Dawley rats, prostaglandin E2 (PGE2)-induced short-term hyperalgesia depends on protein kinase A (PKA) activity, whereas long-lasting hyperalgesia induced by PGE2 with carrageenan pre-injection, requires protein kinase Cε (PKCε). However, the mechanism underlying the kinase switch with short- to long-term hyperalgesia remains unclear. In this study, we used the inflammatory agents carrageenan or complete Freund's adjuvant (CFA) to induce long-term hyperalgesia, and examined PKA and PKCε dependence and switching time. Hyperalgesia induced by both agents depended on PKA/PKCε and Gs/Gi-proteins, and the switching time from PKA to PKCε and from Gs to Gi was about 3 to 4 h after inflammation induction. Among the single inflammatory mediators tested, PGE2 and 5-HT induced transient hyperalgesia, which depended on PKA and PKCε, respectively. Only acidic solution-induced hyperalgesia required Gs-PKA and Gi-PKCε, and the switch time for kinase dependency matched inflammatory hyperalgesia, in approximately 2 to 4 h. Thus, acidosis in inflamed tissues may be a decisive factor to regulate switching of PKA and PKCε dependence via proton-sensing G-protein-coupled receptors.

  12. Acidosis Mediates the Switching of Gs-PKA and Gi-PKCε Dependence in Prolonged Hyperalgesia Induced by Inflammation.

    Directory of Open Access Journals (Sweden)

    Wei-Yu Huang

    Full Text Available Chronic inflammatory pain, when not effectively treated, is a costly health problem and has a harmful effect on all aspects of health-related quality of life. Previous studies suggested that in male Sprague Dawley rats, prostaglandin E2 (PGE2-induced short-term hyperalgesia depends on protein kinase A (PKA activity, whereas long-lasting hyperalgesia induced by PGE2 with carrageenan pre-injection, requires protein kinase Cε (PKCε. However, the mechanism underlying the kinase switch with short- to long-term hyperalgesia remains unclear. In this study, we used the inflammatory agents carrageenan or complete Freund's adjuvant (CFA to induce long-term hyperalgesia, and examined PKA and PKCε dependence and switching time. Hyperalgesia induced by both agents depended on PKA/PKCε and Gs/Gi-proteins, and the switching time from PKA to PKCε and from Gs to Gi was about 3 to 4 h after inflammation induction. Among the single inflammatory mediators tested, PGE2 and 5-HT induced transient hyperalgesia, which depended on PKA and PKCε, respectively. Only acidic solution-induced hyperalgesia required Gs-PKA and Gi-PKCε, and the switch time for kinase dependency matched inflammatory hyperalgesia, in approximately 2 to 4 h. Thus, acidosis in inflamed tissues may be a decisive factor to regulate switching of PKA and PKCε dependence via proton-sensing G-protein-coupled receptors.

  13. EP2 receptor antagonism reduces peripheral and central hyperalgesia in a preclinical mouse model of endometriosis

    Science.gov (United States)

    Greaves, Erin; Horne, Andrew W.; Jerina, Helen; Mikolajczak, Marta; Hilferty, Lisa; Mitchell, Rory; Fleetwood-Walker, Sue M.; Saunders, Philippa T. K.

    2017-01-01

    Endometriosis is an incurable gynecological disorder characterized by debilitating pain and the establishment of innervated endometriosis lesions outside the uterus. In a preclinical mouse model of endometriosis we demonstrated overexpression of the PGE2-signaling pathway (including COX-2, EP2, EP4) in endometriosis lesions, dorsal root ganglia (DRG), spinal cord, thalamus and forebrain. TRPV1, a PGE2-regulated channel in nociceptive neurons was also increased in the DRG. These findings support the concept that an amplification process occurs along the pain neuroaxis in endometriosis. We then tested TRPV1, EP2, and EP4 receptor antagonists: The EP2 antagonist was the most efficient analgesic, reducing primary hyperalgesia by 80% and secondary hyperalgesia by 40%. In this study we demonstrate reversible peripheral and central hyperalgesia in mice with induced endometriosis. PMID:28281561

  14. Secondary hyperalgesia phenotypes exhibit differences in brain activation during noxious stimulation

    DEFF Research Database (Denmark)

    Asghar, Mohammad Sohail; Pereira, Manuel Pedro; Werner, Mads Utke;

    2015-01-01

    . To study differences in the propensity to develop central sensitization we examined differences in brain activity and anatomy according to individual phenotypical expression of secondary hyperalgesia by magnetic resonance imaging. Forty healthy volunteers received a first-degree burn-injury (47 °C, 7 min...... hyperalgesia areas after burn-injury. In addition, T1-weighted images were used to measure differences in gray-matter density in cortical and subcortical regions of the brain. We found significant differences in neuronal activity between high- and low-sensitization responders at baseline (before application...... in high-sensitization responders in comparison to low-sensitization responders. These findings suggest that brain-structure and neuronal activation to noxious stimulation differs according to secondary hyperalgesia phenotype. This indicates differences in central sensitization according to phenotype...

  15. Cisplatin induces tolerogenic dendritic cells in response to TLR agonists via the abundant production of IL-10, thereby promoting Th2- and Tr1-biased T-cell immunity

    Science.gov (United States)

    Kim, Hongmin; Kwon, Kee Woong; Im, Sin-Hyeog; Lee, Bo Ryeong; Ha, Sang-Jun; Shin, Sung Jae

    2016-01-01

    Although many advantageous roles of cisplatin (cis-diamminedichloroplatinum (II), CDDP) have been reported in cancer therapy, the immunomodulatory roles of cisplatin in the phenotypic and functional alterations of dendritic cells (DCs) are poorly understood. Here, we investigated the effect of cisplatin on the functionality of DCs and the changes in signaling pathways activated upon toll-like receptor (TLR) stimulation. Cisplatin-treated DCs down-regulated the expression of cell surface molecules (CD80, CD86, MHC class I and II) and up-regulated endocytic capacity in a dose-dependent manner. Upon stimulation with various TLR agonists, cisplatin-treated DCs showed markedly increased IL-10 production through activation of the p38 MAPK and NF-κB signaling pathways without altering the levels of TNF-α and IL-12p70, indicating the cisplatin-mediated induction of tolerogenic DCs. This effect was dependent on the production of IL-10 from DCs, as neither DCs isolated from IL-10−/− mice nor IL-10-neutralized DCs generated tolerogenic DCs. Interestingly, DCs that were co-treated with cisplatin and lipopolysaccharide (LPS) exhibited a decreased immunostimulatory capacity for inducing the proliferation of Th1- and Th17-type T cells; instead, these DCs contributed to Th2-type T cell immunity. Furthermore, in vitro and in vivo investigations revealed a unique T cell population, IL-10-producing CD3+CD4+LAG-3+CD49b+CD25−Foxp3− Tr1 cells, that was significantly increased without altering the Foxp3+ regulatory T cell population. Taken together, our results suggest that cisplatin induces immune-suppressive tolerogenic DCs in TLR agonist-induced inflammatory conditions via abundant IL-10 production, thereby skewing Th cell differentiation towards Th2 and Tr1 cells. This relationship may provide cancer cells with an opportunity to evade the immune system. PMID:27172902

  16. Mechanism of drug resistance and reversal with ligustra-zine and cyclosporin A in cisplatin-induced human epithelial ovarian cancer resistant cell line 3Ao/cDDP

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective: To investigate the mechanism of resistance and reversal effect of ligustrazine and cyclosporin A in cisplatin-induced multidrug resistance ovarian cancer cell line 3Ao/cDDP. Methods: Using the corresponding dose calculated from clinical chemotherapy at 30 mg cisplatin per cycle, we established 3Ao/cDDP with 3Ao exposed at regular intervals and repeatedly to high-level concentration of cisplatin at 10 m g/ml for 24 hours each time. Expressions of LRP, MRP, P-gp, GSTp and TopoII were quantitatively detected with FCM. For drug resistance reversal, cyclosporin A and ligustrazine were administered singly or in combination at the maximal dose without cytotoxicity. Inhibition rates were determined by MTT assay. Results: 3Ao/cDDP was established after 4.5 months, with resistance factor 1.6 which was similar to clinical resistance degree. Low expression levels of MRP and P-gp were found in both 3Ao and 3Ao/cDDP (P>0.05), and LRP and GSTp expression levels in 3Ao/cDDP were significantly higher than those in 3Ao (P0.05 vs cDDP), cDDP plus cyclosporin A 49.635± 0.021% (P<0.01 vs cDDP), and cDDP plus ligustrazine and cyclosporin A 58.861± 0.014% (P<0.01 vs cDDP). Conclusions: 3Ao/cDDP, induced by cisplatin and established by imitating the characteristics of clinical chemotherapy for epithelial ovarian cancer, was an ideal model for investigation of cisplatin resistance in vitro. Cisplatin resistance in 3Ao/cDDP could be accounted for by higher LRP, GSTp and lower TopoII expression and was not associated with MRP or P-gp. Ligustrazine had no significant reversal effect on cisplatin resistance, but cyclosporin A could reverse the resistance effectively.

  17. Sphingosine 1-phosphate mediates hyperalgesia via a neutrophil-dependent mechanism.

    Directory of Open Access Journals (Sweden)

    Amanda Finley

    Full Text Available Novel classes of pain-relieving molecules are needed to fill the void between non-steroidal anti-inflammatory agents and narcotics. We have recently shown that intraplantar administration of sphingosine 1-phosphate (S1P in rats causes peripheral sensitization and hyperalgesia through the S1P(1 receptor subtype (S1PR(1: the mechanism(s involved are largely unknown and were thus explored in the present study. Intraplantar injection of carrageenan in rats led to a time-dependent development of thermal hyperalgesia that was associated with pronounced edema and infiltration of neutrophils in paw tissues. Inhibition of 1 S1P formation with SK-I, a sphingosine kinase inhibitor, 2 S1P bioavailability with the S1P blocking antibody Sphingomab, LT1002 (but not its negative control, LT1017 or 3 S1P actions through S1PR(1 with the selective S1PR(1 antagonist, W146 (but not its inactive enantiomer, W140 blocked thermal hyperalgesia and infiltration of neutrophils. Taken together, these findings identify S1P as an important contributor to inflammatory pain acting through S1PR(1 to elicit hyperalgesia in a neutrophil-dependant manner. In addition and in further support, we demonstrate that the development of thermal hyperalgesia following intraplantar injection of S1P or SEW2871 (an S1PR(1 agonist was also associated with neutrophilic infiltration in paw tissues as these events were attenuated by fucoidan, an inhibitor of neutrophilic infiltration. Importantly, FTY720, an FDA-approved S1P receptor modulator known to block S1P-S1PR(1 signaling, attenuated carrageenan-induced thermal hyperalgesia and associated neutrophil infiltration. Targeting the S1P/S1PR(1 axis opens a therapeutic strategy for the development of novel non-narcotic anti-hyperalgesic agents.

  18. Local and Widespread Hyperalgesia After Isolated Tibial Shaft Fractures Treated with Intramedullary Nailing

    DEFF Research Database (Denmark)

    Larsen, Peter; Elsøe, Rasmus; Graven-Nielsen, Thomas

    2016-01-01

    OBJECTIVES: Knee pain is accepted as a common complication to intramedullary nailing of tibial fractures. However, no studies have systematically studied the pain sequel following tibial fractures. The objective of this study was to assess pain and hyperalgesia from 6 weeks to 12 months postopera......OBJECTIVES: Knee pain is accepted as a common complication to intramedullary nailing of tibial fractures. However, no studies have systematically studied the pain sequel following tibial fractures. The objective of this study was to assess pain and hyperalgesia from 6 weeks to 12 months...

  19. A comprehensive review of opioid-induced hyperalgesia.

    Science.gov (United States)

    Lee, Marion; Silverman, Sanford M; Hansen, Hans; Patel, Vikram B; Manchikanti, Laxmaiah

    2011-01-01

    Opioid-induced hyperalgesia (OIH) is defined as a state of nociceptive sensitization caused by exposure to opioids. The condition is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain could actually become more sensitive to certain painful stimuli. The type of pain experienced might be the same as the underlying pain or might be different from the original underlying pain. OIH appears to be a distinct, definable, and characteristic phenomenon that could explain loss of opioid efficacy in some patients. Findings of the clinical prevalence of OIH are not available. However, several observational, cross-sectional, and prospective controlled trials have examined the expression and potential clinical significance of OIH in humans. Most studies have been conducted using several distinct cohorts and methodologies utilizing former opioid addicts on methadone maintenance therapy, perioperative exposure to opioids in patients undergoing surgery, and healthy human volunteers after acute opioid exposure using human experimental pain testing. The precise molecular mechanism of OIH, while not yet understood, varies substantially in the basic science literature, as well as clinical medicine. It is generally thought to result from neuroplastic changes in the peripheral and central nervous system (CNS) that lead to sensitization of pronociceptive pathways. While there are many proposed mechanisms for OIH, 5 mechanisms involving the central glutaminergic system, spinal dynorphins, descending facilitation, genetic mechanisms, and decreased reuptake and enhanced nociceptive response have been described as the important mechanisms. Of these, the central glutaminergic system is considered the most common possibility. Another is the hypothesis that N-methyl-D-aspartate (NMDA) receptors in OIH include activation, inhibition of the glutamate transporter system, facilitation of calcium regulated intracellular protein kinase C, and cross

  20. Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long-term administration?

    DEFF Research Database (Denmark)

    Sjøgren, P; Thunedborg, L P; Christrup, Lona Louring

    1998-01-01

    Recently, clinical reports have suggested a relationship between the occurrence of hyperalgesia, allodynia and/or myoclonus and treatment with high doses of morphine in humans. Although few clinical descriptions of these phenomena are available, experimental work supports the notion that high doses...... of morphine may play a pathogenetic role in the observed behavioural syndrome....

  1. S-ketamine modulates hyperalgesia in patients with chronic pancreatitis pain

    NARCIS (Netherlands)

    Bouwense, S.A.W.; Buscher, H.C.J.L.; Goor, H. van; Wilder-Smith, O.H.G.

    2011-01-01

    BACKGROUND AND OBJECTIVES: Upper abdominal pain is a dominant feature of chronic pancreatitis. A key phenomenon in this context is hyperalgesia, typically associated with N-methyl-d-aspartate receptor activation. This exploratory study evaluates acute effects of S-ketamine, a noncompetitive N-methyl

  2. Peripheral lidocaine, but not ketamine inhibit capsaicin-induced hyperalgesia in humans

    DEFF Research Database (Denmark)

    Gottrup, Hanne; Bach, Flemming Winther; Arendt-Nielsen, Lars

    2000-01-01

    or lidocaine. Lidocaine produced no side-effects, whereas ketamine produced paraesthesia, dizziness and sleepiness in six out of 24 (25%) cases. Blocking peripheral sodium channels with locally administered lidocaine reduces spontaneous pain and capsaicin-induced hyperalgesia but local block with the NMDA...

  3. Pioglitazone attenuates tactile allodynia and thermal hyperalgesia in mice subjected to peripheral nerve injury.

    Science.gov (United States)

    Maeda, Takehiko; Kiguchi, Norikazu; Kobayashi, Yuka; Ozaki, Masanobu; Kishioka, Shiroh

    2008-11-01

    To clarify the role of peroxisome proliferator activated receptor gamma (PPARgamma) in neuropathic pain, we examined the effect of pioglitazone, a PPARgamma agonist, on tactile allodynia and thermal hyperalgesia in a neuropathic pain model. Mice were subjected to partial sciatic nerve ligation (PSL) and given pioglitazone (1 - 25 mg/kg, p.o.) once daily. PPARgamma was distributed in the neurons of the dorsal root ganglion and the dorsal horn of the spinal cord and in the adipocytes at the epineurium of the sciatic nerve in naive mice. PSL elicited tactile allodynia and thermal hyperalgesia for two weeks. Administration of pioglitazone for the first week after PSL attenuated thermal hyperalgesia and tactile allodynia, which was dose-dependent and blocked by GW9662 (2 mg/kg, i.p.), a PPARgamma antagonist. Administration of pioglitazone for the second week also relieved tactile allodynia, but administration one week before PSL had no effect. A single administration of pioglitazone to mice on day 7 of PSL did not alter tactile allodynia and thermal hyperalgesia. PSL-induced upregulation of tumor necrosis factor-alpha and interleukin-6, which are essential for neuropathic pain, was suppressed by pioglitazone for the first week. This suggests that pioglitazone alleviates neuropathic pain through attenuation of proinflammatory cytokine upregulation by PPARgamma stimulation.

  4. Evaluation of antivenoms in the neutralization of hyperalgesia and edema induced by Bothrops jararaca and Bothrops asper snake venoms

    Directory of Open Access Journals (Sweden)

    Picolo G.

    2002-01-01

    Full Text Available Neutralization of hyperalgesia induced by Bothrops jararaca and B. asper venoms was studied in rats using bothropic antivenom produced at Instituto Butantan (AVIB, 1 ml neutralizes 5 mg B. jararaca venom and polyvalent antivenom produced at Instituto Clodomiro Picado (AVCP, 1 ml neutralizes 2.5 mg B. aspar venom. The intraplantar injection of B. jararaca and B. asper venoms caused hyperalgesia, which peaked 1 and 2 h after injection, respectively. Both venoms also induced edema with a similar time course. When neutralization assays involving the independent injection of venom and antivenom were performed, the hyperalgesia induced by B. jararaca venom was neutralized only when bothropic antivenom was administered iv 15 min before venom injection, whereas edema was neutralized when antivenom was injected 15 min or immediately before venom injection. On the other hand, polyvalent antivenom did not interfere with hyperalgesia or edema induced by B. asper venom, even when administered prior to envenomation. The lack of neutralization of hyperalgesia and edema induced by B. asper venom is not attributable to the absence of neutralizing antibodies in the antivenom, since neutralization was achieved in assays involving preincubation of venom and antivenom. Cross-neutralization of AVCP or AVIB against B. jararaca and B. asper venoms, respectively, was also evaluated. Only bothropic antivenom partially neutralized hyperalgesia induced by B. asper venom in preincubation experiments. The present data suggest that hyperalgesia and edema induced by Bothrops venoms are poorly neutralized by commercial antivenoms even when antibodies are administered immediately after envenomation.

  5. Traumatic Stress Promotes Hyperalgesia via Corticotropin-Releasing Factor-1 Receptor (CRFR1) Signaling in Central Amygdala.

    Science.gov (United States)

    Itoga, Christy A; Roltsch Hellard, Emily A; Whitaker, Annie M; Lu, Yi-Ling; Schreiber, Allyson L; Baynes, Brittni B; Baiamonte, Brandon A; Richardson, Heather N; Gilpin, Nicholas W

    2016-09-01

    Hyperalgesia is an exaggerated response to noxious stimuli produced by peripheral or central plasticity. Stress modifies nociception, and humans with post-traumatic stress disorder (PTSD) exhibit co-morbid chronic pain and amygdala dysregulation. Predator odor stress produces hyperalgesia in rodents. Systemic blockade of corticotropin-releasing factor (CRF) type 1 receptors (CRFR1s) reduces stress-induced thermal hyperalgesia. We hypothesized that CRF-CRFR1 signaling in central amygdala (CeA) mediates stress-induced hyperalgesia in rats with high stress reactivity. Adult male Wistar rats were exposed to predator odor stress in a conditioned place avoidance paradigm and indexed for high (Avoiders) and low (Non-Avoiders) avoidance of predator odor-paired context, or were unstressed Controls. Rats were tested for the latency to withdraw hindpaws from thermal stimuli (Hargreaves test). We used pharmacological, molecular, and immunohistochemical techniques to assess the role of CRF-CRFR1 signaling in CeA in stress-induced hyperalgesia. Avoiders exhibited higher CRF peptide levels in CeA that did not appear to be locally synthesized. Intra-CeA CRF infusion mimicked stress-induced hyperalgesia. Avoiders exhibited thermal hyperalgesia that was reversed by systemic or intra-CeA injection of a CRFR1 antagonist. Finally, intra-CeA infusion of tetrodotoxin produced thermal hyperalgesia in unstressed rats and blocked the anti-hyperalgesic effect of systemic CRFR1 antagonist in stressed rats. These data suggest that rats with high stress reactivity exhibit hyperalgesia that is mediated by CRF-CRFR1 signaling in CeA.

  6. Relation cellular- molecular between serum IL10 levels and hyperalgesia variation in adjuvant- induced arthritis

    Directory of Open Access Journals (Sweden)

    Zenab Akhtari

    2015-01-01

    Full Text Available Background: Regarding to the important anti-inflammatory role of IL10 during inflammation process and hyperalgesia and edema variation during CFA-induced arthritis and also the increase of Spinal mu opioid receptor (mOR expression, in this study researchers investigate the role of serum IL10 level on mOR expression and edema and hyperalgesia variation during different stages of Complete Freund`s Adjuvant (CFA - induced arthritis in male Wistar rats. Materials and Methods: Mono-arthritis was induced by CFA and inflammatory symptoms (hyperalgesia and edema were assessed on 0, 3, 7, 14th and 21st days of study. Anti-IL10 was administered during the 21 days of study in different experimental groups. mOR expression were detected by western blotting on 0, 3,7, 14th and 21st days of study. Data was analyzed by SPSS statistical software version 19 with using one way ANOVA (post hoc Tokey's. Results: Our results showed that anti-IL10 administration in AA group (Adjuvant Arthritis caused an increase in the paw volume and hyperalgesia until 21st of study. Our study stated that there were no significant differences in spinal mOR expression between AA and AA+anti-IL10rats. Conclusion: Our study confirmed that anti-IL10administration caused to hyperalgesia and edema during AA inflammation. Also these findings suggested that mOR expression increased in chronic phase of AA inflammation, however an increase in the level of spinal mu opioid receptor (mOR expression during AA inflammation is not mediated directly via the effect of serum IL-10.

  7. Blocking TNF-α with infliximab alleviates ovariectomy induced mechanical and thermal hyperalgesia in rats.

    Science.gov (United States)

    Chen, Bai Ling; Li, Yi Qiang; Xie, Deng Hui; He, Qiu Lan; Yang, Xiao Xi

    2012-06-01

    Studies have proved an increased expression of tumor necrosis factor alpha (TNF-α) in estrogen deficiency animals, and TNF-α also plays a role in inflammation and neuropathic pain. This study aimed to explore the relationship between TNF-α and ovariectomy induced hyperalgesia. 36 female Sparague-Dawley were included, estrogen depletion models were established by ovariectomy. Then infliximab (a TNF-α blocker) was administrated to the ovariectomized rats for 8 weeks. Pain behavioral tests were performed once a week. The bone mineral density (BMD), serum estradiol and TNF-α level were determined at the 8th week after ovariectomy. The expression of TNF-α in lumbar 5 dorsal root ganglions (L5 DRGs) was examined by immunofluorescence method. Significant hyperalgesia to mechanical and thermal stimuli in groups Ovx-1 and Ovx-2 was observed 1 week after the operation. After treated with infliximab, the pain threshold of Ovx-2 was partially restored, although still lower than the Sham group. The serum TNF-α level of Ovx-1 was significantly higher than Sham and Ovx-2. TNF-α immunofluorescence indicated a significant increase in the expression of TNF-α at L5 DRGs in group Ovx-1 when compared with groups Sham and Ovx-2. The BMD of group Ovx-2 was significantly higher than group Ovx-1 and lower than group Sham. In conclusion, TNF-α plays an important role in estrogen deficiency induced mechanical and thermal hyperalgesia, and DRG may be one site on which TNF-α acts to cause hyperalgesia. Blocking the effect of TNF-α could partially alleviate the estrogen deficiency induced hyperalgesia in rats. Thus, TNF-α may contribute to chronic pain in postmenopausal women.

  8. Experimental study of cisplatin inducement in establishment of the rat model of premature ovarian failure%顺铂诱导大鼠卵巢早衰的实验研究

    Institute of Scientific and Technical Information of China (English)

    梁丹; 曹保利; 李继坤; 季萍; 田甜

    2012-01-01

    Objective It is to explore the optimal dosage of cisplatin inducement in establishment of the rats model of pre -mature ovarian failure ( POF). Methods Adult female Wistar rats were divided into 5 groups by treated with the different doses of cisplatin to establish models of POF : group A 3 mg/kg for 7 days, group B 2.5 mg/kg for 7 days) , group C 2.0 mg/kg for 7 days) , group D 2. 5 mg/kg for 5 days) and with saline in group E. The changes of general state , weight, genesial hormones , organs index and pathological changes were observed in the rats after the injection of cisplatin o Results The weight as higher and the duration of estrous cycle as longer in all cisplatin groups after injection than before the injection . In groupA,B, C, D, E the mortalities were 70% , 50% 30 % , 0,0 o For the serum FSH levels, there was no statistical significance between group E and group D (P > 0. 05 ) , but significantly higher in group C ( P 0 05).血清E2水平C、D 2组均显著低于E组(P<0.05).卵巢及子宫指数C组显著低于E组(P<0.05),肾上腺指数C组显著高于E组(P<0.05).顺铂组大鼠卵巢原始卵泡数和初级卵泡数均明显降低,而闭锁卵泡数均明显增加.结论 2.0mg/(kg·7d)模型组是最理想的卵巢早衰动物模型.此化疗损伤性卵巢早衰大鼠模型血FSH明显升高,卵巢组织学衰退性改变与人类化疗损伤性卵巢早衰病变过程相似.

  9. Effects of sufentanil and morphine on cisplatin-induced acute kidney injury in rats%舒芬太尼和吗啡对顺铂致大鼠急性肾损伤的影响

    Institute of Scientific and Technical Information of China (English)

    梁桦; 赖晓红; 尹媛萍; 廖美娟; 郑雪琴; 杨承祥

    2015-01-01

    目的 评价舒芬太尼和吗啡对顺铂致大鼠急性肾损伤的影响.方法 健康雄性SD大鼠32只,8~10周龄,体重220~280 g,采用随机数字表法分为4组(n=8):对照组(C组)、顺铂(Cis组)、舒芬太尼组(S组)和吗啡组(M组).Cis组腹腔注射顺铂16 mg/kg;S组腹腔注射顺铂16mg/kg后,经5 min尾静脉注射舒芬太尼2μg/kg,连续注射3 d;M组腹腔注射顺铂16 mg/kg后,经5min尾静脉注射吗啡2 mg/kg,连续注射3 d;C组注射等容量生理盐水.第3天给药结束后,采集眼眶静脉血样,检测血清BUN和Cr的浓度,然后处死大鼠,取左侧肾组织,行碘酸-Schiff's染色,光镜下观察病理学结果,并行肾小管损伤评分;采用ELISA法检测肾组织TNF-α、IL-1β和IL-6的含量,采用Western blot法检测肾组织X连锁凋亡抑制蛋白(XIAP)、生存素和caspase-3的表达水平.结果 与C组比较,Cis组、S组和M组血清BUN、Cr的浓度和肾小管损伤评分升高,肾组织TNF-α、 IL-1β和IL-6的含量升高,肾组织XIAP和生存素的表达下调,caspase-3表达上调(P<0.05);与Cis组比较,S组和M组血清BUN、Cr的浓度和肾小管损伤评分降低,肾组织TNF-α、IL-1β和IL-6的含量降低,肾组织XIAP和生存素的表达上调,caspase-3表达下调(P<0.05).S组和M组间上述各指标比较差异无统计学意义(P>0.05).结论 舒芬太尼和吗啡均可减轻顺铂致大鼠急性肾损伤,且2种药物作用相当,其机制可能与抑制炎性反应和细胞凋亡有关.%Objective To evaluate the effects of sufentanil and morphine on cisplatin-induced acute kidney injury in rats.Methods Thirty-two healthy Sprague-Dawley rats, aged 8-10 weeks, weighing 220-280 g, were randomly divided into 4 groups (n =8 each) using a random number table: control group (group C);cisplatin group (group Cis);sufentanil group (group S);morphine group (group M).Cisplatin 16 mg/kg was injected intraperitoneally in group Cis.In group S, cisplatin 16 mg/kg was injected

  10. The intervention effect of Schisandrin B on cisplatin induced acute kidney injury in mice%五味子乙素对顺铂所致小鼠急性肾损伤的干预作用

    Institute of Scientific and Technical Information of China (English)

    吴银娜; 谭小月; 张勉之

    2015-01-01

    Objective To observe the intervention effect of Schisandrin B (Sch B) on cisplatin induced acute kidney injury (AKI) in mice and its possible mechanism.Methods Twenty-five BALB/c mice were randomly divided into blank control group, model group, low and high dose of Sch B intervention groups and Sch B control group. Olive oil with Sch B was administered by gavage at the dose of 20 mg/kg or 100 mg/kg for low and high dose of Sch B intervention groups respectively; olive oil with Sch B 100 mg/kg was applied by gavage to the Sch B control group; the same volume of olive oil was perfused into the gastric cavity in the blank control group and model group; the above measures in various groups were consecutively used for 5 days. On the 3rd day of the experiment, AKI mice model was established by intraperitoneal injection of cisplatin (20 mg/kg) once and the same measure was given to the low and high dose of Sch B intervention groups; 1 mL/kg normal saline was injected into the peritoneal cavity in the bland control group and Sch B control group. At the end of the experiment, the serum creatinine (SCr) level was determined; apoptosis of renal tubular epithelial cells were detected by using terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay; the morphological changes of renal tubular epithelial cells were observed by hematoxylin eosin (HE) staining, and renal tubular injury score was evaluated; p53 protein content in the kidney tissue was measured by immunohistochemical analysis; furthermore, expressional level of p53 protein in renal tissue was tested by Western Blot.Results Compared with the blank control group, the level of SCr (μmol/L: 86.77±10.97 vs. 14.37±0.81), renal tubular injury score (9.67±1.20 vs. 1.00±0.45), the count of apoptotic renal tubular epithelial cells (cells/200 power field: 20.00±2.13 vs. 2.30±0.40) in the model group were all increased (P < 0.05 orP < 0.01), and p53 protein content (cells/400 power field: 13

  11. 线粒体功能障碍参与顺铂诱导的小鼠急性肾损伤%Mitochondrial dysfunction in the process of cisplatin-induced acute kidney injury in mice

    Institute of Scientific and Technical Information of China (English)

    潘晶晶; 宣小燕; 张爱华; 丁桂霞

    2013-01-01

    目的 通过观察顺铂在不同剂量下诱导小鼠急性肾损伤的特点,进一步了解线粒体功能障碍参与急性肾损伤的机制.方法 雄性C57BL/6J小鼠18只,随机分为正常对照组(n=6)及顺铂处理组(n=12),其中顺铂处理组按顺铂给予剂量不同又分为10 mg/kg组(n=6)和20 mg/kg组(n=6).采用顺铂单次腹腔注射建立急性肾损伤模型,72 h后处死小鼠.测定肾功能相关生化指标、肾组织病理改变、肾损伤标志物的变化以及肾脏线粒体功能及结构变化指标.结果 (1)顺铂注射72 h后,顺铂处理组与对照组相比出现明显急性肾损伤表现,其中20 mg/kg组肾损伤程度更为严重,表现为随着顺铂剂量加大,肾生化指标血肌酐、尿蛋白等水平逐渐升高.(2)顺铂处理组肾小管结构破坏,蛋白管型形成,同时肾损伤标志物肾损伤分子1(KIM-1)mRNA升高(P<0.05).(3)顺铂处理组肾小管线粒体结构破坏明显,同时线粒体DNA拷贝数下降(P<0.05),线粒体相关蛋白过氧化物酶体增殖活化受体γ辅助活化因子1α(PGC-1α)及ATP合酶表达降低(P<0.01),细胞色素C从线粒体向胞质释放;且不同浓度顺铂组间各项指标差异亦有统计学意义(P<0.05).结论 顺铂能够呈剂量依赖性的诱导急性肾损伤发生,线粒体功能障碍参与了肾损伤发生,并与肾损伤的病理改变密切相关.%Objective To assess the characteristics of different doses of cisplatin-induced acute kidney injury,further to understand mitochondrial dysfunction and its role in acute kidney injury (AKI).Methods Male C57BL/6J mice were first randomly divided into two groups:control group (n =6) and AKI group (n =12).Then,AKI group was subsequently divided into other two groups according to different dose of cisplatin (10 mg/kg or 20 mg/kg).AKI group received intraperitoneal injection of cisplatin.All mice were sacrificed after 72 h of injection.Renal biochemical function,renal pathological changes

  12. Effect of different doses of propofol on cisplatin-induced hepatotoxicity in rats%不同剂量异丙酚对顺铂致大鼠肝细胞毒性的影响

    Institute of Scientific and Technical Information of China (English)

    赵立梅; 赖仁纯; 王晶; 范艳婷; 王琴; 王旭东

    2012-01-01

    Objective To investigate the effect of different doses of propofol on cisplatin-induced hepatotoxicity in rats.Methods Eighty male SD rats weighing 200-250 g,aged 3 months,were randomly divided into 8 groups (n =10 each) ∶ control group (group C),cisplatin 7.5 mg/kg group (group Cis),propofol 180 mg/kg group (group P),intralipid 15 ml/kg group (group Ⅰ),cisplatin 7.5 mg/kg + intralipid 15 ml/kg group (group CisI),cisplatin 7.5 mg/kg + propofol 60 mg/kg group (group CisP1),cisplatin 7.5 mg/kg + propofol 120 mg/kg group (group CisP2),and cisplatin 7.5 mg/kg + propofol 180 mg/kg group (group CisP3).The rats in groups C,Cis,P and I received single intraperitoneal injection of normal saline,cisplatin,propofol and intralipid respectively.While in the groups CisI,CisP1,CisP2 and CisP3,rats received a single intraperitoneal injection of propofol or intralipid at 1 min before a single intraperitoneal injection of cisplatin.At 24 h after cisplatin injection,venous blood samples were taken from inferior vena cava for measurement of plasma ALT and AST activities.The liver tissues were taken for microscopic examination.Results Compared with group C,plasma ALT and AST activities were significantly increased and pathological injury was aggravated in groups Cis,CisI and CisP1-3 (P < 0.05).The activities of ALT and AST were gradually decreased and the pathologic injury was attenuated in groups Cis and CisP1-3 (P < 0.05).Conclusion Propofol can reduce cisplatin-induced hepatotoxicity in a dose-dependent manner in rats.%目的 评价不同剂量异丙酚对顺铂致大鼠肝细胞毒性的影响.方法 健康雄性SD大鼠80只,体重200 ~ 250 g,3月龄,采用随机数字表法,将其随机分为8组(n=10)∶对照组(C组)、顺铂7.5 mg/kg组(Cis组)、异丙酚180 mg/kg组(P组)、脂肪乳15 ml/kg组(Ⅰ组)、顺铂7.5 mg/kg+脂肪乳15ml/kg组(CisI组)、顺铂7.5 mg/kg+异丙酚60 mg/kg组(CisP1组)、顺铂7.5 mg/kg+异丙酚120 mg/kg组(CisP2组)、顺铂7.5 mg

  13. Cisplatin-induced hyperglycaemic hyperosmolar coma

    NARCIS (Netherlands)

    Komdeur, R.; Derksen, J.; Legdeur, M-C.; Hylkema, B. S.

    2007-01-01

    We present a case of severe hyperglycaemic hyperosmolar derangement after treatment with cisplatin in a patient without previous diabetes mellitus. Limited data are available on this adverse reaction, explaining why impaired glucose handling due to cisplatin is not generally recognised.

  14. Future opportunities in preventing cisplatin induced ototoxicity

    NARCIS (Netherlands)

    J.H. van den Berg; J.H. Beijnen; A.J.M. Balm; J.H.M. Schellens

    2006-01-01

    Cisplatin is one of the most commonly used cytotoxic agents. ototoxicity is an important and dose-limiting side-effect of cisplatin therapy. It is believed that cisplatin suppresses the formation of endogenous anti-oxidants that normally prevent the inner ear against reactive oxygen species (ROS). T

  15. Neuroplastic alteration of TTX-resistant sodium channel with visceral pain and morphine-induced hyperalgesia

    Directory of Open Access Journals (Sweden)

    Chen J

    2012-11-01

    Full Text Available Jinghong Chen,1,2,4 Ze-hui Gong,4 Hao Yan,2 Zhijun Qiao,3 Bo-yi Qin41Department of Internal Medicine, Neuroscience Program, The University of Texas Medical Branch, Galveston, TX, USA; 2The Divisions of Pharmacy, Pharmacology core lab, MD Anderson Cancer Center, Houston, TX, USA; 3University of Texas-Pan American, Edinburg, TX, USA; 4Beijing Institute of Pharmacology and Toxicology, Beijing, China Abstract: The discovery of the tetrodotoxin-resistant (TTX-R Na+ channel in nociceptive neurons has provided a special target for analgesic intervention. In a previous study we found that both morphine tolerance and persistent visceral inflammation resulted in visceral hyperalgesia. It has also been suggested that hyperexcitability of sensory neurons due to altered TTX-R Na+ channel properties and expression contributes to hyperalgesia; however, we do not know if some TTX-R Na+ channel property changes can be triggered by visceral hyperalgesia and morphine tolerance, or whether there are similar molecular or channel mechanisms in both situations. To evaluate the effects of morphine tolerance and visceral inflammation on the channel, we investigated the dorsal root ganglia (DRG neuronal change following these chronic treatments. Using whole-cell patch clamp recording, we recorded TTX-R Na+ currents in isolated adult rat lumbar and sacral (L6-S2 DRG neurons from normal and pathologic rats with colon inflammatory pain or chronic morphine treatment. We found that the amplitudes of TTX-R Na+ currents were signiflcantly increased in small-diameter DRG neurons with either morphine tolerance or visceral inflammatory pain. Meanwhile, the result also showed that those treatments altered the kinetics properties of the electrical current (ie, the activating and inactivating speed of the channel was accelerated. Our current results suggested that in both models, visceral chronic inflammatory pain and morphine tolerance causes electrophysiological changes in voltage

  16. LVV-hemorphin 7 and angiotensin IV in correlation with antinociception and anti-thermal hyperalgesia in rats.

    Science.gov (United States)

    Cheng, Bor-Chih; Tao, Pao-Luh; Cheng, Ya-Yun; Huang, Eagle Yi-Kung

    2012-07-01

    Hemorphins, a family of atypical endogenous opioid peptides, are produced by the cleavage of hemoglobin β-chain. Hemorphins were proved to bind to the μ-opioid receptors (agonist) and angiotensin IV receptors (insulin-regulated aminopeptidase; IRAP) (inhibitor). Among the hemorphins, LVV-hemorphin-7 (LVV-H7) was found to be abundant and with a longer half life in the CNS. Using intrathecal and intracerebroventricular injections, LVV-H7 and angiotensin IV were given to the rats, which were then subjected to the plantar test and the tail-flick test. Our results showed that LVV-H7 attenuated carrageenan-induced hyperalgesia at the spinal level, which could not be reversed by the co-administration of naloxone. At the supraspinal level, LVV-H7 also produced a significant anti-hyperalgesia effect but with a lower extent. Angiotensin IV showed a similar anti-hyperalgesia effect at the spinal level, but had no effect at the supraspinal level. In the tail-flick test and paw edema test, both peptides showed no effect. These results suggest that LVV-H7 mainly exert the anti-hyperalgesia effect at the spinal level, possibly through IRAP but not μ-opioid receptors. In addition, we observed the expression of IRAP in the CNS of animals with/without carrageenan-induced hyperalgesia. Our results showed a significant expression of IRAP in the spinal cord of rats. However, there was no significant quantitative change of IRAP after the development of hyperalgesia. The serum level of LVV-H7 was also found to be with no change caused by hyperalgesia. These results indicated that the endogenous LVV-H7 and IRAP may not regulate the severity of hyperalgesia through a quantitative change.

  17. SPINAL CORD MECHANISMS MEDIATING BEHAVIORAL HYPERALGESIA INDUCED BY NEUROKININ-1 TACHYKININ RECEPTOR ACTIVATION IN THE ROSTRAL VENTROMEDIAL MEDULLA

    OpenAIRE

    Lagraize, S. C.; Guo, W; Yang, K.; Wei, F.; Ren, K; Dubner, R.

    2010-01-01

    Hyperalgesia in animal injury models is linked to activation of descending raphespinal modulatory circuits originating in the rostral ventromedial medulla (RVM). A neurokinin-1 (NK-1) receptor antagonist microinjected into the RVM before or after inflammation produced by complete Freund’s adjuvant (CFA) resulted in an attenuation of thermal hyperalgesia. A transient (acute) or a continuous infusion of Substance P (SP) microinjected into the RVM of non-inflamed animals led to similar pain hype...

  18. Acid-sensing ion channel 3 mediates peripheral anti-hyperalgesia effects of acupuncture in mice inflammatory pain

    Directory of Open Access Journals (Sweden)

    Chen Wei-Hsin

    2011-11-01

    Full Text Available Abstract Background Peripheral tissue inflammation initiates hyperalgesia accompanied by tissue acidosis, nociceptor activation, and inflammation mediators. Recent studies have suggested a significantly increased expression of acid-sensing ion channel 3 (ASIC3 in both carrageenan- and complete Freund's adjuvant (CFA-induced inflammation. This study tested the hypothesis that acupuncture is curative for mechanical hyperalgesia induced by peripheral inflammation. Methods Here we used mechanical stimuli to assess behavioral responses in paw and muscle inflammation induced by carrageenan or CFA. We also used immunohistochemistry staining and western blot methodology to evaluate the expression of ASIC3 in dorsal root ganglion (DRG neurons. Results In comparison with the control, the inflammation group showed significant mechanical hyperalgesia with both intraplantar carrageenan and CFA-induced inflammation. Interestingly, both carrageenan- and CFA-induced hyperalgesia were accompanied by ASIC3 up-regulation in DRG neurons. Furthermore, electroacupuncture (EA at the ST36 rescued mechanical hyperalgesia through down-regulation of ASIC3 overexpression in both carrageenan- and CFA-induced inflammation. Conclusions In addition, electrical stimulation at the ST36 acupoint can relieve mechanical hyperalgesia by attenuating ASIC3 overexpression.

  19. Peripheral mechanisms underlying the essential role of P2X7 receptors in the development of inflammatory hyperalgesia.

    Science.gov (United States)

    Teixeira, Juliana Maia; Oliveira, Maria Cláudia G; Parada, Carlos Amílcar; Tambeli, Cláudia Herrera

    2010-10-10

    Activation of P2X7 receptors by endogenous ATP contributes to the development of inflammatory hyperalgesia. Given the clinical importance of mechanical hyperalgesia in inflammatory states, we hypothesized that the activation of the P2X7 receptor by endogenous ATP contributes to carrageenan-induced mechanical hyperalgesia, and that this contribution is mediated by an indirect sensitization of the primary afferent nociceptors. Co-administration of the selective P2X7 receptor antagonist, A-438079, or the P2X7 receptor antagonist, oATP, with carrageenan blocked the mechanical hyperalgesia induced by carrageenan and significantly reduced the increased concentration of TNF-alpha, IL-6 and CINC-1, but not of IL-1beta induced by carrageenan in the subcutaneous tissue of the rat's hind paw. We concluded that the activation of P2X7 receptors by endogenous ATP is essential to the development of the mechanical hyperalgesia induced by carrageenan in the subcutaneous tissue. It is suggested that this essential role of P2X7 receptors in the development of carrageenan-induced mechanical hyperalgesia is mediated by an indirect sensitization of the primary afferent nociceptors dependent on the previous release of TNF-alpha, IL-6 and CINC-1, but not of IL-1beta.

  20. A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition

    Directory of Open Access Journals (Sweden)

    Huynh Truc

    2007-12-01

    Full Text Available Abstract Mechanical hyperalgesia is a clinically-relevant form of pain sensitization that develops through largely unknown mechanisms. TRPA1, a Transient Receptor Potential ion channel, is a sensor of pungent chemicals that may play a role in acute noxious mechanosensation and cold thermosensation. We have developed a specific small molecule TRPA1 inhibitor (AP18 that can reduce cinnameldehyde-induced nociception in vivo. Interestingly, AP18 is capable of reversing CFA-induced mechanical hyperalgesia in mice. Although TRPA1-deficient mice develop normal CFA-induced hyperalgeisa, AP18 is ineffective in the knockout mice, consistent with an on-target mechanism. Therefore, TRPA1 plays a role in sensitization of nociception, and that compensation in TRPA1-deficient mice masks this requirement.

  1. MicroRNA-124 as a novel treatment for persistent hyperalgesia

    Directory of Open Access Journals (Sweden)

    Willemen Hanneke LDM

    2012-06-01

    Full Text Available Abstract Background Chronic pain is often associated with microglia activation in the spinal cord. We recently showed that microglial levels of the kinase G protein–coupled receptor kinase (GRK2 are reduced in models of chronic pain. We also found that mice with a cell-specific reduction of around 50% in GRK2 level in microglia/macrophages (LysM-GRK2+/− mice develop prolonged inflammatory hyperalgesia concomitantly with ongoing spinal microglia/macrophage activation. The microRNA miR-124 is thought to keep microglia/macrophages in brain and spinal cord in a quiescent state. In the present study, we investigated the contribution of miR-124 to regulation of hyperalgesia and microglia/macrophage activation in GRK2-deficient mice. In addition, we investigated the effect of miR-124 on chronic inflammatory and neuropathic pain in wild-type (WT mice. Methods Hyperalgesia was induced by intraplantar IL-1β in WT and LysM-GRK2+/− mice. We determined spinal cord microglia/macrophage miR-124 expression and levels of pro-inflammatory M1 and anti-inflammatory M2 activation markers. The effect of intrathecal miR-124 treatment on IL-1β-induced hyperalgesia and spinal M1/M2 phenotype, and on carrageenan-induced and spared nerve injury-induced chronic hyperalgesia in WT mice was analyzed. Results Transition from acute to persistent hyperalgesia in LysM-GRK2+/− mice is associated with reduced spinal cord microglia miR-124 levels. In our LysM-GRK2+/− mice, there was a switch towards a pro-inflammatory M1 phenotype together with increased pro-inflammatory cytokine production. Intrathecal administration of miR-124 completely prevented the transition to persistent pain in response to IL-1β in LysM-GRK2+/− mice. The miR-124 treatment also normalized expression of spinal M1/M2 markers of LysM-GRK2+/− mice. Moreover, intrathecal miR-124 treatment reversed the persistent hyperalgesia induced by carrageenan in WT mice and prevented development of

  2. Opioid-induced hyperalgesia in chronic pain patients and the mitigating effects of gabapentin.

    Science.gov (United States)

    Stoicea, Nicoleta; Russell, Daric; Weidner, Greg; Durda, Michael; Joseph, Nicholas C; Yu, Jeffrey; Bergese, Sergio D

    2015-01-01

    Chronic pain patients receiving opioid drugs are at risk for opioid-induced hyperalgesia (OIH), wherein opioid pain medication leads to a paradoxical pain state. OIH involves central sensitization of primary and secondary afferent neurons in the dorsal horn and dorsal root ganglion, similar to neuropathic pain. Gabapentin, a gamma-aminobutyric acid (GABA) analog anticonvulsant used to treat neuropathic pain, has been shown in animal models to reduce fentanyl hyperalgesia without compromising analgesic effect. Chronic pain patients have also exhibited lower opioid consumption and improved pain response when given gabapentin. However, few human studies investigating gabapentin use in OIH have been performed in recent years. In this review, we discuss the potential mechanisms that underlie OIH and provide a critical overview of interventional therapeutic strategies, especially the clinically-successful drug gabapentin, which may reduce OIH.

  3. Caspase Inhibitors may Attenuate Opioid-induced Hyperalgesia and Tolerance via Inhibiting Microglial Activation and Neuroinflammation

    Directory of Open Access Journals (Sweden)

    Jiancheng Zhang

    2013-07-01

    Full Text Available Prolonged exposure to an opioid induces hyperalgesia and tolerance, which negatively affect pain management in turn and significantly hamper the application of opioids. A growing body of evidence has demonstrated that glial activation contributes to the development of these two side effects. Recent studies have demonstrated that morphine, binding to an accessory protein of Toll-like receptor 4 (TLR4, activates microglia and produces neuroinflammation in amanner parallel to lipopolysaccharide. Meanwhile, lipopolysaccharide activates microglia through TLR4/caspase signalling. Therefore, we hypothesise that morphine may activate microglia throughTLR4/caspase signalling and that caspase inhibitors may attenuate opioid-induced hyperalgesia and tolerance via inhibiting microglial activation and neuroinflammation

  4. PLGA-Curcumin Attenuates Opioid-Induced Hyperalgesia and Inhibits Spinal CaMKIIα.

    Directory of Open Access Journals (Sweden)

    Xiaoyu Hu

    Full Text Available Opioid-induced hyperalgesia (OIH is one of the major problems associated with prolonged use of opioids for the treatment of chronic pain. Effective treatment for OIH is lacking. In this study, we examined the efficacy and preliminary mechanism of curcumin in attenuating OIH. We employed a newly developed PLGA-curcumin nanoformulation (PLGA-curcumin in order to improve the solubility of curcumin, which has been a major obstacle in properly characterizing curcumin's mechanism of action and efficacy. We found that curcumin administered intrathecally or orally significantly attenuated hyperalgesia in mice with morphine-induced OIH. Furthermore, we demonstrated that the effects of curcumin on OIH correlated with the suppression of chronic morphine-induced CaMKIIα activation in the superficial laminae of the spinal dorsal horn. These data suggest that PLGA-curcumin may reverse OIH possibly by inhibiting CaMKIIα and its downstream signaling.

  5. Opioid-Induced Hyperalgesia in Chronic Pain Patients and the Mitigating Effects of Gabapentin

    Directory of Open Access Journals (Sweden)

    Nicoleta eStoicea

    2015-05-01

    Full Text Available Chronic pain patients receiving opioid drugs are at risk for opioid-induced hyperalgesia (OIH, wherein opioid pain medication leads to a paradoxical pain state. OIH involves central sensitization of primary and secondary afferent neurons in the dorsal horn and dorsal root ganglion, similar to neuropathic pain. Gabapentin, a gamma-aminobutyric acid (GABA analogue anticonvulsant used to treat neuropathic pain, has been shown in animal models to reduce fentanyl hyperalgesia without compromising analgesic effect. Chronic pain patients have also exhibited lower opioid consumption and improved pain response when given gabapentin. However, few human studies investigating gabapentin use in OIH have been performed in recent years. In this review, we discuss the potential mechanisms that underlie OIH and provide a critical overview of interventional therapeutic strategies, especially the clinically-successful drug gabapentin, which may reduce OIH.

  6. PLGA-Curcumin Attenuates Opioid-Induced Hyperalgesia and Inhibits Spinal CaMKIIα.

    Science.gov (United States)

    Hu, Xiaoyu; Huang, Fang; Szymusiak, Magdalena; Tian, Xuebi; Liu, Ying; Wang, Zaijie Jim

    2016-01-01

    Opioid-induced hyperalgesia (OIH) is one of the major problems associated with prolonged use of opioids for the treatment of chronic pain. Effective treatment for OIH is lacking. In this study, we examined the efficacy and preliminary mechanism of curcumin in attenuating OIH. We employed a newly developed PLGA-curcumin nanoformulation (PLGA-curcumin) in order to improve the solubility of curcumin, which has been a major obstacle in properly characterizing curcumin's mechanism of action and efficacy. We found that curcumin administered intrathecally or orally significantly attenuated hyperalgesia in mice with morphine-induced OIH. Furthermore, we demonstrated that the effects of curcumin on OIH correlated with the suppression of chronic morphine-induced CaMKIIα activation in the superficial laminae of the spinal dorsal horn. These data suggest that PLGA-curcumin may reverse OIH possibly by inhibiting CaMKIIα and its downstream signaling.

  7. The beta-lactam antibiotic, ceftriaxone, inhibits the development of opioid-induced hyperalgesia in mice.

    Science.gov (United States)

    Chen, Zhijun; He, Ying; Wang, Zaijie Jim

    2012-02-16

    The glutamate transporter GLT-1 is primarily responsible for glutamate clearance in the spinal cord. beta-Lactam antibiotics have been shown to attenuate neuropathic pain behaviors by promoting GLT-1 expression and function in the CNS. The present study tested the hypothesis that ceftriaxone, a prototype beta-lactam antibiotic, can prevent the development of opioid-induced hyperalgesia (OIH) in mice. Repeated morphine administration produced mechanical allodynia and thermal hyperalgesia, signs of OIH, and reduced spinal GLT-1 expression in mice. Ceftriaxone (200mg/kg/d, i.p., for 7 d) inhibited OIH. Correlating with the behavioral effects, ceftriaxone reversed downregulation of GLT-1 expression that was induced by OIH. These results suggest that ceftriaxone inhibited the development of OIH by up-regulating spinal GLT-1 expression.

  8. Duration and distribution of experimental muscular hyperalgesia in humans following combined infusions of serotonin and bradykinin

    DEFF Research Database (Denmark)

    Babenko, Victor; Svensson, Peter; Graven-Nielsen, Thomas;

    2000-01-01

    -infusions interval of 3 min. Infusions of isotonic saline (NaCl, 0.9%) were given as control. Pain intensity was continuously scored on a visual analogue scale (VAS), and subjects drew the distribution of the pain areas on an anatomical map. Pressure pain thresholds (PPTs) were assessed with an electronic algometer....... In addition, PPTs were significantly decreased (Peffect of bradykinin in producing experimental muscle pain and muscle hyperalgesia to mechanical stimuli. The combination of serotonin and bradykinin can produce muscle...

  9. Opioid-Induced Hyperalgesia - Worsening Pain in Opioid-Dependent Patients

    Science.gov (United States)

    2013-02-01

    shown to reduce pain . Amantadine is an NMDA receptor antagonist that may mitigate central sensitization. Adjuvant analgesics may lessen nociceptive ...FEB 2013 2. REPORT TYPE N/A 3. DATES COVERED - 4. TITLE AND SUBTITLE Opioid-induced hyperalgesia--worsening pain in opioid-dependent...Report Opioid-induced hyperalgesia—worsening pain in opioid-dependent patients☆ Abstract Patients with chronic opioid use are commonly treated in the

  10. Increased capsaicin-induced secondary hyperalgesia in patients with multiple chemical sensitivity

    DEFF Research Database (Denmark)

    Holst, Helle; Arendt-Nielsen, Lars; Mosbech, Holger;

    2011-01-01

    in experimental pain models to provoke peripheral and central sensitization. In patients with symptoms elicited by odorous chemicals capsaicin-induced secondary hyperalgesia and temporal summation were assessed as markers for abnormal central nociceptive processing together with neurogenic inflammation (flare).......the underlying cause of pathophysiological mechanisms triggering multiple chemical sensitivity (MCS) remains disputed.Recently, alterations in the central nervous system, for example,central sensitization, similar to various chronic pain disorders, have been suggested. Capsaicin is used...

  11. Nocebo hyperalgesia: contributions of social observation and body-related cognitive styles

    OpenAIRE

    2016-01-01

    Elisabeth Vögtle,1 Birgit Kröner-Herwig,1 Antonia Barke21Department of Clinical Psychology and Psychotherapy, Georg-Elias-Müller-Institute for Psychology, University of Göttingen, Göttingen, 2Department of Psychology, Division of Clinical Psychology and Psychotherapy, Philipps University Marburg, Marburg, Germany Purpose: Recently, it has been shown that nocebo hyperalgesia can be acquired through observational learning. The aim of this study was ...

  12. RhoA/Rho kinase pathway contributes to the pathogenesis of thermal hyperalgesia in diabetic mice.

    Science.gov (United States)

    Ohsawa, Masahiro; Aasato, Megumi; Hayashi, Shun-Suke; Kamei, Junzo

    2011-01-01

    Diabetic neuropathy is one of the most common complications of diabetes and causes various problems in daily life. Several investigations have noted that many factors in the spinal cord are involved in the symptoms of painful diabetic neuropathy, and there are very few effective therapeutic regimens. In the present study, we sought to elucidate the role of the RhoA/Rho kinase (ROCK) pathway in thermal hyperalgesia in diabetic mice. The intracellular localization of RhoA and the expression of eNOS were measured by western blotting. Thermal hyperalgesia was assessed by the tail-flick test and mechanical allodynia was assessed by automated von Frey filament test in streptozotocin(STZ)-induced diabetic mice. The spinal cord of STZ-treated diabetic mice showed increased membrane-bound RhoA compared to non-diabetic control. Treatment with the RhoA inhibitor exoenzyme C3, Clostridium botulinum, and the ROCK inhibitor Y27632 attenuated thermal hyperalgesia and mechanical allodynia in diabetic mice. Moreover, daily treatment with simvastatin attenuated all of those changes in diabetic mice. The expression of eNOS and NO metabolite contents in the spinal cord was decreased in diabetic mice, and these changes were normalized by treatment with simvastatin. The present results show that HMG-CoA reductase inhibitors have an inhibitory effect on thermal hyperalgesia in diabetic mice, which is mediated by an increase in NO production through the inhibition of RhoA/ROCK pathways. These results suggest that ROCK inhibitors and HMG-CoA inhibitors may be attractive compounds to relieve the symptoms of painful diabetic neuropathies.

  13. Spared nerve injury rats exhibit thermal hyperalgesia on an automated operant dynamic thermal escape Task

    OpenAIRE

    Chialvo Dante R; Calvo Oscar; Baliki Marwan; Apkarian A Vania

    2005-01-01

    Abstract Well-established methods are available to measure thermal and mechanical sensitivity in awake behaving rats. However, they require experimenter manipulations and tend to emphasize reflexive behaviors. Here we introduce a new behavioral test, with which we examine thermal sensitivity of rats with neuropathic injury. We contrast thermal hyperalgesia between spared nerve injury and chronic constriction injury rats. This device is a fully automated thermal sensitivity assessment tool des...

  14. Hyperalgesia in Heroin Dependent Patients and the Effects of Opioid Substitution Therapy

    OpenAIRE

    2012-01-01

    Evidence suggests that patients on opiate maintenance therapy for the treatment of addiction present with opioid-induced hyperalgesia (OIH). This study compared the experimental (cold-pressor, electrical stimulation) pain responses of 82 treatment-seeking heroin-dependent adults randomized to methadone (METH, n = 11) or buprenorphine (BUP, n = 64) therapy, with matched drug free controls (n = 21). Heroin-dependent participants were evaluated at baseline (treatment entry), medication (METH or ...

  15. Influence of repeated painful procedures and sucrose analgesia on the development of hyperalgesia in newborn infants.

    Science.gov (United States)

    Taddio, Anna; Shah, Vibhuti; Atenafu, Eshetu; Katz, Joel

    2009-07-01

    This study determined the effects of cumulative exposure to painful needle procedures and sucrose analgesia on the development of remote hyperalgesia in newborn infants, defined as an increase in response to a normally painful stimulus at a site distal from the site of injury. One-hundred and twenty healthy newborns and 120 healthy newborn infants of diabetic mothers equally randomized to sucrose analgesia or placebo prior to all needle procedures in the first two days after birth were divided into two exposure groups according to number of needle procedures they had undergone [high (> or =5) or low (pain response during a subsequent venipuncture distal to the site of previous injury, assessed by the Premature Infant Pain Profile (PIPP) [7.1 vs. 8.4; p=0.012] and Visual Analog Scale (VAS) [2.5 cm vs. 3.2 cm; p=0.047], and a trend for longer cry duration [25.7 s vs. 33.8 s; p=0.171]. PIPP scores did not differ during a routine diaper change, suggesting a nociceptive specific mechanism for the remote hyperalgesia to venipuncture. Sucrose reduced PIPP, VAS, and cry duration scores during venipuncture, but did not prevent hyperalgesia (p>0.05). There was a preponderance of infants of diabetic mothers in the high exposure group; however, the analysis did not demonstrate this to be a confounding factor. In conclusion, sucrose analgesia for repeated painful procedures in the first day of life does not prevent development of remote hyperalgesia in newborns.

  16. Persephin在顺铂诱导的急性肾损伤小鼠中的作用初探%The effect of Persephin in cisplatin-induced acute kidney injury in mice

    Institute of Scientific and Technical Information of China (English)

    袁莉; 沈晓晔; 陈挺; 戴厚永; 黄新忠; 张义德

    2016-01-01

    Objective: To observe the change of Persephin (PSP) in renal cortex in cisplatin-induced acute kidney injury. Methods: The male C57BL/6 mice were divided into the control group and the model group. AKI was induced by subcutaneous injection of cisplatin (15mg/kg), the mice in the control group was injected by the same volume saline.Three days after cisplatin injection, the renal function and tubular structure were tested in each group.Expression of PSP was tested by real-time PCR and Western blot in renal cortex. Results: Compared with the control group, mice in the model group showed symptoms of malaise and reduced activity. Three days after cisplatin injection, the renal function, the number of tubular cast(0.63±0.62/HPF) and necrosis(3.71±1.14/HPF)were significantly increased in the model group(P<0.05).The mRNA and protein expression of PSP in the renal cortex increased in the model group (P<0.05). Conclusion: The increasing expression of PSP in the renal cortex suggests that PSP may participate in the process of AKI.%目的:观察顺铂诱导急性肾损伤(acute kidney injury,AKI)模型中肾皮质Persephin(PSP)的变化。方法:雄性C57BL/6小鼠随机分为对照组及模型组,模型组应用顺铂单次腹腔注射(15mg/kg)制备AKI小鼠模型,对照组小鼠予以同等容积的0.9%的生理盐水单次腹腔注射,造模3天后观察各组小鼠肾功能变化、肾脏病理学改变、实时PCR法及Western印记法检测肾脏皮质PSP的表达。结果:与对照组相比,模型组小鼠出现精神萎靡不振,反应迟钝,活动减少,造模后第3天尿素氮明显上升(P<0.05),肾脏病理改变中模型组肾小管管型计数(0.63±0.62个/HPF)及坏死计数(3.71±1.14个/HPF)均高于正常对照组(P<0.05)。PSP在模型组肾皮质的表达高于对照组(P<0.05)。结论:AKI模型中肾脏皮质PSP表达升高,提示PSP可能参与了AKI的病程,但其相关作用机制尚需进一步研究。

  17. Model of methadone-induced hyperalgesia in rats and effect of memantine.

    Science.gov (United States)

    Hay, Justin L; Kaboutari, Jahangir; White, Jason M; Salem, Abdallah; Irvine, Rod

    2010-01-25

    Methadone used for opioid dependence therapy is associated with increased pain sensitivity. This study aimed to investigate whether methadone administration lowers nociceptive threshold in adult male Sprague-Dawley (SD) rats, and if this threshold could be altered by the NMDA receptor antagonist memantine. Rats were implanted with osmotic pumps delivering 1mg/kg/day methadone (n=6), or saline placebo (n=6) (0.51 microl/h). A separate cohort of rats received either methadone 1mg/kg/day (n=8) or methadone 1mg/kg/day with 20mg/kg/day memantine (n=8). Nociception was measured by the Hargreave's paw withdrawal test. Baseline nociception was measured on day 0 prior to osmotic pump implantation and was measured daily for the following 21 days. Osmotic pumps were removed following nociceptive testing on day 14. Methadone only treated rats had a mean paw withdrawal latency significantly lower than the corresponding values for saline on days 8, 9, 10, 11, 12, 14, and 17 (P0.05). Paw withdrawal latency of rats treated with methadone co-administered with memantine did not differ significantly compared to methadone only (P>0.05). This demonstrates that methadone induces hyperalgesia in the SD rat yet this hyperalgesia resolves following discontinuation of methadone administration. Furthermore, memantine does not alter the development of methadone-induced hyperalgesia.

  18. Pharmacological treatment of opioid-induced hyperalgesia: a review of the evidence.

    Science.gov (United States)

    Ramasubbu, Chitra; Gupta, Anita

    2011-01-01

    Opioids are commonly used to treat moderate to severe pain. Opioid-induced hyperalgesia is a paradoxical response to opioid agonists resulting in an increased perception of pain rather than an antinociceptive effect. Even though there is a debate regarding its clinical relevance, it is becoming a challenge in both acute and chronic pain settings. The study of opioid-induced hyperalgesia is an emerging field with multiple challenges faced by investigators with regard to defining the diagnosis and characterizing the findings. The objective of this study was to review the preliminary evidence related to the treatment and management of opioid-induced hyperalgesia. Lack of data, small patient numbers, short-term follow-up, and variations in study design limited the review. With the literature on this subject being sparse, this study attempts to provide a preliminary look at the available data and to set the stage for an eventual meta-analysis. Case reports in the literature have shown success with various pharmacological interventions. Possible treatment regimens include ketamine, dextromethorphan, and nonsteroidal anti-inflammatory drugs (NSAIDs), opioid switching, amantadine, buprenorphine, α(2) agonists, and methadone. These agents are briefly discussed in this paper. Further well-designed, placebo-controlled trials are needed to assess the effectiveness of the interventions investigated in this review.

  19. Chronic CRF1 receptor blockade reduces heroin intake escalation and dependence-induced hyperalgesia.

    Science.gov (United States)

    Park, Paula E; Schlosburg, Joel E; Vendruscolo, Leandro F; Schulteis, Gery; Edwards, Scott; Koob, George F

    2015-03-01

    Opioids represent effective drugs for the relief of pain, yet chronic opioid use often leads to a state of increased sensitivity to pain that is exacerbated during withdrawal. A sensitization of pain-related negative affect has been hypothesized to closely interact with addiction mechanisms. Neuro-adaptive changes occur as a consequence of excessive opioid exposure, including a recruitment of corticotropin-releasing factor (CRF) and norepinephrine (NE) brain stress systems. To better understand the mechanisms underlying the transition to dependence, we determined the effects of functional antagonism within these two systems on hyperalgesia-like behavior during heroin withdrawal utilizing models of both acute and chronic dependence. We found that passive or self-administered heroin produced a significant mechanical hypersensitivity. During acute opioid dependence, systemic administration of the CRF1 receptor antagonist MPZP (20 mg/kg) alleviated withdrawal-induced mechanical hypersensitivity. In contrast, several functional adrenergic system antagonists (clonidine, prazosin, propranolol) failed to alter mechanical hypersensitivity in this state. We then determined the effects of chronic MPZP or clonidine treatment on extended access heroin self-administration and found that MPZP, but not clonidine, attenuated escalation of heroin intake, whereas both drugs alleviated chronic dependence-associated hyperalgesia. These findings suggest that an early potentiation of CRF signaling occurs following opioid exposure that begins to drive both opioid-induced hyperalgesia and eventually intake escalation.

  20. Reduction of spinal PGE2 concentrations prevents swim stress-induced thermal hyperalgesia.

    Science.gov (United States)

    Guevara, Coram; Fernandez, Ana Cristina; Cardenas, Ricardo; Suarez-Roca, Heberto

    2015-03-30

    We evaluated the association between spinal PGE2 and thermal hyperalgesia following repeated stress. Thermal nociception was determined in male Sprague-Dawley rats using the hot-plate test, before and after forced-swimming; non-conditioned rats served as controls. Animals were pretreated with ketoprofen or meloxicam, preferential COX-1 and COX-2 inhibitors, respectively. After the second hot-plate test, we measured serum corticosterone (stress marker), and lumbar spinal PGE2 (neuroinflammation marker) under peripheral inflammation (1% formalin plantar injection). Stressed rats displayed response latencies 40% shorter and inflammatory spinal PGE2 levels 95% higher than controls. Pretreatment with ketoprofen or meloxicam prevented hyperalgesia and elevation of spinal PGE2, increasing the escape behavior time during forced swimming 95% respect to saline-treated rats. Corticosterone levels in stressed rats were 97% higher than controls; COX inhibitors reduced them by 84%. PGE2 could participate in stress-induced hyperalgesia, learned helplessness, and corticosterone production, supporting the use of non-steroidal anti-inflammatory drugs (NSAIDs) for persistent pain associated with chronic stress and depression.

  1. Kinin B1 receptor antagonists inhibit diabetes-induced hyperalgesia in mice.

    Science.gov (United States)

    Gabra, Bichoy H; Sirois, Pierre

    2003-02-01

    Insulin-dependent diabetes mellitus (type 1 diabetes) is an inflammatory autoimmune disease associated with vascular permeability changes leading to many complications including nephropathy, retinopathy, neuropathy, hypertension and hyperalgesia. The bradykinin B(1) receptors (BKB(1)-R) were recently found to be upregulated alongside the development of type 1 diabetes and to be involved in its complications. Kinins are important mediators of a variety of biological effects including cardiovascular homeostasis, inflammation and nociception. In the present study, we studied the effect of a selective BKB(1)-R agonist desArg(9)-BK (DBK) and two selective receptor antagonists, the R-715 (Ac-Lys-[D-beta Nal(7), Ile(8)] desArg(9)-BK) and the R-954 (Ac-Orn-[Oic(2), alphaMe Phe(5), D-beta Nal(7), Ile(8)] desArg(9)-BK) on diabetic hyperalgesia. Type 1 diabetes was induced in male CD-1 mice via a single injection of streptozotocin (STZ, 200mg/kg, i.p.), one week before the test. Nociception, a measure of hyperalgesia, was assessed using the plantar stimulation (Hargreaves) and the tail-immersion tests. The induction of type 1 diabetes provoked a significant hyperalgesic activity in diabetic mice, causing an 11% decrease in plantar stimulation reaction time and 13% decrease in tail-immersion reaction time, compared to normal mice. Following acute administration of R-715 (100-600 microg/kg, i.p.), or R-954 (50-400 microg/kg, i.p.), the STZ-induced hyperalgesic activity was blocked in a dose-dependent manner and the hot plate and tail-immersion latencies of diabetic mice returned to normal values observed in control healthy mice. In addition, the acute administration of DBK (400 microg/kg, i.p.) significantly potentiated diabetes-induced hyperalgesia, an effect that was totally reversed by R-715 (1.6-2.4 mg/kg, i.p.) and R-954 (0.8-1.2mg/kg, i.p.). These results provide further evidence for the implication of the BKB(1)-R in type 1 diabetic hyperalgesia and suggest a novel

  2. Dextromethorphan attenuated the higher vulnerability to inflammatory thermal hyperalgesia caused by prenatal morphine exposure in rat offspring

    Science.gov (United States)

    2011-01-01

    Background Co-administration of dextromethorphan (DM) with morphine during pregnancy and throughout lactation has been found to reduce morphine physical dependence and tolerance in rat offspring. No evidence was presented, however, for the effect of DM co-administered with morphine during pregnancy on inflammatory hyperalgesia in morphine-exposed offspring. Therefore, we attempt to investigate the possible effect of prenatal morphine exposure on the vulnerability to hyperalgesia and the possible therapeutic effect of DM in the present study. Methods Fifty μl of carrageenan (20 mg/ml) was injected subcutaneously into the plantar surface of the right hind paw in p18 rats to induce hyperalgesia. Mean paw withdrawal latency was measured in the plantar test to index the severity of hyperalgesia. Using Western blotting and RT-PCR, the quantitative analyses of NMDA receptor NR1 and NR2B subunits were performed in spinal cords from different groups of animals. Results In the carrageenan-induced hyperalgesia model, rat offspring passively exposed to morphine developed a severe hyperalgesia on postnatal day 18 (p18), which also had a more rapid time course than those in the controls. Co-administration of DM with morphine in the dams prevented this adverse effect of morphine in the offspring rats. Western blot and RT-PCR analysis showed that the levels of protein and mRNA of NMDA receptor NR1 and NR2B subunits were significantly higher in the lumbar spinal cords of rats (p14) exposed to prenatal morphine; the co-administration of DM could reverse the effect of morphine on NR1 and attenuate the effect on NR2B. Conclusions Thus, DM may have a great potential in the prevention of higher vulnerability to inflammatory thermal hyperalgesia in the offspring of morphine-addicted mothers. PMID:21861871

  3. Dextromethorphan attenuated the higher vulnerability to inflammatory thermal hyperalgesia caused by prenatal morphine exposure in rat offspring

    Directory of Open Access Journals (Sweden)

    Chen Chien-Fang

    2011-08-01

    Full Text Available Abstract Background Co-administration of dextromethorphan (DM with morphine during pregnancy and throughout lactation has been found to reduce morphine physical dependence and tolerance in rat offspring. No evidence was presented, however, for the effect of DM co-administered with morphine during pregnancy on inflammatory hyperalgesia in morphine-exposed offspring. Therefore, we attempt to investigate the possible effect of prenatal morphine exposure on the vulnerability to hyperalgesia and the possible therapeutic effect of DM in the present study. Methods Fifty μl of carrageenan (20 mg/ml was injected subcutaneously into the plantar surface of the right hind paw in p18 rats to induce hyperalgesia. Mean paw withdrawal latency was measured in the plantar test to index the severity of hyperalgesia. Using Western blotting and RT-PCR, the quantitative analyses of NMDA receptor NR1 and NR2B subunits were performed in spinal cords from different groups of animals. Results In the carrageenan-induced hyperalgesia model, rat offspring passively exposed to morphine developed a severe hyperalgesia on postnatal day 18 (p18, which also had a more rapid time course than those in the controls. Co-administration of DM with morphine in the dams prevented this adverse effect of morphine in the offspring rats. Western blot and RT-PCR analysis showed that the levels of protein and mRNA of NMDA receptor NR1 and NR2B subunits were significantly higher in the lumbar spinal cords of rats (p14 exposed to prenatal morphine; the co-administration of DM could reverse the effect of morphine on NR1 and attenuate the effect on NR2B. Conclusions Thus, DM may have a great potential in the prevention of higher vulnerability to inflammatory thermal hyperalgesia in the offspring of morphine-addicted mothers.

  4. Protective effects of dexmedetomidine combined with flurbiprofen axetil on remifentanil-induced hyperalgesia: A randomized controlled trial

    Science.gov (United States)

    Yu, Zenggui; Wu, Weilan; Wu, Xiaodan; Lei, Hongyi; Gong, Cansheng; Xu, Shiyuan

    2016-01-01

    High dosages of intra-operative remifentanil are associated with opioid-induced hyperalgesia (OIH). The aim of the present study was to investigate the effect of combined dexmedetomidine and flurbiprofen axetil treatment on remifentanil-induced hyperalgesia. Patients with an American Society of Anesthesiologists physical status of I–II who were diagnosed with hysteromyoma and scheduled for laparoscopic assisted vaginal hysterectomy (LAVH) were randomly divided into three groups. Group hyperalgesia (Group H, n=29) received intra-operative remifentanil, Group hyperalgesia and dexmedetomidine (Group HD, n=28) received remifentanil and a continuous infusion of dexmedetomidine, and Group hyperalgesia, dexmedetomidine and flurbiprofen axetil (Group HDF, n=29) received remifentanil, flurbiprofen axetil and dexmedetomidine. Mechanical pain thresholds were measured during the preoperative visit and postoperatively at 1, 6 and 24-h time points. Visual analog scale (VAS) scores, time to analgesic requirement, total sufentanil consumption and side effects were assessed postoperatively. Mechanical pain threshold at the incision site was significantly lower in Group H compared with Groups HD and HDF (both P<0.05), and significantly higher in Group HDF than in Group HD (P<0.05). The area of secondary hyperalgesia at the incision site was greater in Group H than in the other two groups (both P<0.05), and significantly smaller in Group HDF compared with Group HD (P<0.05). VAS scores and total sufentanil consumption were significantly higher in Group H compared with the other two groups (both P<0.05), and were significantly lower in Group HDF compared with Group HD (P<0.05). Dexmedetomidine combined with flurbiprofen axetil exhibits synergetic effects in the prevention of remifentanil-induced hyperalgesia in patients undergoing LAVH. PMID:27698764

  5. Intradermal injection of Botulinum toxin type A alleviates infraorbital nerve constriction-induced thermal hyperalgesia in an operant assay.

    Science.gov (United States)

    Kumada, A; Matsuka, Y; Spigelman, I; Maruhama, K; Yamamoto, Y; Neubert, J K; Nolan, T A; Watanabe, K; Maekawa, K; Kamioka, H; Yamashiro, T; Kuboki, T; Oguma, K

    2012-01-01

    Recent studies have shown that infraorbital nerve constriction (IoNC)-induced mechanical allodynia has been attenuated by administration of highly purified 150-kDa Botulinum neurotoxin type A (BoNT/A). Here, we extend these studies to determine whether BoNT/A could attenuate IoNC-induced symptoms of thermal hyperalgesia. Instead of testing head withdrawal thresholds, a thermal operant assay was used to evaluate cortical processing of sensory input following IoNC. In this assay, a fasted rat's desire to obtain a food reward (sweetened condensed milk) is coupled to its ability to tolerate facial contact with a warm (45 °C) thermode. Bilateral IoNC decreased the ratio of thermode contact duration/event, which is an indicative of thermal hyperalgesia. BoNT/A injection intradermally in the area of infraorbital nerve (IoN) innervation 7 days after IoNC resulted in decreased number of facial contacts and increased the ratio of contact duration/event (measured at 14 days after IoNC). The BoNT/A (2-200 pg) effects were dose dependent and statistically significant at 100 and 200 pg (P thermal hyperalgesia symptoms was obtained with a 200-pg dose, without affecting sham rat behaviour. Off-site (neck) injection of BoNT/A did not relieve thermal hyperalgesia, while co-injection of BoNT/A with a neutralising antibody in the area of IoN innervation prevented relief of thermal hyperalgesia. Neither IoNC nor BoNT/A injection affected operant assay parameters with a 24 °C thermode, indicating selectivity of thermal hyperalgesia measurements. These results strongly suggest that intradermal injection of BoNT/A in the area of IoN innervation alleviates IoNC-induced thermal hyperalgesia in an operant assay.

  6. Hyperalgesia and Contributing Factors%痛觉过敏与其发生机制的相关因子

    Institute of Scientific and Technical Information of China (English)

    吕兴业

    2011-01-01

    Injuries can induce pain hypersensitivity and hyperalgesia in the injured tissue, adjacent tissue, or remote area.Hyperalgesia consists of thermal hyperalgesia and mechanical hyperalgesia.Activated N-Methyl-D-aspartate receptor leads to thermal hyperalgesia and is caused by calcium influx.It further activates protein kinase C and nitric oxide synthase,and enhances the production of nitric oxide.Mechanical hyperalgesia is mainly induced by activated a-amino-3-hydroxy-5-methyl-4-isoxa-zolep-propionate and metabtropic receptors.The interaction among excitatory amino acids and its receptors, protein kinase C and nitric oxide plays an important role in the development and progression of hyperalgesia.%外周组织损伤后,在受损部位及周围组织或远处可产生各种敏感性增强的疼痛和痛觉过敏.痛觉过敏分为热痛觉过敏和机械性痛觉过敏.热痛觉过敏主要是兴奋了N-甲基-D-天冬氨酸受体后引起钙离子向细胞内流,激活蛋白激酶C(PKC)的同时又激活了一氧化氮合酶,促进了一氧化氮的生成.机械性痛觉过敏主要是激活了α氨基羟甲基异唑丙酸受体和代谢型受体.兴奋性氮基酸及其受体、PKC及一氧化氮之间的相互影响在痛觉过敏的发生、发展过程中起着重要作用.

  7. 损毁炎症大鼠下丘脑弓状核对痛觉过敏的影响%The effect of hypothalamic arcuate nucleus lesion on the hyperalgesia of inflammatory rats

    Institute of Scientific and Technical Information of China (English)

    戴友爱; 龚珊; 蒋星红

    2012-01-01

    目的 观察损毁炎症大鼠下丘脑弓状核( ARC)对炎症大鼠痛觉过敏的影响.方法 用完全弗氏佐剂(CFA)建立大鼠外周组织炎症模型;采用新生期大鼠注射谷氨酸单钠(MSG)破坏ARC神经元或电解损毁成年大鼠的ARC;用辐射热-缩腿法测定炎症大鼠热痛阈的变化,用von Frey法测定机械痛阈的变化.结果 (1)大鼠在注射CFA后热痛阈和机械痛阈均明显降低,出现痛觉过敏,3h达到高峰,到第3天有所恢复并且稳定维持痛觉过敏状态,一直维持到本实验观察的第14天;(2)新生期注射MSG的大鼠在注射CFA后3h,热痛阈和机械痛阈也明显降低,出现痛觉过敏,但其痛阈降低的幅度明显小于注射高渗盐水对照的CFA组;(3)CFA炎症大鼠在电解损毁ARC之后,其热痛阈和机械痛阈与假损毁组相比,均明显上升,即痛觉过敏减轻.结论 在外周存在炎症条件下,两种方法损毁ARC都能减轻痛觉过敏.提示ARC参与外周组织炎症引起的痛觉过敏,对痛觉过敏的发生有下行易化作用.%Objective To study the effect of hypothalamic arcuate nucleus ( ARC) lesion on the hyperalgesia of inflammatory rats and investigate the descending modulation on hyperalgesia from ARC. Methods The peripheral inflammation model was established by sub-plantar injection of complete Freund' s adjuvant ( CFA) in rats. ARC was lesioned electrolytically and by neonatal injection of monosodium glutamate ( MSG). The thermal pain threshold was measured by radiant heat-withdrawal method and the mechanical pain threshold was measured by von Frey method. Results ( 1 ) Hyperalgesia ( decrease of thermal and mechanical pain threshold) appeared after injection of CFA, the peak time was at 3h, and the hyperalgesic state could last for 14 days (2) In MSG-treated neonatal rats the thermal and mechanical pain threshold were decreased at 3h after CFA injection, but the amplitude of decrement was significantly less as compared with

  8. Patients with chronic pain after abdominal surgery show less preoperative endogenous pain inhibition and more postoperative hyperalgesia: a pilot study.

    Science.gov (United States)

    Wilder-Smith, Oliver Hamilton; Schreyer, Tobias; Scheffer, Gert Jan; Arendt-Nielsen, Lars

    2010-06-01

    Chronic pain is common and undesirable after surgery. Progression from acute to chronic pain involves altered pain processing. The authors studied relationships between presence of chronic pain versus preoperative descending pain control (diffuse noxious inhibitory controls; DNICs) and postoperative persistence and spread of skin and deep tissue hyperalgesia (change in electric/pressure pain tolerance thresholds; ePTT/pPTT) up to 6 months postoperatively. In 20 patients undergoing elective major abdominal surgery under standardized anesthesia, we determined ePTT/pPTT (close to [abdomen] and distant from [leg] incision), eDNIC/pDNIC (change in ePTT/pPTT with cold pressor pain task; only preoperatively), and a 100 mm long pain visual analogue scale (VAS) (0 mm = no pain, 100 mm = worst pain imaginable), both at rest and on movement preoperatively, and 1 day and 1, 3, and 6 months postoperatively. Patients reporting chronic pain 6 months postoperatively had more abdominal and leg skin hyperalgesia over the postoperative period. More inhibitory preoperative eDNIC was associated with less late postoperative pain, without affecting skin hyperalgesia. More inhibitory pDNIC was linked to less postoperative leg deep tissue hyperalgesia, without affecting pain VAS. This pilot study for the first time links chronic pain after surgery, poorer preoperative inhibitory pain modulation (DNIC), and greater postoperative degree, persistence, and spread of hyperalgesia. If confirmed, these results support the potential clinical utility of perioperative pain processing testing.

  9. Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy.

    Science.gov (United States)

    Bierhaus, Angelika; Fleming, Thomas; Stoyanov, Stoyan; Leffler, Andreas; Babes, Alexandru; Neacsu, Cristian; Sauer, Susanne K; Eberhardt, Mirjam; Schnölzer, Martina; Lasitschka, Felix; Lasischka, Felix; Neuhuber, Winfried L; Kichko, Tatjana I; Konrade, Ilze; Elvert, Ralf; Mier, Walter; Pirags, Valdis; Lukic, Ivan K; Morcos, Michael; Dehmer, Thomas; Rabbani, Naila; Thornalley, Paul J; Edelstein, Diane; Nau, Carla; Forbes, Josephine; Humpert, Per M; Schwaninger, Markus; Ziegler, Dan; Stern, David M; Cooper, Mark E; Haberkorn, Uwe; Brownlee, Michael; Reeh, Peter W; Nawroth, Peter P

    2012-06-01

    This study establishes a mechanism for metabolic hyperalgesia based on the glycolytic metabolite methylglyoxal. We found that concentrations of plasma methylglyoxal above 600 nM discriminate between diabetes-affected individuals with pain and those without pain. Methylglyoxal depolarizes sensory neurons and induces post-translational modifications of the voltage-gated sodium channel Na(v)1.8, which are associated with increased electrical excitability and facilitated firing of nociceptive neurons, whereas it promotes the slow inactivation of Na(v)1.7. In mice, treatment with methylglyoxal reduces nerve conduction velocity, facilitates neurosecretion of calcitonin gene-related peptide, increases cyclooxygenase-2 (COX-2) expression and evokes thermal and mechanical hyperalgesia. This hyperalgesia is reflected by increased blood flow in brain regions that are involved in pain processing. We also found similar changes in streptozotocin-induced and genetic mouse models of diabetes but not in Na(v)1.8 knockout (Scn10(-/-)) mice. Several strategies that include a methylglyoxal scavenger are effective in reducing methylglyoxal- and diabetes-induced hyperalgesia. This previously undescribed concept of metabolically driven hyperalgesia provides a new basis for the design of therapeutic interventions for painful diabetic neuropathy.

  10. Central immune overactivation in the presence of reduced plasma corticosterone contributes to swim stress-induced hyperalgesia.

    Science.gov (United States)

    Suarez-Roca, H; Quintero, L; Avila, R; Medina, S; De Freitas, M; Cárdenas, R

    2014-01-01

    Although it is widely known that immunological, hormonal and nociceptive mechanisms are altered by exposure to repeated stress, the interplaying roles of each function in the development of post-stress hyperalgesia are not completely clear. Thus, we wanted to establish how interleukin 1-beta (IL-1β), corticosterone and microglia interact to contribute in the development of hyperalgesia following repeated forced swim. Rats were subjected to either forced swim, sham swim or non-conditioned. Each group was then treated with minocycline, ketoconazole, or saline. Thermal nociception was measured via the hot plate test, before and after the behavioral conditioning, whereas blood and lumbar spinal cord tissue samples were obtained at the end of the protocol. Serum levels of corticosterone, spinal tissue concentration of IL-1β and spinal OX-42 labeling (microglial marker) were determined. Rats exposed to forced swim stress developed thermal hyperalgesia along with elevated spinal tissue IL-1β, increased OX-42 labeling and relatively diminished serum corticosterone. Pre-treatment with minocycline and ketoconazole prevented the development of thermal hyperalgesia and the increase in IL-1β, without significantly modifying serum corticosterone. These results suggest that the development of forced swim-induced thermal hyperalgesia requires the simultaneous presence of increased spinal IL-1β, microglial activation, and relatively decreased serum corticosterone.

  11. Sprouted innervation into uterine transplants contributes to the development of hyperalgesia in a rat model of endometriosis.

    Science.gov (United States)

    McAllister, Stacy L; Dmitrieva, Natalia; Berkley, Karen J

    2012-01-01

    Endometriosis is an enigmatic painful disorder whose pain symptoms remain difficult to alleviate in large part because the disorder is defined by extrauteral endometrial growths whose contribution to pain is poorly understood. A rat model (ENDO) involves autotransplanting on abdominal arteries uterine segments that grow into vascularized cysts that become innervated with sensory and sympathetic fibers. ENDO rats exhibit vaginal hyperalgesia. We used behavioral, physiological, and immunohistochemical methods to test the hypothesis that cyst innervation contributes to the development of this hyperalgesia after transplant. Rudimentary sensory and sympathetic innervation appeared in the cysts at two weeks, sprouted further and more densely into the cyst wall by four weeks, and matured by six weeks post-transplant. Sensory fibers became abnormally functionally active between two and three weeks post-transplant, remaining active thereafter. Vaginal hyperalgesia became significant between four and five weeks post-transplant, and stabilized after six to eight weeks. Removing cysts before they acquired functional innervation prevented vaginal hyperalgesia from developing, whereas sham cyst removal did not. Thus, abnormally-active innervation of ectopic growths occurs before hyperalgesia develops, supporting the hypothesis. These findings suggest that painful endometriosis can be classified as a mixed inflammatory/neuropathic pain condition, which opens new avenues for pain relief. The findings also have implications beyond endometriosis by suggesting that functionality of any transplanted tissue can be influenced by the innervation it acquires.

  12. Sprouted innervation into uterine transplants contributes to the development of hyperalgesia in a rat model of endometriosis.

    Directory of Open Access Journals (Sweden)

    Stacy L McAllister

    Full Text Available Endometriosis is an enigmatic painful disorder whose pain symptoms remain difficult to alleviate in large part because the disorder is defined by extrauteral endometrial growths whose contribution to pain is poorly understood. A rat model (ENDO involves autotransplanting on abdominal arteries uterine segments that grow into vascularized cysts that become innervated with sensory and sympathetic fibers. ENDO rats exhibit vaginal hyperalgesia. We used behavioral, physiological, and immunohistochemical methods to test the hypothesis that cyst innervation contributes to the development of this hyperalgesia after transplant. Rudimentary sensory and sympathetic innervation appeared in the cysts at two weeks, sprouted further and more densely into the cyst wall by four weeks, and matured by six weeks post-transplant. Sensory fibers became abnormally functionally active between two and three weeks post-transplant, remaining active thereafter. Vaginal hyperalgesia became significant between four and five weeks post-transplant, and stabilized after six to eight weeks. Removing cysts before they acquired functional innervation prevented vaginal hyperalgesia from developing, whereas sham cyst removal did not. Thus, abnormally-active innervation of ectopic growths occurs before hyperalgesia develops, supporting the hypothesis. These findings suggest that painful endometriosis can be classified as a mixed inflammatory/neuropathic pain condition, which opens new avenues for pain relief. The findings also have implications beyond endometriosis by suggesting that functionality of any transplanted tissue can be influenced by the innervation it acquires.

  13. Pharmacogenomic study of the role of the nociceptin/orphanin FQ receptor and opioid receptors in diabetic hyperalgesia.

    Science.gov (United States)

    Rutten, Kris; Tzschentke, Thomas M; Koch, Thomas; Schiene, Klaus; Christoph, Thomas

    2014-10-15

    Targeting functionally independent receptors may provide synergistic analgesic effects in neuropathic pain. To examine the interdependency between different opioid receptors (µ-opioid peptide [MOP], δ-opioid peptide [DOP] and κ-opioid peptide [KOP]) and the nociceptin/orphanin FQ peptide (NOP) receptor in streptozotocin (STZ)-induced diabetic polyneuropathy, nocifensive activity was measured using a hot plate test in wild-type and NOP, MOP, DOP and KOP receptor knockout mice in response to the selective receptor agonists Ro65-6570, morphine, SNC-80 and U50488H, or vehicle. Nocifensive activity was similar in non-diabetic wild-type and knockout mice at baseline, before agonist or vehicle administration. STZ-induced diabetes significantly increased heat sensitivity in all mouse strains, but MOP, DOP and KOP receptor knockouts showed a smaller degree of hyperalgesia than wild-type mice and NOP receptor knockouts. For each agonist, a significant antihyperalgesic effect was observed in wild-type diabetic mice (all Preceptor compared with wild-type diabetic mice. Morphine was the only agonist that demonstrated near-full antihyperalgesic efficacy across all non-cognate receptor knockouts. Partial or near-complete reductions in efficacy were observed with Ro65-6570 in DOP and KOP receptor knockouts, with SNC-80 in NOP, MOP and KOP receptor knockouts, and with U50488H in NOP and DOP receptor knockouts. There was no evidence of NOP and MOP receptor interdependency in response to selective agonists for these receptors. These findings suggest that concurrent activation of NOP and MOP receptors, which showed functional independence, may yield an effective and favorable therapeutic analgesic profile.

  14. 灯盏花素对顺铂所致豚鼠耳蜗损伤的拮抗作用%The Anti-Toxic Effect of Breviscapine on Cisplatin Induced Cochlea Damage in Guinea Pig

    Institute of Scientific and Technical Information of China (English)

    洪丽; 赖晃文; 熊敏

    2011-01-01

    目的 探讨灯盏花素对顺铂致豚鼠耳毒性的拮抗作用.方法 将30只豚鼠分为三组:正常对照组(A组)、实验对照组(B组)、实验组(C组),每组10只.B组和C组一次性腹腔注顺铂10 mg/kg,同时C组连续10天腹腔注射灯盏花素15 mg·kg-1·d-1,B组等时程腹腔注等量生理盐水.每组豚鼠在实验前后均行听性脑干反应(ABR)检测.在豚鼠顺铂致耳毒性模型完成并检测ABR反应阈后,用免疫组织化学方法检测4-羟基-2-壬烯醛(4-HNE)在各组动物耳蜗的表达,同时用扫描电镜观察各组豚鼠耳蜗形态.结果 实验前三组豚鼠ABR反应阈差异无统计学意义(P>0.05),实验后B组和C组豚鼠ABR反应阈分别为50.12±18.45、36.32±15.63 dB SPL,均明显高于实验前,且B组显著高于C组(P<0.05),B组豚鼠听功能损伤明显重于C组.4-HNE在A组表达呈阴性,在B组和C组耳蜗表达呈阳性,且在B组的表达明显强于C组.B组耳蜗外毛细胞的损伤明显较C组重.结论 4-HNE在顺铂所致豚鼠耳蜗损伤中呈阳性表达.灯盏花素对4-HNE的形成有明显抑制作用,且能拮抗顺铂对豚鼠的耳蜗毒性,表明活性氧(ROS)在顺铂所致豚鼠耳蜗损伤中起重要作用.%Objective To investigate the antitoxic effect of breviscapine on cisplatin induced cochlea damage in guinea pig. Methods The experiment consisted of three groups s normal control group ( group A) , experimental control group ( group B) and experimental group (group C) with 10 guinea pigs in every group. Cisplatin was administrated intraperitoneally to animals in group B and C for a single injection at the dose of 10 mg/kg. While cisplatin was delivered intraperitoneally to animals in group C for continuous 10 days, and same volume of physiologicalsaline was delivered to animals in group B. The auditory brain response (ABR) thresholds of guinea pigs in each group were measured before and after experiment. And the expression of 4 - hydroxynonenal (4- HNE) in

  15. Prediction and early diagnosis on cisplatin induced acute kidney injury through NGAL%NGAL预测和早期诊断顺铂所致急性肾损伤的研究

    Institute of Scientific and Technical Information of China (English)

    张立元; 朱振红; 王敏; 刘剑华; 李玉; 朱正秋

    2013-01-01

    ,the levels of AKI group increased at 2,4 and 8 h after chemotherapy,which was significant different (P<0.01).The high levels would be kept at 8 and 12 h,but it was no significant difference (P>0.05) compared with that before chemotherapy; compared with non-AKI group AKI group after 2,4,6 and 8 h urine NGAL levels were significantly higher,the difference was significant (P<0.01).2-4 hours after chemotherapy urine NGAL levels was elevated and urinary NGAL levels in AKI group was still high 6 hours after chemotherapy,rather than the the AKI group falling to the normal reference range.Taking NGAL levels ((x)±s) of non-AKI urine as the referent limitation for diagnosis of AKI,and according to the NGAL levels 6-8 hours after chemotherapy,the specificity for diagnosis was 100% (49/49),the sensitivity was 100 % and diagnostic accuracy was 100%.For AKI group after chemotherapy,there is a linear correlation between Scr level at 24 h and urinary NGAL level at 2 h (r=0.864 4).CONCLUSIONS:Compared with the detection of serum creatinine,urine NGAL levels are more sensitive,more conductive to the occurrence of AKI after cisplatin chemotherapy.It can be used as an early diagnosis method for cisplatin-induced AKI.

  16. Withania somnifera root extract prolongs analgesia and suppresses hyperalgesia in mice treated with morphine.

    Science.gov (United States)

    Orrù, Alessandro; Marchese, Giorgio; Casu, Gianluca; Casu, Maria Antonietta; Kasture, Sanjay; Cottiglia, Filippo; Acquas, Elio; Mascia, Maria Paola; Anzani, Nicola; Ruiu, Stefania

    2014-04-15

    Previous studies demonstrated that Withania somnifera Dunal (WS), a safe medicinal plant, prevents the development of tolerance to the analgesic effect of morphine. In the present study, we investigated whether WS extract (WSE) (100 mg/kg, i.p.) may also modulate the analgesic effect induced by acute morphine administration (2.5, 5, 10 mg/kg, s.c.) in the tail-flick and in the hot plate tests, and if it may prevent the development of 2.5 mg/kg morphine-induced rebound hyperalgesia in the low intensity tail-flick test. Further, to characterize the receptor(s) involved in these effects, we studied, by receptor-binding assay, the affinity of WSE for opioid (μ, δ, k), cannabinoid (CB1, CB2), glutamatergic (NMDA), GABAergic (GABAA, GABAB), serotoninergic (5HT2A) and adrenergic (α2) receptors. The results demonstrated that (i) WSE alone failed to alter basal nociceptive threshold in both tests, (ii) WSE pre-treatment significantly protracted the antinociceptive effect induced by 5 and 10 mg/kg of morphine only in tail-flick test, (iii) WSE pre-treatment prevented morphine-induced hyperalgesia in the low intensity tail-flick test, and (iv) WSE exhibited a high affinity for the GABAA and moderate affinity for GABAB, NMDA and δ opioid receptors. WSE prolongs morphine-induced analgesia and suppresses the development of morphine-induced rebound hyperalgesia probably through involvement of GABAA, GABAB, NMDA and δ opioid receptors. This study suggests the therapeutic potential of WSE as a valuable adjuvant agent in opioid-sparing therapies.

  17. Antagonists of toll like receptor 4 maybe a new strategy to counteract opioid-induced hyperalgesia and opioid tolerance.

    Science.gov (United States)

    Li, Qian

    2012-12-01

    Long term opioid treatment results in hyperalgesia and tolerance, which is a troublesome phenomenon in clinic application. Recent studies have revealed a critical role of toll-like receptor 4 (TLR4) in the neuropathological process of opioid-induced hyperalgesia and tolerance. TLR4 is predominantly expressed by microglial cells and is a key modulator in the activation of the innate immune system. Activation of TLR4 may initiate the activation of microglia and hence a number of neurotransmitters and neuromodulators that could enhance neuronal excitability are released. Blockade of TLR4 activation by its antagonists alleviate neuropathic pain. We hypothesized that opioid antagonists such as naloxone and naltrexone, which were also demonstrated to be TLR4 antagonist, may have clinic application value in attenuation of opioid-induced hyperalgesia and tolerance.

  18. Optokinetic stimulation increases limb pain and forehead hyperalgesia in complex regional pain syndrome

    DEFF Research Database (Denmark)

    Knudsen, Lone F.; Drummond, Peter D.

    2015-01-01

    to investigate the mechanisms underlying the link between sensory conflicts and pain in CRPS using optokinetic stimulation (OKS) - a method known to induce motion sickness. METHODS: Twenty-one CRPS patients underwent OKS and rated symptoms of motion sickness. Patients also rated limb pain and pain....... In a subgroup of nauseated patients who withdrew early from OKS, hyperalgesia to pressure in the ipsilateral forehead persisted longer than in the remaining participants. Sharpness sensations remained constant at all sites. CONCLUSIONS: Sensory conflicts may facilitate pain in CRPS by activating the mechanisms...

  19. [MORPHOLOGICAL CHANGES OF SKIN IN OPERATIVE WOUND IN SYNDROME OF OPIOID-INDUCED HYPERALGESIA].

    Science.gov (United States)

    Dmytriyev, D V; Konoplytskyi, V S

    2015-10-01

    Morphological changes of skin in region of operative wound were investigated. There was established, that while application of fentanyl in high doses, using constant infusion for anesthesia in early postoperative period in children, operated for abdominal cavity tumors, the opioid-induced hyperalgesia occurrence is possible, what is accompanied by morphological changes in skin around operative wound, necrosis in centre of focus, pronounced perifocal reactive changes in a kind of significant inflammation and essential disorder of microcirculation with formation of small neural fibers on the 14th day. Pronounced fibrosis of derma, formation of big quantity of collagen fibers with edema, stratification.

  20. Opioid-induced hyperalgesia: a review of epidemiology, mechanisms and management.

    Science.gov (United States)

    Low, Yinghui; Clarke, Collin F; Huh, Billy K

    2012-05-01

    There has been a growing interest in opioid-induced hyperalgesia (OIH), which is an increased sensitivity to pain caused by opioid exposure. Multiple underlying pathways may contribute to the development of OIH, and the mechanism may vary with the duration of opioid exposure, dose, type and route of administration. In addition, the distinction between OIH, tolerance and withdrawal should be made in both the basic and clinical science literature so as to help translate findings to the clinical phenomenon and to help determine the best strategies to prevent or treat OIH.

  1. Activation of JNK pathway in spinal astrocytes contributes to acute ultra-low-dose morphine thermal hyperalgesia.

    Science.gov (United States)

    Sanna, Maria Domenica; Ghelardini, Carla; Galeotti, Nicoletta

    2015-07-01

    Accumulating evidence suggests that opioid analgesics can lead to paradoxical sensitization to pain when delivered in different administration patterns. Although opioid tolerance-induced hyperalgesia is largely studied, little is known about the mechanisms underlying acute ultra-low-dose morphine hyperalgesia. Activation of spinal glial cells is reported to regulate pain hypersensitivity. To elucidate the mechanism involved in acute ultra-low-dose morphine hyperalgesia, we tested whether an opioid agonist promoted the activation of spinal astrocytes and microglia and investigated the cellular pathways involved. Ultra-low-dose morphine activated spinal astrocytes with no effect on microglia. The astrocyte activation was selectively prevented by the opioid antagonist naloxone, the μ-opioid receptor (MOR) silencing and the JNK inhibitor SP600125. Morphine elevated spinal JNK1, JNK2, and c-Jun phosphorylation. Conversely, phosphorylation of cAMP response element-binding protein (CREB) and signal transducer and activator of transcription-1 (STAT-1) was not elevated, and nuclear factor kappa B (NF-κB) levels remained unmodified. Administration of SP600125 and the N-methyl-D-aspartate (NMDA) antagonist MK801 prevented morphine hyperalgesia. Ultra-low-dose morphine increased protein kinase C (PKC) γ phosphorylation. Pretreatment with a PKC inhibitor prevented morphine hyperalgesia and JNK and c-Jun overphosphorylation, indicating PKC is a JNK upstream modulator and illustrating the presence of a pathway involving PKC, NMDA, and JNK activated by morphine. Immunofluorescence experiments indicated the neuronal localization of spinal MOR. However, JNK was not detected in MOR-expressing cells, showing the presence of a neuron-astrocyte signaling pathway. These results illustrate the selective activation of an astrocyte JNK pathway after the stimulation of neuronal MOR, which contributes to ultra-low-dose morphine hyperalgesia.

  2. Development of a peptidomimetic antagonist of neuropeptide FF receptors for the prevention of opioid-induced hyperalgesia.

    Science.gov (United States)

    Bihel, Frédéric; Humbert, Jean-Paul; Schneider, Séverine; Bertin, Isabelle; Wagner, Patrick; Schmitt, Martine; Laboureyras, Emilie; Petit-Demoulière, Benoît; Schneider, Elodie; Mollereau, Catherine; Simonnet, Guy; Simonin, Frédéric; Bourguignon, Jean-Jacques

    2015-03-18

    Through the development of a new class of unnatural ornithine derivatives as bioisosteres of arginine, we have designed an orally active peptidomimetic antagonist of neuropeptide FF receptors (NPFFR). Systemic low-dose administration of this compound to rats blocked opioid-induced hyperalgesia, without any apparent side-effects. Interestingly, we also observed that this compound potentiated opioid-induced analgesia. This unnatural ornithine derivative provides a novel therapeutic approach for both improving analgesia and reducing hyperalgesia induced by opioids in patients being treated for chronic pain.

  3. The chemokine CCL5 induces CCR1-mediated hyperalgesia in mice inoculated with NCTC 2472 tumoral cells.

    Science.gov (United States)

    Pevida, M; Lastra, A; Meana, Á; Hidalgo, A; Baamonde, A; Menéndez, Luis

    2014-02-14

    Although the expression of the chemokine receptor CCR1 has been demonstrated in several structures related to nociception, supporting the nociceptive role of chemokines able to activate it, the involvement of CCR1 in neoplastic pain has not been previously assessed. We have assayed the effects of a CCR1 antagonist, J113863, in two murine models of neoplastic hyperalgesia based on the intratibial injection of either NCTC 2472 fibrosarcoma cells, able to induce osteolytic bone injury, or B16-F10 melanoma cells, associated to mixed osteolytic/osteoblastic bone pathological features. The systemic administration of J113863 inhibited thermal and mechanical hyperalgesia but not mechanical allodynia in mice inoculated with NCTC 2472 cells. Moreover, in these mice, thermal hyperalgesia was counteracted following the peritumoral (10-30μg) but not spinal (3-5μg) administration of J113863. In contrast, hyperalgesia and allodynia measured in mice inoculated with B16-F10 cells remained unaffected after the administration of J113863. The inoculation of tumoral cells did not modify the levels of CCL3 at tumor or spinal cord. In contrast, although the concentration of CCL5 remained unmodified in mice inoculated with B16-F10 cells, increased levels of this chemokine were measured in tumor-bearing limbs, but not the spinal cord, of mice inoculated with NCTC 2472 cells. Increased levels of CCL5 were also found following the incubation of NCTC 2472, but not B16-F10, cells in the corresponding culture medium. The intraplantar injection of CCL5 (0.5ng) to naïve mice evoked thermal hyperalgesia prevented by the coadministration of J113863 or the CCR5 antagonist, d-Ala-peptide T-amide (DAPTA), demonstrating that CCL5 can induce thermal hyperalgesia in mice through the activation of CCR1 or CCR5. However, contrasting with the inhibitory effect evoked by J113863, the systemic administration of DAPTA did not prevent tumoral hyperalgesia. Finally, the peritumoral administration of an anti

  4. Evidence for an inhibitory role of central histamine on carrageenin-induced hyperalgesia.

    Science.gov (United States)

    Netti, C; Sibilia, V; Guidobono, F; Villani, P; Pecile, A; Braga, P C

    1994-02-01

    The effects of intracerebroventricular (i.c.v.) injection of histamine, the H1 agonist 2-methyl-histamine and the H2 agonist dimaprit were tested on carrageenin induced hyperalgesia by the Randall-Selitto paw pressure test in the rat. Treatment with histamine (0.1, 0.2, 0.4 mumol/rat, i.c.v.) 150 min after intraplantar carrageenin (0.1 ml of 1% solution) caused a significant increase of paw pressure thresholds in inflamed (but not in non-inflamed) paws. The magnitude and the duration of the antinociceptive effects of histamine were dose-dependent. Administration of 2-methyl-histamine (0.2, 0.4, 0.8, 1.0 mumol/rat, i.c.v.) and dimaprit (0.1, 0.2, 0.4, 0.8 mumol/rat, i.c.v.) also displayed dose-dependent blockade of carrageenin-induced hyperalgesia. Antinociceptive ED50 values calculated 30 min after drug treatments were: histamine 0.18 mumol/rat; 2-methyl-histamine 0.65 mumol/rat; dimaprit 0.33 mumol/rat. These data indicate that histamine through central H1 and H2 receptors exerts an inhibitory role in the control of nociception in pain resulting from inflammation.

  5. 5-HT7 receptor activation attenuates thermal hyperalgesia in streptozocin-induced diabetic mice.

    Science.gov (United States)

    Ulugol, Ahmet; Oltulu, Cagatay; Gunduz, Ozgur; Citak, Cihad; Carrara, Roberto; Shaqaqi, Mohammad Reza; Sanchez, Alicia Mansilla; Dogrul, Ahmet

    2012-08-01

    The role of 5-HT7 receptors in the nociceptive processing received most attention during the last few years. The involvement of 5-HT₇ receptors in nerve injury-induced neuropathic pain states have been reported only recently; however, there are no reports on its contribution in diabetic neuropathic pain. We therefore planned to investigate the effect of 5-HT₇ receptor activation on the changes of nociceptive threshold in diabetic mice. Diabetes was induced by a single intraperitoneal injection of streptozocin (150 mg/kg, i.p.). The nociceptive responses in normal and diabetic animals were tested in the hot-plate and tail-flick assays. Both hot-plate and tail-flick latencies significantly shortened at 1-3/4 weeks (thermal hyperalgesia) and prolonged at 6-7 weeks (thermal hypoalgesia) after streptozocin administration. At the dose of 10 mg/kg, systemic injections of AS-19, a selective 5-HT₇ receptor agonist, reduced thermal hyperalgesia at early stage of diabetes, but did not influence thermal hypoalgesia at late stage. Co-administration of SB-258719, a selective 5-HT₇ receptor antagonist, at a dose that had no effect on its own (10 mg/kg), reversed the anti-hyperalgesic effect of AS-19. Our results indicate that systemic administration of 5-HT₇ receptor agonists may have clinical utility in treating diabetic neuropathic pain.

  6. Detection of cold pain, cold allodynia and cold hyperalgesia in freely behaving rats

    Directory of Open Access Journals (Sweden)

    Woolf Clifford J

    2005-12-01

    Full Text Available Abstract Background Pain is elicited by cold, and a major feature of many neuropathic pain states is that normally innocuous cool stimuli begin to produce pain (cold allodynia. To expand our understanding of cold induced pain states we have studied cold pain behaviors over a range of temperatures in several animal models of chronic pain. Results We demonstrate that a Peltier-cooled cold plate with ± 1°C sensitivity enables quantitative measurement of a detection withdrawal response to cold stimuli in unrestrained rats. In naïve rats the threshold for eliciting cold pain behavior is 5°C. The withdrawal threshold for cold allodynia is 15°C in both the spared nerve injury and spinal nerve ligation models of neuropathic pain. Cold hyperalgesia is present in the spared nerve injury model animals, manifesting as a reduced latency of withdrawal response threshold at temperatures that elicit cold pain in naïve rats. We also show that following the peripheral inflammation produced by intraplantar injection of complete Freund's adjuvant, a hypersensitivity to cold occurs. Conclusion The peltier-cooled provides an effective means of assaying cold sensitivity in unrestrained rats. Behavioral testing of cold allodynia, hyperalgesia and pain will greatly facilitate the study of the neurobiological mechanisms involved in cold/cool sensations and enable measurement of the efficacy of pharmacological treatments to reduce these symptoms.

  7. Visceral hyperalgesia caused by peptide YY deletion and Y2 receptor antagonism

    Science.gov (United States)

    Hassan, Ahmed M.; Jain, Piyush; Mayerhofer, Raphaela; Fröhlich, Esther E.; Farzi, Aitak; Reichmann, Florian; Herzog, Herbert; Holzer, Peter

    2017-01-01

    Altered levels of colonic peptide YY (PYY) have been reported in patients suffering from functional and inflammatory bowel disorders. While the involvement of neuropeptide Y (NPY) and Y receptors in the regulation of nociception is well established, the physiological role of PYY in somatic and visceral pain is poorly understood. In this work, the role of PYY in pain sensitivity was evaluated using PYY knockout (PYY(−/−)) mice and Y2 receptor ligands. PYY(−/−) mice were more sensitive to somatic thermal pain compared to wild type (WT) mice. Visceral pain was assessed by evaluating pain-related behaviors, mouse grimace scale (MGS) and referred hyperalgesia after intrarectal administration of allyl isothiocyanate (AITC, 1 or 2%) or its vehicle, peanut oil. The pain-related behaviors induced by AITC were significantly exaggerated by PYY deletion, whereas the MGS readout and the referred hyperalgesia were not significantly affected. The Y2 receptor antagonist, BII0246, increased pain-related behaviors in response to intrarectal AITC compared to vehicle treatment while the Y2 receptor agonist, PYY(3–36), did not have a significant effect. These results indicate that endogenous PYY has a hypoalgesic effect on somatic thermal and visceral chemical pain. The effect on visceral pain seems to be mediated by peripheral Y2 receptors. PMID:28106168

  8. Remifentanil-acute opioid tolerance and opioid-induced hyperalgesia: a systematic review.

    Science.gov (United States)

    Kim, Sang Hun; Stoicea, Nicoleta; Soghomonyan, Suren; Bergese, Sergio D

    2015-01-01

    The use of opioids may seem to be a double-edged sword; they provide straight analgesic and antihyperalgesic effects initially, but subsequently are associated with the expression of acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH) that have been reported in experimental studies and clinical observations. It has been suggested that opioids can induce an acute tolerance and hyperalgesia in dose- and/or time-dependent manners even when used within the clinically accepted doses. Recently, remifentanil has been used for pain management in clinical anesthesia and in the intensive care units because of its rapid onset and offset. We reviewed articles analyzing AOT and/or OIH by remifentanil and focused on the following issues: (1) evidence of remifentanil inducing AOT and/or OIH and (2) importance of AOT and/or OIH in considering the reduction of remifentanil dosage or adopting preventive modulations. Twenty-four experimental and clinical studies were identified using electronic searches of MEDLINE (PubMed, Ovid, Springer, and Elsevier). However, the development of AOT and OIH by remifentanil administration remains controversial. There is no sufficient evidence to support or refute the existence of OIH in humans.

  9. Pain referral and regional deep tissue hyperalgesia in experimental human hip pain models.

    Science.gov (United States)

    Izumi, Masashi; Petersen, Kristian Kjær; Arendt-Nielsen, Lars; Graven-Nielsen, Thomas

    2014-04-01

    Hip disorder patients typically present with extensive pain referral and hyperalgesia. To better understand underlying mechanisms, an experimental hip pain model was established in which pain referrals and hyperalgesia could be studied under standardized conditions. In 16 healthy subjects, pain was induced by hypertonic saline injection into the gluteus medius tendon (GMT), adductor longus tendon (ALT), or gluteus medius muscle (GMM). Isotonic saline was injected contralaterally as control. Pain intensity was assessed on a visual analogue scale (VAS), and subjects mapped the pain distribution. Before, during, and after injections, passive hip joint pain provocation tests were completed, together with quantitative sensory testing as follows: pressure pain thresholds (PPTs), cuff algometry pain thresholds (cuff PPTs), cutaneous pin-prick sensitivity, and thermal pain thresholds. Hypertonic saline injected into the GMT resulted in higher VAS scores than hypertonic injections into the ALT and GMM (Ppain areas spread to larger parts of the leg after GMT and GMM injections compared with more regionalized pain pattern after ALT injections (Ppain provocation tests after hypertonic compared with isotonic saline injections (Ppain mechanisms associated with painful hip disorders.

  10. Heme oxygenase-1 regulates cyclin-dependent kinase inhibitor p18INK4C in mice with cisplatin-induced acute kidney injury%周期素依赖性激酶抑制剂p18INK4C在急性肾损伤中的表达受血红素加氧酶1调控

    Institute of Scientific and Technical Information of China (English)

    张懿; 谌卫; 付莉莉; 胡惠民; 梅长林

    2011-01-01

    目的 初步探讨周期素依赖性激酶抑制剂p18INK4C(p18)在急性肾损伤(AKI)中的肾保护作用机制.方法 利用血红素加氧酶(HO)-1的化学诱导剂(hemin)和抑制剂(锌原卟啉,ZnPP)观察在顺铂诱导的小鼠肾脏上皮细胞(TCMK-1)损伤中HO-1与p18之间的关系.利用p18基因敲除鼠,观察p18基因缺失对于顺铂诱导的HO-1表达的影响.结果 在顺铂诱导的AKI小鼠肾组织及损伤的TCMK-1细胞中,p18、HO-1的mRNA和蛋白表达均明显上调(P值均<0.05),HO-1的诱导表达峰值先于p18上调峰值.在无血清培养的TCMK-1细胞中,HO-1诱导剂hemin与细胞共同孵育后明显上调TCMK-1细胞中HO-1和p18蛋白的表达(P值均<0.05).相反,HO-1抑制剂ZnPP与顺铂共同孵育TCMK-1后的第8和16小时,ZnPP不仅抑制了顺铂诱导的HO-1蛋白表达的上调,而且使p18的表达受到明显抑制.p18-/-与p18+/+小鼠肾组织中HO-1蛋白表达基线值的差异无统计学意义(P>0.05),顺铂注射后第3天,p18-/-与p18+/+小鼠肾组织中HO-1蛋白的诱导表达量的差异亦无统计学意义(P>0.05).顺铂注射后第3天,p18+/+(WT)小鼠肾组织中p18蛋白表达上调,而p18-/-小鼠肾脏中p18蛋白表达缺失.结论 在顺铂诱导的AKI中,HO-1调控p18的表达,p18部分介导了HO-1在AKI中的保护作用.%Objective To determine the protective role of cyclin-dependent kinase inhibitor p18INMO(p18) in cisplatin-induced acute kidney injury (AKI) by using p18 gene knockout mice and investigate the renoprotective mechanism of p18. Methods Chemical inducer (hemin) and inhibitor of HO-1 (ZnPP) were used to study the relationship between p18 and HO-1 in cisplatin-induced mouse kidney epithelial cells (TCMK-1). Further, p18 gene knockout mice were used to demonstrate the effect of p18 on the inducible expression of HO-1 in cisplatin-induced AKI. Results Expressions of p18 and HO-1 were both upregulated at mRNA and protein levels in cisplatin-induced kidneys and

  11. Self-reported Recovery is Associated with Improvement in Localised Hyperalgesia Among Adolescent Females with Patellofemoral Pain

    DEFF Research Database (Denmark)

    Rathleff, Michael Skovdal; Roos, Ewa M.; Olesen, Jens Lykkegaard;

    2016-01-01

    to the manifestations of pain. The objective of this study was to compare the change in localised and distal hyperalgesia among female adolescents with Patellofemoral Pain (PFP) deeming themselves recovered compared to those not recovered 3 months after patient education with or without exercise therapy. METHODS...

  12. Toll-like receptor 4 mutant and null mice retain morphine-induced tolerance, hyperalgesia, and physical dependence.

    Directory of Open Access Journals (Sweden)

    Theresa Alexandra Mattioli

    Full Text Available The innate immune system modulates opioid-induced effects within the central nervous system and one target that has received considerable attention is the toll-like receptor 4 (TLR4. Here, we examined the contribution of TLR4 in the development of morphine tolerance, hyperalgesia, and physical dependence in two inbred mouse strains: C3H/HeJ mice which have a dominant negative point mutation in the Tlr4 gene rendering the receptor non-functional, and B10ScNJ mice which are TLR4 null mutants. We found that neither acute antinociceptive response to a single dose of morphine, nor the development of analgesic tolerance to repeated morphine treatment, was affected by TLR4 genotype. Likewise, opioid induced hyperalgesia and opioid physical dependence (assessed by naloxone precipitated withdrawal were not altered in TLR4 mutant or null mice. We also examined the behavioural consequence of two stereoisomers of naloxone: (- naloxone, an opioid receptor antagonist, and (+ naloxone, a purported antagonist of TLR4. Both stereoisomers of naloxone suppressed opioid induced hyperalgesia in wild-type control, TLR4 mutant, and TLR4 null mice. Collectively, our data suggest that TLR4 is not required for opioid-induced analgesic tolerance, hyperalgesia, or physical dependence.

  13. Docosahexaenoic acid inhibits mechanical allodynia and thermal hyperalgesia in diabetic rats by decreasing the excitability of DRG neurons.

    Science.gov (United States)

    Heng, Li-Jun; Qi, Rui; Yang, Rui-Hua; Xu, Guo-Zheng

    2015-09-01

    Diabetes mellitus is a common metabolic disease in human beings with characteristic symptoms of hyperglycemia, chronic inflammation and insulin resistance. One of the most common complications of early-onset diabetes mellitus is peripheral diabetic neuropathy, which is manifested either by loss of nociception or by allodynia and hyperalgesia. Dietary fatty acids, especially polyunsaturated fatty acids, have been shown the potential of anti-inflammation and modulating neuron excitability. The present study investigated the effects of docosahexaenoic acid (DHA) on the excitability of dorsal root ganglion (DRG) neurons in streptozotocin (STZ)-induced diabetes rats. The effects of DHA on the allodynia and hyperalgesia of diabetic rats were also evaluated. Dietary DHA supplementation effectively attenuated both allodynia and hyperalgesia induced by STZ injection. DHA supplementation decreased the excitability of DRG neurons by decreasing the sodium currents and increasing potassium currents, which may contribute to the effect of alleviating allodynia and hyperalgesia in diabetic rats. The results suggested that DHA might be useful as an adjuvant therapy for the prevention and treatment of painful diabetic neuropathy.

  14. Posttranslational nitration of tyrosine residues modulates glutamate transmission and contributes to N-methyl-D-aspartate-mediated thermal hyperalgesia.

    Science.gov (United States)

    Muscoli, Carolina; Dagostino, Concetta; Ilari, Sara; Lauro, Filomena; Gliozzi, Micaela; Bardhi, Erlisa; Palma, Ernesto; Mollace, Vincenzo; Salvemini, Daniela

    2013-01-01

    Activation of the N-methyl-D-aspartate receptor (NMDAR) is fundamental in the development of hyperalgesia. Overactivation of this receptor releases superoxide and nitric oxide that, in turn, forms peroxynitrite (PN). All of these events have been linked to neurotoxicity. The receptors and enzymes involved in the handling of glutamate pathway--specifically NMDARs, glutamate transporter, and glutamine synthase (GS)--have key tyrosine residues which are targets of the nitration process causing subsequent function modification. Our results demonstrate that the thermal hyperalgesia induced by intrathecal administration of NMDA is associated with spinal nitration of GluN1 and GluN2B receptor subunits, GS, that normally convert glutamate into nontoxic glutamine, and glutamate transporter GLT1. Intrathecal injection of PN decomposition catalyst FeTM-4-PyP(5+) prevents nitration and overall inhibits NMDA-mediated thermal hyperalgesia. Our study supports the hypothesis that nitration of key proteins involved in the regulation of glutamate transmission is a crucial pathway used by PN to mediate the development and maintenance of NMDA-mediated thermal hyperalgesia. The broader implication of our findings reinforces the notion that free radicals may contribute to various forms of pain events and the importance of the development of new pharmacological tool that can modulate the glutamate transmission without blocking its actions directly.

  15. Paclitaxel-induced hyperalgesia modulates negative affective component of pain and NR1 receptor expression in the frontal cortex in rats.

    Science.gov (United States)

    Noda, Kazuko; Akita, Hisanao; Ogata, Masanori; Saji, Makoto

    2014-03-01

    Paclitaxel, one of the chemotherapeutic agents clinically used to treat several types of cancer, produces side effects such as peripheral neuropathy, sensory abnormalities, and hyperalgesia. Since hyperalgesia remains after cessation of paclitaxel therapy and becomes chronic, we hypothesize that alteration in memory and the cognitive process of pain underlies hyperalgesia. To test this hypothesis, we examined whether drug-induced hyperalgesia alters the affective component of pain and the NMDA-NR1 and mGluR1 receptors as a mediator for signal transmission and memory of pain. Mechanical sensitivity was measured by von Frey filament test after intraperitoneal injection of paclitaxel in rats. Paclitaxel-induced hyperalgesia was confirmed over almost the entire 14-day period of observation after the treatment. The effect of paclitaxel-induced hyperalgesia on the affective component of pain was assessed using pain-induced place aversion. The formalin-induced conditioned place aversion was completely abolished in the paclitaxel-treated rats. Immunoblot analysis of NR1 and mGluR1 protein levels in various brain regions was performed after paclitaxel treatment. Treatment reduced only the NR1 expression within the frontal cortex. These results suggest that the hypofunction of memory processes with the reduced NMDA receptors in the frontal cortex might be involved in the expression of abnormal emotional behaviors accompanied by hyperalgesia.

  16. Local loperamide inhibits thermal hyperalgesia but not mechanical allodynia induced by intratibial inoculation of melanoma cells in mice.

    Science.gov (United States)

    Curto-Reyes, Verdad; Juárez, Lucía; García-Pérez, Eva; Fresno, Manuel Florentino; Hidalgo, Agustín; Menéndez, Luis; Baamonde, Ana

    2008-11-01

    The stimulation of peripheral opioid receptors counteracts thermal hyperalgesia produced by the intratibial inoculation of NCTC 2472 cells in mice, through the activation of the nitric oxide/cGMP/ATP-sensitive K+-channels (NO/cGMP/K(+) (ATP)) cascade (Menéndez et al. 2007, Neuropharmacology 53:71-80). We aimed to elucidate whether this peripheral opioid antihyperalgesic effect is exclusive to this model or might also occur in other types of bone neoplastic processes. In C57BL/6 mice intratibially inoculated with B16-F10 melanoma cells, the progressive tumoral damage was accompanied by the establishment of thermal hyperalgesia (unilateral hot plate test) and mechanical allodynia (von Frey test). Intraplantar administration of loperamide (15 microg, 30 min before) inhibited thermal hyperalgesia, but did not modify the intense mechanical allodynia. The fact that the coadministration of naloxone-methiodide (5 microg) completely suppressed the thermal antihyperalgesic effect induced by loperamide indicates its production through the stimulation of peripheral opioid receptors. Furthermore, its prevention by the coadministration of the non-selective inhibitor of the NO synthase, N(G)-monomethyl-L-arginine (L-NMMA, 10 microg), the selective inhibitor of neural NOS, N-omega-propyl-L-arginine (1-10 microg), or the K+ (ATP) channel blocker, glibenclamide (10 microg) demonstrated the involvement of the NO/cGMP/K(+) (ATP) pathway in the antihyperalgesic effect induced by loperamide. Overall, the present results show that the intratibial inoculation of B16-F10 cells to C57BL/6 mice evokes thermal hyperalgesia and mechanical allodynia and that, as occurred in the osteosarcoma model, the stimulation of peripheral opioid receptors is not effective in modifying neoplastic allodynia but completely inhibits thermal hyperalgesia through the activation of the NO/cGMP/K+ (ATP) cascade.

  17. Is mechanism and symptom-based analgesia an answer to opioid-Induced hyperalgesia?

    Directory of Open Access Journals (Sweden)

    Mayank Gupta

    2015-01-01

    Full Text Available "Cancer Pain" and "Pain in cancer patient" are not synonymous. Opioid-induced Hyperalgesia (OIH is a paradoxical state of nociceptive sensitization caused by exposure to opioids. Neuropathic pain is only partially responsive to opioids; injudicious increase in dose of opioids in neuropathic pain may not only result in inadequate pain relief but also OIH. Majority of literature on OIH is in non-cancer pain with systemic use of opioids. We describe the development and successful treatment of OIH in a 55-year-old male patient with Small cell Carcinoma Lung. Opioid tapering, rotation, systemic desensitization helps in combatting OIH. The use of anti-neuropathic adjuvant analgesics helps not only in preventing and treating OIH but also in understanding putative mechanisms underlying neuropathic pain and OIH.

  18. Pharmacological inhibition of eicosanoid synthesis and hyperalgesia in yeast-injected rat paws

    Energy Technology Data Exchange (ETDEWEB)

    Opas, E.E.; Dallob, A.; Herold, E.; Luell, S.; Humes, J.L.

    1986-03-01

    Brewer's yeast caused an inflammation characterized by edema and hyperalgesia when injected into the hindpaw of a rat. These events were temporally distinct and each was associated with increases of specific arachidonic and oxygenation products. As determined by radioimmunoassay (RIA) on whole paw lipid extracts, the 5-lipoxygenase (5-LO) products, leukotrienes C/sub 4/ and D/sub 4/ and 5-hydroxyeicosatetraendic acid (5-HETE) were synthesized concurrently with the onset of edema (maximal at 15 minutes after yeast injection). The hyperalgesic phase of the inflammation (3-4 hr after yeast injection) was associated with increased tissue levels of the cyclooxygenase (CO) products, prostaglandin E/sub 2/ and thromboxane B/sub 2/ (TXB/sub 2/) as well as increases in levels of the 5-LO products, leukotriene B/sub 4/ (LTB/sub 4/) and 5-HETE. Pharmacological agents modulated the synthesis of eicosanoids and suppressed the hyperalgesic response.

  19. Acute-onset opioid-induced hyperalgesia in a child with juvenile idiopathic arthritis.

    Science.gov (United States)

    Vijayan, Vini; Moran, Ryan; Elder, Melissa E; Sukumaran, Sukesh

    2012-10-01

    We describe a child with polyarticular juvenile idiopathic arthritis (JIA) presenting with severe diffuse pain refractory to nonsteroidal anti-inflammatory agents and high-dose opioids. Her JIA involved her knees and ankles and was mildly active on etanercept and nonsteroidal anti-inflammatory agents. At presentation, she complained of hip pain progressing to severe diffuse pain and allodynia involving her extremities. No abnormalities were seen in her laboratory parameters and imaging of her lower extremities. After appreciating no substantial benefit by increasing her opioids, her opioids were tapered and discontinued, and this was followed by significant alleviation in her pain, and a diagnosis of opioid-induced hyperalgesia (OIH) was made. Despite reports in adults, the phenomenon of OIH has been reported infrequently in children. To our knowledge, OIH has not been described in children with rheumatologic conditions. We recommend investigating the possibility of OIH when treating a child with JIA and severe refractory pain.

  20. Is mechanism and symptom-based analgesia an answer to opioid-induced hyperalgesia?

    Science.gov (United States)

    Gupta, Mayank; Gupta, Priyanka

    2015-01-01

    "Cancer Pain" and "Pain in cancer patient" are not synonymous. Opioid-induced Hyperalgesia (OIH) is a paradoxical state of nociceptive sensitization caused by exposure to opioids. Neuropathic pain is only partially responsive to opioids; injudicious increase in dose of opioids in neuropathic pain may not only result in inadequate pain relief but also OIH. Majority of literature on OIH is in non-cancer pain with systemic use of opioids. We describe the development and successful treatment of OIH in a 55-year-old male patient with Small cell Carcinoma Lung. Opioid tapering, rotation, systemic desensitization helps in combatting OIH. The use of anti-neuropathic adjuvant analgesics helps not only in preventing and treating OIH but also in understanding putative mechanisms underlying neuropathic pain and OIH.

  1. Lateral Hypothalamic Stimulation Reduces Hyperalgesia Through Spinally Descending Orexin-A Neurons in Neuropathic Pain.

    Science.gov (United States)

    Wardach, Jacob; Wagner, Monica; Jeong, Younhee; Holden, Janean E

    2016-03-01

    No evidence to date shows that lateral hypothalamic (LH) stimulation produces orexin-A-mediated antinociception in the spinal cord dorsal horn (SCDH) in a model of neuropathic pain. We conducted experiments to examine the effect of orexin-A-mediated LH stimulation in female rats with chronic constriction injury (CCI) on thermal hyperalgesia. Rats receiving carbachol into the LH demonstrated antinociception on both the left CCI and right nonligated paws (p orexin-1 (OX1) receptor antagonist SB-334867, which blocked LH-induced antinociception compared with control groups (p orexin-A connection between the LH and the SCDH. Identification of this pathway may lead to studies using orexins to manage clinical pain.

  2. Amitriptyline reverses hyperalgesia and improves associated mood-like disorders in a model of experimental monoarthritis.

    Science.gov (United States)

    Amorim, D; David-Pereira, A; Pertovaara, A; Almeida, A; Pinto-Ribeiro, F

    2014-05-15

    Affective disorders are common comorbidities of chronic inflammatory pain that are often overlooked in primary care. As the impact of inflammatory pain upon mood-like disorders in animal models is not well known, our objective was to assess whether prolonged experimental monoarthritis (ARTH) induced the development of anxiety and depressive-like behaviours in rodents and if amitriptyline, an antidepressant commonly used in the treatment of chronic pain, could reverse both nociceptive and mood-like impairments. Experimental ARTH was induced through an injection of kaolin/carrageenan into the right knee joint with control (SHAM) animals injected with saline. Four weeks after induction, ARTH animals displayed mechanical hyperalgesia and a depressive-like phenotype as they showed a significant increase in immobility and a decrease in the latency to immobility in the forced-swimming test at the expense of the time spent climbing/swimming. ARTH animals also displayed a decreased sucrose preference, an index of anhedonia and anxiety-like behaviour as time spent exploring the open arms of the elevated-plus-maze was decreased when compared to controls. The anxiety-like phenotype was also supported by an increase in the number of fecal boli left in the open field. In ARTH animals, the administration of amitriptyline decreased mechanical hyperalgesia and increased sucrose preference and the time spent climbing, although it had a deleterious effect in the performance of control animals. Our data show that this model of ARTH can be useful for the study of chronic pain-mood disorders comorbidities and that amitriptyline is able to partly reverse the associated nociceptive and emotional impairments.

  3. Effects of symptomatic treatments on cutaneous hyperalgesia and laser evoked potentials during migraine attack.

    Science.gov (United States)

    de Tommaso, M; Losito, L; Libro, G; Guido, M; Di Fruscolo, O; Sardaro, M; Sciruicchio, V; Lamberti, P; Livrea, P

    2005-05-01

    Previously an amplitude enhancement of laser evoked potentials (LEPs) was detected during migraine attack: we further examined pain threshold to CO2 laser stimuli and LEPs during attacks, evaluating the effect of almotriptan, lysine-acetylsalicylate and placebo treatment on cutaneous hyperalgesia to thermal stimuli delivered by CO2 laser and on LEP components. Eighteen patients suffering from migraine without aura were analysed. They were divided into three groups of six patients each, randomly assigned to lysine acetyl-salicylate, almotriptan or placebo treatments. The supraorbital zones and the dorsum of the hand were stimulated on both the symptomatic and not symptomatic side in all patients. The LEPs were recorded by 25 scalp electrodes. During attacks, the P2 wave was significantly enhanced; the amplitude of the P2 component obtained by the stimulation of the supraorbital zone during the attack on the side of the headache was significantly correlated with the intensity of pain and the frequency of headache. Both almotriptan and lysine acetyl-salicylate significantly reduced the P2 amplitude but they showed no effects on hyperalgesia to laser stimulation; headache relief following therapy was correlated with the reduction of the P2 amplitude. The cortical elaboration of laser-induced experimental pain seemed increased during migraine attack, and the severity of headache was mainly related to the increase of the later LEPs components expressing the attentive and emotive compounds of suffering. Reversion of this process appeared to be primarily responsible for the efficacy of drugs in treating migraine, though both almotriptan and lysine-acetil salicilate seemed to have no effect in reducing sensitization at second and third order nociceptive neurons.

  4. Effect of painless diabetic neuropathy on pressure pain hypersensitivity (hyperalgesia after acute foot trauma

    Directory of Open Access Journals (Sweden)

    Tobias Wienemann

    2014-11-01

    Full Text Available Introduction and objective: Acute injury transiently lowers local mechanical pain thresholds at a limb. To elucidate the impact of painless (diabetic neuropathy on this post-traumatic hyperalgesia, pressure pain perception thresholds after a skeletal foot trauma were studied in consecutive persons without and with neuropathy (i.e. history of foot ulcer or Charcot arthropathy. Design and methods: A case–control study was done on 25 unselected clinical routine patients with acute unilateral foot trauma (cases: elective bone surgery; controls: sprain, toe fracture. Cases were 12 patients (11 diabetic subjects with severe painless neuropathy and chronic foot pathology. Controls were 13 non-neuropathic persons. Over 1 week after the trauma, cutaneous pressure pain perception threshold (CPPPT and deep pressure pain perception threshold (DPPPT were measured repeatedly, adjacent to the injury and at the opposite foot (pinprick stimulators, Algometer II®. Results: In the control group, post-traumatic DPPPT (but not CPPPT at the injured foot was reduced by about 15–25%. In the case group, pre- and post-operative CPPPT and DPPPT were supranormal. Although DPPPT fell post-operatively by about 15–20%, it remained always higher than the post-traumatic DPPPT in the control group: over musculus abductor hallucis 615 kPa (kilopascal versus 422 kPa, and over metatarsophalangeal joint 518 kPa versus 375 kPa (medians; case vs. control group; CPPPT did not decrease post-operatively. Conclusion: Physiological nociception and post-traumatic hyperalgesia to pressure are diminished at the foot with severe painless (diabetic neuropathy. A degree of post-traumatic hypersensitivity required to ‘pull away’ from any one, even innocuous, mechanical impact in order to avoid additional damage is, therefore, lacking.

  5. Intraoperative Use of Remifentanil and Opioid Induced Hyperalgesia/Acute Opioid Tolerance - Systematic review

    Directory of Open Access Journals (Sweden)

    Sang Hun eKim

    2014-05-01

    Full Text Available IntroductionThe use of opioids has been increasing in operating room and intensive care unit to provide perioperative analgesia as well as stable hemodynamics. However, many authors have suggested that the use of opioids is associated with the expression of acute opioid tolerance (AOT and opioid-induced hyperalgesia (OIH in experimental studies and clinical observations in dose and/or time dependent exposure even when used within the clinically accepted doses. Recently, remifentanil has been used for pain management during anesthesia as well as in the intensive care units because of its rapid onset and offset. ObjectivesSearch of the available literature to assess remifentanil AOT and OIH based on available published data.MethodsWe reviewed articles analyzing remifentanil AOT and OIH, and focused our literature search on evidence based information. Experimental and clinical studies were identified using electronic searches of Medline (PubMed, Ovid, Springer, and Elsevier, ClinicalKey. ResultsOur results showed that the development of remifentanil AOT and OIH is a clinically significant phenomenon requiring further research.Discussions and ConclusionsAOT - defined as an increase in the required opioid dose to maintain adequate analgesia, and OIH - defined as decreased pain threshold, should be suspected with any unexplained pain report unassociated with the disease progression.The clinical significance of these findings was evaluated taking into account multiple methodological issues including the dose and duration of opioids administration, the different infusion mode, the co-administrated anesthetic drug’s effect, method assessing pain sensitivity, and the repetitive and potentially tissue damaging nature of the stimuli used to determine the threshold during opioid infusion.Future studies need to investigate the contribution of remifentanil induced hyperalgesia to chronic pain and the role of pharmacological modulation to reverse this process.

  6. Pain Modulation by Lignans (Phyllanthin and Hypophyllanthin) and Tannin (Corilagin) Rich Extracts of Phyllanthus amarus in Carrageenan-induced Thermal and Mechanical Chronic Muscle Hyperalgesia.

    Science.gov (United States)

    Chopade, Atul R; Sayyad, F J

    2015-08-01

    The current study was aimed at evaluating the antihyperalgesic effects of lignans (phyllanthin and hypophyllanthin) and tannin (corilagin) rich three standardized extracts of Phyllanthus amarus in a model of chronic musculoskeletal inflammatory pain. Three percent carrageenan injected in the gastrocnemius muscle produced hyperalgesia to mechanical and heat stimuli ipsilaterally, which spreads to the contralateral side within 7 to 9 days. To investigate the effects on chronic thermal and mechanical hypersensitivity, three extracts of P. amarus in three doses (100, 200, and 400 mg/kg) were administered to animals intraperitoneally from 14th day to 22nd day after intramuscular injection of carrageenan. It was observed that intraperitoneal administrations of Phyllanthus extracts showed antihyperalgesic activity, as they elevated thermal and mechanical threshold, which was supported by histopathological observations along with reduction in prostaglandin E2 (PGE2) concentration. In conclusion, we strongly suggest that the observed antihyperalgesic and antiinflammatory effects of P. amarus in current pain model are mediated via spinal or supraspinal neuronal mechanisms, mainly by inhibition of PGE2. Modulation of chronic muscular inflammation may be due to presence of phytoconstituents like phyllanthin, hypophyllanthin, and corilagin, which offers a promising means for treatment of chronic muscle pain.

  7. Mild moxibustion at Tianshu (ST 25) decreases expression of prokineticin-1 and prokineticin receptor-1 in colon tissue of rats with chronic visceral hyperalgesia

    Institute of Scientific and Technical Information of China (English)

    Luyi Wu; Chunhui Bao; Linbao Ge; Cili Zhou; Huirong Liu; Li Qi; Tao Yi; Huangan Wu; Xiaomei Wang

    2011-01-01

    Prokineticin-1 and prokineticin receptor-1 play important roles in visceral hypersensitivity and in-flammatory pain. Visceral hypersensitivity is closely associated with irritable bowel syndrome. Mild moxibustion can relieve chronic visceral hyperalgesia in rats with irritable bowel syndrome. We hypothesized that prokineticin-1 and prokineticin receptor-1 is the key target in the mechanism. This study established chronic visceral hyperalgesia rat models by colorectal distention. Protein and mRNA expression of prokineticin-1 and prokineticin receptor-1 were determined by immunohisto-chemical method and fluorescence quantitative-PCR, respectively, and were found to be signifi-cantly increased in visceral hyperalgesic rats. Mild moxibustion at Tianshu (ST 25) decreased prokineticin-1 and prokineticin receptor-1 expression in chronic visceral hyperalgesia rats and lessen the chronic visceral hyperalgesia in rats with irritable bowel syndrome at different levels of colorectal distention pressure.

  8. Tyrosine phosphorylation of the N-Methyl-D-Aspartate receptor 2B subunit in spinal cord contributes to remifentanil-induced postoperative hyperalgesia: the preventive effect of ketamine

    Directory of Open Access Journals (Sweden)

    Cui Songqin

    2009-12-01

    Full Text Available Abstract Background Experimental and clinical studies showed that intraoperative infusionof remifentanil has been associated with postoperative hyperalgesia. Previous reports suggested that spinal N-methyl-D-aspartate (NMDA receptors may contribute to the development and maintenance of opioid-induced hyperalgesia. In the present study, we used a rat model of postoperative pain to investigate the role of tyrosine phosphorylation of NMDA receptor 2B (NR2B subunit in spinal cord in the postoperative hyperalgesia induced by remifentanil and the intervention of pretreatment with ketamine. Results Intraoperative infusion of remifentanil (0.04 mg/kg, subcutaneous significantly enhanced mechanical allodynia and thermal hyperalgesia induced by the plantar incision during the postoperative period (each lasting between 2 h and 48 h, which was attenuated by pretreatment with ketamine (10 mg/kg, subcutaneous. Correlated with the pain behavior changes, immunocytochemical and western blotting experiments in our study revealed that there was a marked increase in NR2B phosphorylation at Tyr1472 in the superficial dorsal horn after intraoperative infusion of remifentanil, which was attenuated by pretreatment with ketamine. Conclusions This study provides direct evidence that tyrosine phosphorylation of the NR2B at Tyr1472 in spinal dosal horn contributes to postoperative hyperalgesia induced by remifentanil and supports the potential therapeutic value of ketamine for improving postoperative hyperalgesia induced by remifentanil.

  9. Mechanisms of opioid-induced hyperalgesia in the spinal cord level%阿片类药物引起痛觉过敏的脊髓机制

    Institute of Scientific and Technical Information of China (English)

    雷洪伊; 徐世元

    2012-01-01

    Background Opioid-induced hyperalgesia has received increasing attention,and the mechanisms need further investigation.Objective To expound some possible mechanisms of opioid-induced hyperalgesia in the spinal cord level,which may offer some methods for prevention of the hyperalgesia in clinic.Content This review provides some information about opioidinduced hyperalgesia in the spinal cord level,such as the receptors pathway,signal transduction pathway,neuropeptide and so on.Trend The detailed mechanism of opioid-induced hyperalgesia in the spinal cord level needs further study.%背景 阿片类药物引起的痛觉过敏(opioid-induced hyperalgesia,OIH)日益引起关注,其机制有待深入研究.目的 论述脊髓水平OIH的机制,以供临床研究防治此类痛觉过敏参考.内容 就脊髓水平受体通路、信号转导路径及神经肽等方面,论述OIH的机制.趋向 脊髓水平多种途径参与OIH,值得进一步研究.

  10. Complement factor C5a and C5a receptor contribute to morphine tolerance and withdrawal-induced hyperalgesia in rats.

    Science.gov (United States)

    Li, Yan-Hua; Jin, Hua; Xu, Jing-Shu; Guo, Guang-Qiong; Chen, DA-Lin; Bo, Yun

    2012-10-01

    Morphine is a potent opioid analgesic. However, the repeated use of morphine causes tolerance and hyperalgesia. Neuroinflammation has been reported to be involved in morphine tolerance and withdrawal-induced hyperalgesia. The complement system is a crucial effector mechanism of immune responses. The present study investigated the roles of complement factor C5a and C5a receptor (C5aR) in the development of morphine tolerance and withdrawal-induced hyperalgesia. In the present study, the levels of C5a and C5aR were increased in the L5 lumbar spinal cords of morphine-tolerant rats. The administration of C5a promoted the development of hyperalgesia and the expression of spinal antinociceptive tolerance to intrathecal morphine in both mechanical and thermal test. However, these phenomena caused by morphine were significantly attenuated by the C5aR antagonist PMX53. These results suggest that complement activation within the spinal cord is involved in morphine tolerance and withdrawal-induced hyperalgesia. C5a and C5aR may serve as novel targets for the control of morphine tolerance and withdrawal-induced hyperalgesia.

  11. Minocycline injection in the ventral posterolateral thalamus reverses microglial reactivity and thermal hyperalgesia secondary to sciatic neuropathy.

    Science.gov (United States)

    LeBlanc, Brian W; Zerah, Michele L; Kadasi, Laith M; Chai, Noori; Saab, Carl Y

    2011-07-08

    We hypothesized that microglia in the ventral posterolateral (VPL) nucleus of the thalamus are reactive following peripheral nerve injury, and that inhibition of microglia by minocycline injection in the VPL attenuates thermal hyperalgesia. Our results show increased expression of OX-42 co-localized with phosphorylated p38MAPK (P-p38) in the VPL seven days after chronic constriction injury (CCI) of the sciatic nerve. However, astrocytic GFAP expression in the VPL is unchanged 7 and 14 days after CCI. Microinjection of minocycline into the VPL contralateral to CCI reverses thermal hyperalgesia, whereas vehicle injection has no effect on paw withdrawal latency. Minocycline abrogates the increased expression of OX-42 in the VPL after CCI. Therefore, peripheral nerve injury favors a hyperactive microglial phenotype in the VPL, suggesting remote neuroimmune signaling from the damaged nerve to the brain, concomitant with neuropathic behavior that is reversed by local intervention in the VPL to inhibit microglia.

  12. TRPV3 and TRPV4 ion channels are not major contributors to mouse heat sensation

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    Wang Juan

    2011-05-01

    Full Text Available Abstract Background The discovery of heat-sensitive Transient Receptor Potential Vanilloid (TRPV ion channels provided a potential molecular explanation for the perception of innocuous and noxious heat stimuli. TRPV1 has a significant role in acute heat nociception and inflammatory heat hyperalgesia. Yet, substantial innocuous and noxious heat sensitivity remains in TRPV1 knockout animals. Here we investigated the role of two related channels, TRPV3 and TRPV4, in these capacities. We studied TRPV3 knockout animals on both C57BL6 and 129S6 backgrounds, as well as animals deficient in both TRPV3 and TRPV4 on a C57BL6 background. Additionally, we assessed the contributions of TRPV3 and TRPV4 to acute heat nociception and inflammatory heat hyperalgesia during inhibition of TRPV1. Results TRPV3 knockout mice on the C57BL6 background exhibited no obvious alterations in thermal preference behavior. On the 129S6 background, absence of TRPV3 resulted in a more restrictive range of occupancy centered around cooler floor temperatures. TRPV3 knockout mice showed no deficits in acute heat nociception on either background. Mice deficient in both TRPV3 and TRPV4 on a C57BL6 background showed thermal preference behavior similar to wild-type controls on the thermal gradient, and little or no change in acute heat nociception or inflammatory heat hyperalgesia. Masking of TRPV1 by the TRPV1 antagonist JNJ-17203212 did not reveal differences between C57BL6 animals deficient in TRPV3 and TRPV4, compared to their wild-type counterparts. Conclusions Our results support the notion that TRPV3 and TRPV4 likely make limited and strain-dependent contributions to innocuous warm temperature perception or noxious heat sensation, even when TRPV1 is masked. These findings imply the existence of other significant mechanisms for heat perception.

  13. The effect of intrathecal gabapentin on mechanical and thermal hyperalgesia in neuropathic rats induced by spinal nerve ligation.

    OpenAIRE

    Cho, Hyun Sung; Kim, Myung Hee; Choi, Duck Hwan; LEE, JUNG IL; Gwak, Mi Sook; Hahm, Tae Soo

    2002-01-01

    Gabapentin decreases the level of glutamate and elevates that of alpha-amino-butyric acid in the central nervous system. Gabapentin was shown to have antinociceptive effects in several facilitated pain models. Intrathecal gabapentin was also known to be effective in reducing mechanical allodynia in animals with neuropathic pain. In this study, we investigated to see whether intrathecal gabapentin produces antihyperalgesic effects on thermal and mechanical hyperalgesia in neuropathic rats and ...

  14. Allodynia and hyperalgesia in diabetic rats are mediated by GABA and depletion of spinal potassium-chloride co-transporters

    OpenAIRE

    2008-01-01

    Diabetic rats show behavioral indices of painful neuropathy that may model the human condition. Hyperalgesia during the formalin test in diabetic rats is accompanied by the apparently paradoxical decrease in spinal release of excitatory neurotransmitters and increase in the inhibitory neurotransmitter GABA. Decreased expression of the potassium-chloride co-transporter, KCC2, in the spinal cord promotes excitatory properties of GABA. We therefore measured spinal KCC2 expression and explored th...

  15. Transcutaneous Electrical Nerve Stimulation (TENS) reduces pain, fatigue, and hyperalgesia while restoring central inhibition in primary fibromyalgia

    OpenAIRE

    Dailey, Dana L.; Rakel, Barbara A; Vance, Carol GT; Richard E. Liebano; Anand, Amrit S; Bush, Heather M.; Lee, Kyoung S; Lee, Jennifer E.; Sluka, Kathleen A.

    2013-01-01

    Because TENS works by reducing central excitability and activating central inhibition pathways, we tested the hypothesis that TENS would reduce pain and fatigue and improve function and hyperalgesia in people with fibromyalgia who have enhanced central excitability and reduced inhibition. The current study used a double-blinded randomized, placebo controlled cross-over design to test effects of a single treatment of TENS in people with fibromyalgia. Three treatments were assessed in random or...

  16. Different analgesic effects of intrathecal endomorphin-2 on thermal hyperalgesia and evoked inflammatory pain in ovariectomized rats.

    Science.gov (United States)

    Zhao, Xiao-Hui; Zhao, Ya-Qun; Zhu, Chao; Chen, Lei; Hu, Wei; Zhang, Ting; Dong, Yu-Lin; Wu, Sheng-Xi; Kaye, Alan David; Wang, Wen; Li, Yun-Qing

    2015-01-01

    Hormone replacement remains one of the common therapies for menopause-related pain but is associated with risk of orofacial or back pain. Spinal endomorphin-2 (EM-2) is involved in varied pain and its release is steroid-dependent, but whether increasing spinal EM-2 can inhibit thermal hyperalgesia and inflammatory pain in ovariectomized (OVX) female rats, an animal model mimicking menopause, is not clear, nor is the potential involvement of spinal mu-opioid receptor (MOR). In the current study, we revealed that the temporal decrease of spinal EM-2 is accompanied with OVX-induced thermal hyperalgesia that was dose-dependently attenuated by intrathecal (IT) delivery of EM-2. The subcutaneous injection of formalin-induced inflammatory pain in OVX rats was exacerbated and IT delivery of EM-2 dose-dependently inhibited the inflammatory pain. However, the ED50 for IT delivery of EM-2 on thermal hyperalgesia is smaller than that on inflammatory pain in OVX rats, suggesting different contributions of the EM-2 system to these 2 pain modalities in OVX rats. IT pretreatment with MOR antagonist, beta-funaltrexamine (β-FNA), attenuated IT EM-2 analgesia on both thermal hyperalgesia and inflammatory pain in OVX rats. Furthermore, IT delivery of EM-2 did not affect the animals' locomotion or anxiety status. Our findings suggested that IT EM-2 might be a safer analgesia strategy than hormone replacement therapy in reducing risk of orofacial or back pain. However, a long-lasting form of EM-2 with less tolerance is needed to induce sustained analgesia.

  17. Early transcutaneous electrical nerve stimulation reduces hyperalgesia and decreases activation of spinal glial cells in mice with neuropathic pain.

    Science.gov (United States)

    Matsuo, Hideaki; Uchida, Kenzo; Nakajima, Hideaki; Guerrero, Alexander Rodriguez; Watanabe, Shuji; Takeura, Naoto; Sugita, Daisuke; Shimada, Seiichiro; Nakatsuka, Terumasa; Baba, Hisatoshi

    2014-09-01

    Although transcutaneous electrical nerve stimulation (TENS) is widely used for the treatment of neuropathic pain, its effectiveness and mechanism of action in reducing neuropathic pain remain uncertain. We investigated the effects of early TENS (starting from the day after surgery) in mice with neuropathic pain, on hyperalgesia, glial cell activation, pain transmission neuron sensitization, expression of proinflammatory cytokines, and opioid receptors in the spinal dorsal horn. Following nerve injury, TENS and behavioral tests were performed every day. Immunohistochemical, immunoblot, and flow cytometric analysis of the lumbar spinal cord were performed after 8 days. Early TENS reduced mechanical and thermal hyperalgesia and decreased the activation of microglia and astrocytes (PEarly TENS decreased p-p38 within microglia (Pearly TENS relieved hyperalgesia in our mouse model of neuropathic pain by inhibiting glial activation, MAP kinase activation, PKC-γ, and p-CREB expression, and proinflammatory cytokines expression, as well as maintenance of spinal opioid receptors. The findings indicate that TENS treatment is more effective when applied as early after nerve injury as possible.

  18. Allodynia and hyperalgesia in diabetic rats are mediated by GABA and depletion of spinal potassium-chloride co-transporters

    Science.gov (United States)

    Jolivalt, Corinne G.; Lee, Corinne A.; Ramos, Khara M.; Calcutt, Nigel A.

    2008-01-01

    Diabetic rats show behavioral indices of painful neuropathy that may model the human condition. Hyperalgesia during the formalin test in diabetic rats is accompanied by the apparently paradoxical decrease in spinal release of excitatory neurotransmitters and increase in the inhibitory neurotransmitter GABA. Decreased expression of the potassium-chloride co-transporter, KCC2, in the spinal cord promotes excitatory properties of GABA. We therefore measured spinal KCC2 expression and explored the role of the GABAA receptor in rats with painful diabetic neuropathy. KCC2 protein levels were significantly reduced in the spinal cord of diabetic rats while levels of NKCC1 and the GABAA receptor were unchanged. Spinal delivery of the GABAA receptor antagonist bicuculline reduced formalin-evoked flinching in diabetic rats and also dose-dependently alleviated tactile allodynia. GABAA receptor-mediated rate-dependent depression of the spinal H reflex was absent in the spinal cord of diabetic rats. Control rats treated with the KCC2 blocker DIOA, mimicked diabetes by showing increased formalin-evoked flinching and diminished rate dependent depression. The ability of bicuculline to alleviate allodynia and formalin-evoked hyperalgesia in diabetic rats is consistent with a reversal of the properties of GABA predicted by reduced spinal KCC2 and suggests that reduced KCC2 expression and increased GABA release contribute to spinally-mediated hyperalgesia in diabetes. PMID:18755547

  19. Allodynia and hyperalgesia in diabetic rats are mediated by GABA and depletion of spinal potassium-chloride co-transporters.

    Science.gov (United States)

    Jolivalt, Corinne G; Lee, Corinne A; Ramos, Khara M; Calcutt, Nigel A

    2008-11-15

    Diabetic rats show behavioral indices of painful neuropathy that may model the human condition. Hyperalgesia during the formalin test in diabetic rats is accompanied by the apparently paradoxical decrease in spinal release of excitatory neurotransmitters and increase in the inhibitory neurotransmitter GABA. Decreased expression of the potassium-chloride co-transporter, KCC2, in the spinal cord promotes excitatory properties of GABA. We therefore measured spinal KCC2 expression and explored the role of the GABA(A) receptor in rats with painful diabetic neuropathy. KCC2 protein levels were significantly reduced in the spinal cord of diabetic rats, while levels of NKCC1 and the GABA(A) receptor were unchanged. Spinal delivery of the GABA(A) receptor antagonist bicuculline reduced formalin-evoked flinching in diabetic rats and also dose-dependently alleviated tactile allodynia. GABA(A) receptor-mediated rate-dependent depression of the spinal H reflex was absent in the spinal cord of diabetic rats. Control rats treated with the KCC2 blocker DIOA, mimicked diabetes by showing increased formalin-evoked flinching and diminished rate- dependent depression. The ability of bicuculline to alleviate allodynia and formalin-evoked hyperalgesia in diabetic rats is consistent with a reversal of the properties of GABA predicted by reduced spinal KCC2 and suggests that reduced KCC2 expression and increased GABA release contribute to spinally mediated hyperalgesia in diabetes.

  20. Coadministration of indomethacin and minocycline attenuates established paclitaxel-induced neuropathic thermal hyperalgesia: Involvement of cannabinoid CB1 receptors.

    Science.gov (United States)

    Parvathy, Subramanian S; Masocha, Willias

    2015-06-18

    Taxanes such as paclitaxel, which are chemotherapeutic drugs, cause dose-dependent painful neuropathy in some patients. We investigated whether coadministration of minocycline and indomethacin produces antinociceptive effects in mice with paclitaxel-induced neuropathic thermal hyperalgesia and if the cannabinoid system is involved. Previously, we reported that coadministration of these two drugs results in antinociception against inflammatory pain at doses where either drug alone lack significant activity. In the current study, we observed that treatment of female mice with indomethacin or minocycline alone did not affect established paclitaxel-induced thermal hyperalgesia, whereas coadministration of the two drugs attenuated it. In male mice indomethacin had some antihyperalgesic activity, whilst minocycline did not. Coadministration of the two drugs had supraadditive antihyperalgesic activity in male mice. Administration of a cannabinoid CB1 receptor antagonist AM 251 blocked the antihyperalgesic effects of the combination of minocycline and indomethacin in both male and female mice. In conclusion our results indicate that coadministration of minocycline and indomethacin abrogates established paclitaxel-induced neuropathic thermal hyperalgesia in mice, and the potentiation of the antinociceptive effects of this combination involves the cannabinoid system.

  1. Assessment of morphine-induced hyperalgesia and analgesic tolerance in mice using thermal and mechanical nociceptive modalities.

    Science.gov (United States)

    Elhabazi, Khadija; Ayachi, Safia; Ilien, Brigitte; Simonin, Frédéric

    2014-07-29

    Opioid-induced hyperalgesia and tolerance severely impact the clinical efficacy of opiates as pain relievers in animals and humans. The molecular mechanisms underlying both phenomena are not well understood and their elucidation should benefit from the study of animal models and from the design of appropriate experimental protocols. We describe here a methodological approach for inducing, recording and quantifying morphine-induced hyperalgesia as well as for evidencing analgesic tolerance, using the tail-immersion and tail pressure tests in wild-type mice. As shown in the video, the protocol is divided into five sequential steps. Handling and habituation phases allow a safe determination of the basal nociceptive response of the animals. Chronic morphine administration induces significant hyperalgesia as shown by an increase in both thermal and mechanical sensitivity, whereas the comparison of analgesia time-courses after acute or repeated morphine treatment clearly indicates the development of tolerance manifested by a decline in analgesic response amplitude. This protocol may be similarly adapted to genetically modified mice in order to evaluate the role of individual genes in the modulation of nociception and morphine analgesia. It also provides a model system to investigate the effectiveness of potential therapeutic agents to improve opiate analgesic efficacy.

  2. Cold and L-menthol-induced sensitization in healthy volunteers--a cold hypersensitivity analogue to the heat/capsaicin model.

    Science.gov (United States)

    Andersen, Hjalte H; Poulsen, Jeppe N; Uchida, Yugo; Nikbakht, Anahita; Arendt-Nielsen, Lars; Gazerani, Parisa

    2015-05-01

    Topical high-concentration L-menthol is the only established human experimental pain model to study mechanisms underlying cold hyperalgesia. We aimed at investigating the combinatorial effect of cold stimuli and topical L-menthol on cold pain and secondary mechanical hyperalgesia. Analogue to the heat-capsaicin model on skin sensitization, we proposed that cold/menthol enhances or prolong L-menthol-evoked sensitization. Topical 40% L-menthol or vehicle was applied (20 minutes) on the volar forearms of 20 healthy females and males (age, 28.7 ± 0.6 years). Cold stimulation of 5°C for 5 minutes was then applied to the treated area 3 times with 40-minute intervals. Cold detection threshold and pain, mechanical hyperalgesia (pinprick), static and dynamic mechanical allodynia (von Frey and brush), skin blood flow (laser speckle), and temperature (thermocamera) were assessed. Cold detection threshold and cold pain threshold (CPT) increased after L-menthol and remained high after the cold rekindling cycles (P menthol evoked secondary hyperalgesia to pinprick (P menthol (P menthol facilitated and prolonged L-menthol-induced cold pain and hyperalgesia. This model may prove beneficial for testing analgesic compounds when a sufficient duration of time is needed to see drug effects on CPT or mechanical hypersensitivity.

  3. Nocebo hyperalgesia: contributions of social observation and body-related cognitive styles

    Directory of Open Access Journals (Sweden)

    Vögtle E

    2016-04-01

    Full Text Available Elisabeth Vögtle,1 Birgit Kröner-Herwig,1 Antonia Barke21Department of Clinical Psychology and Psychotherapy, Georg-Elias-Müller-Institute for Psychology, University of Göttingen, Göttingen, 2Department of Psychology, Division of Clinical Psychology and Psychotherapy, Philipps University Marburg, Marburg, Germany Purpose: Recently, it has been shown that nocebo hyperalgesia can be acquired through observational learning. The aim of this study was to investigate socially induced nocebo hyperalgesia and its relationship with pain catastrophizing, somatic complaints, hypochondriacal concerns, and empathy. Participants and methods: Ninety-seven women (43.1±15.5 years were randomly assigned to one of the two conditions. Participants in the nocebo condition (NC watched a video in which a female model displayed more pain when an ointment was applied and less pain when no ointment was applied. In the control condition (CC, the model demonstrated low pain with and without the ointment. Subsequently, all participants received three pressure pain stimuli (60 seconds on each hand. On one hand, the ointment was applied prior to the stimulation. The order of the stimulation of the fingers (middle, index, or ring finger, the side of ointment application (left or right hand, and the side with which the stimulation began were randomized within each group and balanced across the groups. Depending on the randomization, the pressure pain application started with or without ointment and on the left or right hand. Pain ratings on a numerical rating scale (0–10 were collected. In addition, the participants completed questionnaires regarding body-related cognitive styles and empathy. Results: There was a significant difference in the pain ratings between the CC and the NC. The effect of ointment application was also significant, but no interaction between condition and ointment application was found. Only in the CC did the nocebo response correlate with

  4. GABAA receptor partially mediated propofol-induced hyperalgesia at superspinal level and analgesia at spinal cord level in rats

    Institute of Scientific and Technical Information of China (English)

    Qin-yun WANG; Jun-li CAO; Yin-ming ZENG; Ti-jun DAI

    2004-01-01

    AIM: To observe effects of propofol on nociceptive response at superspinal and spinal level in rats. METHODS:Two hundreds and fifty-eight Sprague-Dawley male rats were randomized into thirty-two groups. Propofol and bicuculline were microinjected into lateral ventricle (icv), ventrolateral periaqueductal gray (vlPAG), intrathecal (ith), and intraperitoneal (ip). The noxious responses were evaluated by hot plate and formalin test. RESULTS: In hot-plate test, systemic and superspinal administration of propofol (40 mg·kg-1 ip, 100μg in 10μL, icy, and 4μg in 0.4μL vlPAG microinjection) produced hyperalgesia (P<0.01). Hyperalgesia induced by vlPAG microinjection of propofol was significantly antagonized by 69.8%, 71.2%, 98.8% at 10, 20, and 30 min by microinjection of bicuculline (10 ng in 0.4μL, vlPAG) (P<0.01). Analgesia induced by ith propofol (100μg·10μL-1) was antagonized about 81.3%, 54.8%, 80.8%, and 97.4% at 10, 20, 30 and 40 min by ith bicuculline (P<0.05). In formalin test,systemic and superspinal administration of propofol (40 mg·kg-1 ip, 4μg in 0.4μL, vlPAG) also produced hyperalgesia (P<0.01). The increased formalin pain scores were antagonized about 57.1% by bicuculline (10ng, vlPAG)(P<0.05) at 60 min after formalin injection. The decreased formalin pain scores induced by ith propofol (100μg in 10μL) were antagonized about 66.7% at 30 min by ith bicuculline (P<0.05) after formalin injection. Hyperalgesia produced by ip propofol in both hot plate and formalin test could not be antagonized by vlPAG administration of bicuculline. CONCLUSION: GABAA receptor partly mediated propofol-induced hyperalgesia at superspinal and analgesia at spinal cord in rats.

  5. The degree of acute descending control of spinal nociception in an area of primary hyperalgesia is dependent on the peripheral domain of afferent input.

    Science.gov (United States)

    Drake, Robert A R; Hulse, Richard P; Lumb, Bridget M; Donaldson, Lucy F

    2014-08-15

    Descending controls of spinal nociceptive processing play a critical role in the development of inflammatory hyperalgesia. Acute peripheral nociceptor sensitization drives spinal sensitization and activates spino-supraspinal-spinal loops leading to descending inhibitory and facilitatory controls of spinal neuronal activity that further modify the extent and degree of the pain state. The afferent inputs from hairy and glabrous skin are distinct with respect to both the profile of primary afferent classes and the degree of their peripheral sensitization. It is not known whether these differences in afferent input differentially engage descending control systems to different extents or in different ways. Injection of complete Freund's adjuvant resulted in inflammation and swelling of hairy hind foot skin in rats, a transient thermal hyperalgesia lasting hyperalgesia (≥7 days). Much longer lasting thermal hyperalgesia was apparent in glabrous skin (1 h to >72 h). In hairy skin, transient hyperalgesia was associated with sensitization of withdrawal reflexes to thermal activation of either A- or C-nociceptors. The transience of the hyperalgesia was attributable to a rapidly engaged descending inhibitory noradrenergic mechanism, which affected withdrawal responses to both A- and C-nociceptor activation and this could be reversed by intrathecal administration of yohimbine (α-2-adrenoceptor antagonist). In glabrous skin, yohimbine had no effect on an equivalent thermal inflammatory hyperalgesia. We conclude that acute inflammation and peripheral nociceptor sensitization in hind foot hairy skin, but not glabrous skin, rapidly activates a descending inhibitory noradrenergic system. This may result from differences in the engagement of descending control systems following sensitization of different primary afferent classes that innervate glabrous and hairy skin.

  6. An investigation of the antinociceptive effects of Riluzole in hyperalgesia models of mice

    Institute of Scientific and Technical Information of China (English)

    Xiaoping Xia; Zhenliang Ma; Yinming Zeng

    2006-01-01

    Objective: To investigate the antinociceptive effects of Riluzole administered intraperitoneally in three hyperalgesia model of mice. Methods: Antinociceptive tests in C57BL mice were investigated with formalin test、acetic acid induced writhing test and tail-immersion test. The effects of intraperitoneally Riluzole 2 mg/kg、4 mg/kg and 8 mg/kg on the pain threshold were observed. Result: We found that i.p. treatment with Riluzole (4 mg/kg and 8 mg/kg) blocked the second phase flinching behavior compared with vehicle (P < 0.05), but not during the first phase in the formalin test. In addition to the formalin test, Riluzole at different dose (from 2 to 8 mg/kg) attenuated acetic acid induced writhing response when compared to vehicle group (P < 0.05). In the tail-immersion test, Riluzole at the highest dose (8 mg/kg) caused significant increase in tail flick response latency as compared to vehicle animals or compared with Baseline (P < 0.05). Conclusion: Our results suggest that glutamate release inhibitor Riluzole can attenuate nociceptive behavior and has differrent antinociceptive characteristic according to the various pain models.

  7. Role of kinin B2 receptors in opioid-induced hyperalgesia in inflammatory pain in mice.

    Science.gov (United States)

    Grastilleur, Sébastien; Mouledous, Lionel; Bedel, Jerome; Etcheverry, Jonathan; Bader, Michael; Girolami, Jean-Pierre; Fourcade, Olivier; Frances, Bernard; Minville, Vincent

    2013-03-01

    Postoperative pain management is a clinical challenge that can be complicated by opioid-induced hyperalgesia (OIH). Kinin receptors could mediate both the acute and chronic phases of inflammation and pain. A few recent studies suggest that dynorphin A could maintain neuropathic pain by activating the bradykinin (BK) receptor. Thus, the effect of a single administration of sufentanil (a μ-opioid receptor agonist) was investigated in a model of carrageenan-induced inflammatory pain using three strains of mice, i.e., knockout mice for one kinin receptor, B1R or B2R (B1KO, B2KO), and wild-type C57/BL6J mice (WT) treated with either a B1R (R954) or a B2R antagonist (HOE140) or a KKS inhibitor (aprotinin). Pain was assessed and compared between the different groups using two behavioral tests exploring mechanical (von Frey filaments) and thermal (Hargreaves test) sensitivity. Pretreatment with sufentanil induced a sustained increase in pain sensitivity with a delayed return to baseline values characterizing an OIH in carrageenan-injected mice only. Sufentanil-induced OIH was not observed in B2KO but persisted in B1KO and was blunted by aprotinin and the B2R antagonist only. Collectively, our data indicate that the B2R receptor and BK synthesis or availability are essential peripheral steps in the mechanism leading to OIH in a pain context.

  8. Mesenchymal Stem Cells Reversed Morphine Tolerance and Opioid-induced Hyperalgesia.

    Science.gov (United States)

    Hua, Zhen; Liu, LiPing; Shen, Jun; Cheng, Katherine; Liu, Aijun; Yang, Jing; Wang, Lina; Qu, Tingyu; Yang, HongNa; Li, Yan; Wu, Haiyan; Narouze, John; Yin, Yan; Cheng, Jianguo

    2016-08-24

    More than 240 million opioid prescriptions are dispensed annually to treat pain in the US. The use of opioids is commonly associated with opioid tolerance (OT) and opioid-induced hyperalgesia (OIH), which limit efficacy and compromise safety. The dearth of effective way to prevent or treat OT and OIH is a major medical challenge. We hypothesized that mesenchymal stem cells (MSCs) attenuate OT and OIH in rats and mice based on the understanding that MSCs possess remarkable anti-inflammatory properties and that both OT and chronic pain are associated with neuroinflammation in the spinal cord. We found that the development of OT and OIH was effectively prevented by either intravenous or intrathecal MSC transplantation (MSC-TP), which was performed before morphine treatment. Remarkably, established OT and OIH were significantly reversed by either intravenous or intrathecal MSCs when cells were transplanted after repeated morphine injections. The animals did not show any abnormality in vital organs or functions. Immunohistochemistry revealed that the treatments significantly reduced activation level of microglia and astrocytes in the spinal cord. We have thus demonstrated that MSC-TP promises to be a potentially safe and effective way to prevent and reverse two of the major problems of opioid therapy.

  9. Auraptenol attenuates vincristine-induced mechanical hyperalgesia through serotonin 5-HT1A receptors.

    Science.gov (United States)

    Wang, Yunfei; Cao, Shu-e; Tian, Jianmin; Liu, Guozhe; Zhang, Xiaoran; Li, Pingfa

    2013-11-29

    Common chemotherapeutic agents such as vincristine often cause neuropathic pain during cancer treatment in patients. Such neuropathic pain is refractory to common analgesics and represents a challenging clinical issue. Angelicae dahuricae radix is an old traditional Chinese medicine with demonstrated analgesic efficacy in humans. However, the active component(s) that attribute to the analgesic action have not been identified. This work described the anti-hyperalgesic effect of one coumarin component, auraptenol, in a mouse model of chemotherapeutic agent vincristine-induced neuropathic pain. We reported that auraptenol dose-dependently reverted the mechanical hyperalgesia in mice within the dose range of 0.05-0.8 mg/kg. In addition, the anti-hyperalgesic effect of auraptenol was significantly blocked by a selective serotonin 5-HT1A receptor antagonist WAY100635 (1 mg/kg). Within the dose range studied, auraptenol did not significantly alter the general locomotor activity in mice. Taken together, this study for the first time identified an active component from the herbal medicine angelicae dahuricae radix that possesses robust analgesic efficacy in mice. These data support further studies to assess the potential of auraptenol as a novel analgesic for the management of neuropathic pain.

  10. Fucoidan attenuates the existing allodynia and hyperalgesia in a rat model of neuropathic pain.

    Science.gov (United States)

    Hu, Chuanyin; Zhang, Guoping; Zhao, Yun-Tao

    2014-06-13

    Fucoidan is an active constituent found in brown seaweeds, which have potential neuroprotection. The current study aimed to investigate the effects of fucoidan on the maintenance of neuropathic pain induced by L5 spinal nerve ligation (SNL) and the underlying mechanism related to the spinal neuroimmune responses. Animals were randomized into 5 groups: sham-operation with vehicle and SNL with vehicle or fucoidan (15, 50, and 100mg/kg). Different doses of fucoidan or vehicle were administered intrathecally once daily from postoperative day (POD) 11-20. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) was measured on 1 day before operation and days 10, 20, 22, 24, 26, 28, 30 after operation. Glial activation markers such as glial fibrillary acidic protein (GFAP) and macrophage antigen complex-1 (mac-1), inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 activation, and extracellular signalregulated protein kinase (ERK) activation in the lumbar spinal cord were determined on day 30 after operation. The results showed that fucoidan caused dose-dependently attenuation of mechanical allodynia and thermal hyperalgesia. Furthermore, fucoidan could markedly inhibit neuroimmune activation characterized by glial activation, production of cytokines as well as ERK activation. The analgesic effect of intrathecal fucoidan in rats receiving SNL might partly attribute to the inhibition of neuroimmune activation associated with the maintenance of neuropathic pain.

  11. Cisplatin induces drug resistance in human esophageal squamous carcinoma cells by reducing CTR1 expression%顺铂降低铜离子转运蛋白1表达诱导人食管鳞癌细胞耐药

    Institute of Scientific and Technical Information of China (English)

    余乐; 陈明辉; 古春萍; 李亦蕾; 曹之宪; 刘叔文

    2011-01-01

    目的 诱导对顺铂耐药的人食管鳞癌细胞株,并进一步研究细胞耐药性产生的机制.方法 逐渐增加顺铂浓度处理人食管鳞癌细胞HKESC-1,诱导顺铂耐药细胞株HKESC-1/cis.MTT法观察顺铂的细胞毒作用以及细胞的生长曲线.电感耦合等离子体质谱检测细胞内顺铂的蓄积和Pt-DNA加合物的形成.Western blot检测铜离子转运蛋白(copper transporter 1,CTR1)的表达.结果 顺铂耐药细胞株HKESC-1/cis较其亲代细胞HKESC-1对顺铂引起的细胞毒作用敏感性下降,耐药指数为2.9.顺铂耐药细胞株HKESC-1/cis与其亲代细胞HKESC-1的生长速度相似.然而,HKESC-1/cis细胞内顺铂蓄积和Pt-DNA加合物的形成较HKESC-1细胞减少,并且CTR1蛋白表达水平降低.结论 顺铂通过降低细胞膜CTR1蛋白的表达,抑制顺铂进入细胞,导致细胞耐药性的产生.%Aim To induce cisplatin-resistant esophageal squamous carcinoma cell line and investigate the mechanisms by which the cancer cells develop drug resistance. Methods The cisplatin-resistant subline.designated HKESC-1/cis , was originated by growing parental HKESC-1 cells with gradually increasing doses of cisplatin. The cytotoxicity of cisplatin and cell growth curves were determined by MTT assay. Whole-cell cisplatin accumulation and Pt-DNA adduct formation were measured by Inductively Coupled Plasma Mass Spectrometry ( ICP-MS ). Western blot was used to investigate the protein expression of copper transporter 1 ( CTRI ). Results HKESC-1/cis was 2.9 times more resistant to cisplatin-induced cytotoxicity in comparison with its parental cell line HKESC-1. There was no significant difference in growth curves between HKESC-1/cis and HKESC-1. However, compared with HKESC-1 cells, HKESC-1/cis cells exhibited less cisplatin accumulation and Pt-DNA adduct formation, accompanied by decreased CTRI protein expression. Conclusion Cisplatin induces drug resistant phenotype by decreasing protein level of CTR1

  12. Caspase Activation of p21-Activated Kinase 2 Occurs During Cisplatin-Induced Apoptosis of SH-SY5Y Neuroblastoma Cells and in SH-SY5Y Cell Culture Models of Alzheimer’s and Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Jerry W. Marlin

    2010-04-01

    Full Text Available p21-activated kinase 2 (PAK-2 appears to have a dual function in the regulation of cell survival and cell death. Activation of full-length PAK-2 by the p21 G-proteins Rac or Cdc42 stimulates cell survival. However, PAK-2 is unique among the PAK family because it is also activated through proteolytic cleavage by caspase 3 or similar caspases to generate the constitutively active PAK-2p34 fragment. Caspase activation of PAK-2 correlates with the induction of apoptosis in response to many stimuli and recombinant expression of PAK-2p34 has been shown to stimulate apoptosis in several human cell lines. Here, we show that caspase activation of PAK-2 also occurs during cisplatin-induced apoptosis of SH-SY5Y neuroblastoma cells as well as in SH-SY5Y cell culture models for Alzheimer’s and Parkinson’s disease. Inhibition of mitochondrial complex I or of ubiquitin/proteasome-mediated protein degradation, which both appear to be involved in Parkinson’s disease, induce apoptosis and caspase activation of PAK-2 in SH-SY5Y cells. Overexpression of the amyloid precursor protein, which results in accumulation and aggregation of β-amyloid peptide, the main component of β-amyloid plaques in Alzheimer’s disease, also induces apoptosis and caspase activation of PAK-2 in SH-SY5Y cells. Expression of the PAK-2 regulatory domain inhibits caspase-activated PAK-2p34 and prevents apoptosis in 293T human embryonic kidney cells, indicating that caspase activation of PAK-2 is directly involved in the apoptotic response. This is the first evidence