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Sample records for 6-ohda rat model

  1. Protective effects of neurotrophic factor-secreting cells in a 6-OHDA rat model of Parkinson disease.

    Science.gov (United States)

    Sadan, Ofer; Bahat-Stromza, Merav; Barhum, Yael; Levy, Yossef S; Pisnevsky, Anat; Peretz, Hagit; Ilan, Avihay Bar; Bulvik, Shlomo; Shemesh, Noam; Krepel, Dana; Cohen, Yoram; Melamed, Eldad; Offen, Daniel

    2009-10-01

    Stem cell-based therapy is a promising treatment for neurodegenerative diseases. In our laboratory, a novel protocol has been developed to induce bone marrow-derived mesenchymal stem cells (MSC) into neurotrophic factors- secreting cells (NTF-SC), thus combining stem cell-based therapy with the NTF-based neuroprotection. These cells produce and secrete factors such as brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor. Conditioned medium of the NTF-SC that was applied to a neuroblastoma cell line (SH-SY5Y) 1 h before exposure to the neurotoxin 6-hydroxydopamine (6-OHDA) demonstrated marked protection. An efficacy study was conducted on the 6-OHDA-induced lesion, a rat model of Parkinson's disease. The cells, either MSC or NTF-SC, were transplanted on the day of 6-OHDA administration and amphetamine-induced rotations were measured as a primary behavior index. We demonstrated that when transplanted posterior to the 6-OHDA lesion, the NTF-SC ameliorated amphetamine-induced rotations by 45%. HPLC analysis demonstrated that 6-OHDA induced dopamine depletion to a level of 21% compared to the untreated striatum. NTF-SC inhibited dopamine depletion to a level of 72% of the contralateral striatum. Moreover, an MRI study conducted with iron-labeled cells, followed by histological verification, revealed that the engrafted cells migrated toward the lesion. In a histological assessment, we found that the cells induced regeneration in the damaged striatal dopaminergic nerve terminal network. We therefore conclude that the induced MSC have a therapeutic potential for neurodegenerative processes and diseases, both by the NTFs secretion and by the migratory trait toward the diseased tissue.

  2. A Novel Immunosuppressor, (5R)-5-Hydroxytriptolide, Alleviates Movement Disorder and Neuroinflammation in a 6-OHDA Hemiparkinsonian Rat Model.

    Science.gov (United States)

    Su, Ruijun; Sun, Min; Wang, Wei; Zhang, Jianliang; Zhang, Li; Zhen, Junli; Qian, Yanjing; Zheng, Yan; Wang, Xiaomin

    2017-02-01

    Parkinson's disease (PD) is one of the most common age-related neurodegenerative diseases. Promising therapies for PD still need to be explored. Immune dysfunction has been found to be involved in PD pathogenesis. Here, a novel immunosuppressor, (5R)-5-hydroxytriptolide (LLDT8), was used to treat 6-hydroxydopamine (6-OHDA)-induced hemiparkinson rats. We found that oral administration of LLDT8 significantly alleviated apomorphine-induced rotations at a dose of 125 µg/kg, and improved performance in cylinder and rotarod tests at a lower dose of 31.25 µg/kg, in 6-OHDA hemiparkinsonian rats. Moreover, loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the 6-OHDA rat was attenuated in response to LLDT8 treatment in a dose-dependent manner. In addition, inflammatory factors IL-1β, IL-6 and TNF-α, were significantly inhibited in LLDT8-treated hemiparkisonian rats, compared with vehicle. Notably, the level of dopamine (DA) in the striatum of PD rats was restored by LLDT8 treatment. Furthermore, we also detected that the disequilibrium of peripheral lymphocytes was reversed by LLDT8 administration. Taken together, the results imply that the immunosuppressor, LLDT8, can rescue dopaminergic neurodegeneration in 6-OHDA hemiparkinsonian rats, thus providing a potential therapeutic strategy for PD.

  3. Antioxidant effect of Spirulina (Arthrospira) maxima in a neurotoxic model caused by 6-OHDA in the rat striatum.

    Science.gov (United States)

    Tobón-Velasco, J C; Palafox-Sánchez, Victoria; Mendieta, Liliana; García, E; Santamaría, A; Chamorro-Cevallos, G; Limón, I Daniel

    2013-08-01

    There is evidence to support that an impaired energy metabolism and the excessive generation of reactive oxygen species (ROS) contribute to brain injury in neurodegenerative disorders such as Parkinson's disease (PD), whereas diets enriched in foods with an antioxidant action may modulate its progression. Several studies have proved that the antioxidant components produced by Spirulina, a microscopic blue-green alga, might prevent cell death by decreasing free radicals, inhibiting lipoperoxidation and upregulating the antioxidant enzyme systems. In our study, we investigated the protective effect of the Spirulina maxima (S. maxima) against the 6-OHDA-caused toxicity in the rat striatum. The S. maxima (700 mg/kg/day, vo) was administered for 40 days before and 20 days after a single injection of 6-OHDA (16 μg/2 μL) into the dorsal striatum. At 20-day postsurgery, the brain was removed and the striatum was obtained to evaluate the indicators of toxicity, such as nitric oxide levels, ROS formation, lipoperoxidation, and mitochondrial activity. These variables were found significantly stimulated in 6-OHDA-treated rats and were accompanied by declines in dopamine levels and motor activity. In contrast, the animals that received the chronic treatment with S. maxima had a restored locomotor activity, which is associated with the decreased levels of nitric oxide, ROS, and lipoperoxidation in the striatum, although mitochondrial functions and dopamine levels remained preserved. These findings suggest that supplementation with antioxidant phytochemicals (such as contained in S. maxima) represents an effective neuroprotective strategy against 6-OHDA-caused neurotoxicity vía free radical production to preserve striatal dopaminergic neurotransmission in vivo.

  4. Neuroprotective Potential of Superparamagnetic Iron Oxide Nanoparticles Along with Exposure to Electromagnetic Field in 6-OHDA Rat Model of Parkinson's Disease.

    Science.gov (United States)

    Umarao, Preeti; Bose, Samrat; Bhattacharyya, Supti; Kumar, Anil; Jain, Suman

    2016-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting mainly the dopaminergic neurons of the substantia nigra leading to various motor and non-motor deficits. We explored the neuroprotective potential of superparamagnetic iron oxide nanoparticles (IONPs) along with exposure to EMF in 6-OHDA rat model of PD. IONPs were implanted at the site of lesion and 24 h thereafter the rats were exposed to magnetic fields 2 h/day for one week. Bilateral lesions of the striatum were made with 6-OHDA. The rats in all the intervention groups improved progressively over the days and by post-surgery day 4 they were active and bright. We observed a significant beneficial effect of the IONPs implantation and MF exposure on feeding behavior, gait and postural stability. There was a significant enhancement of mitochondrial function and attenuation of lesion volume in all the intervention groups as compared to PD. The results demonstrate neuroprotective effect of iron oxide nanoparticle implantation and magnetic field exposure in an in vivo 6-OHDA rat model of PD.

  5. Neurodegenerative Shielding by Curcumin and Its Derivatives on Brain Lesions Induced by 6-OHDA Model of Parkinson's Disease in Albino Wistar Rats

    Directory of Open Access Journals (Sweden)

    Shyam Sunder Agrawal

    2012-01-01

    Full Text Available Study was undertaken to evaluate the neurodegenerative defending potential of curcumin (CUR, demethoxycurcumin (DMC, and bisdemethoxycurcumin (BDMC on 6-hydroxydopamine-(6-OHDA induced Parkinsonism model in rats. Curcuminoids were administered (60 mg/kg, body weight, per oral for three weeks followed by unilateral injection of 6-OHDA on 22nd day (10 μg/2 μL into the right striatum leading to extensive loss of dopaminergic cells. The behavioral observations, biochemical markers, quantification of dopamine (DA, DOPAC, and HVA followed by dopamine (D2 receptor binding assay and tyrosine hydroxylase (TH, using immunohistochemistry were evaluated using HPLC after three weeks of lesion. Pretreated animals showed significant protection against neuronal degeneration compared to lesion animals by normalizing the deranged levels of biomarkers and showed the potency in the order CUR > DMC > BDMC. The same order of effectiveness was observed in D2 receptors binding assay and TH immunohistochemistry study. We conclude that curcuminoids appear to shield progressive neuronal degeneration from increased oxidative attack in 6-OHDA-lesioned rats through its free radical scavenging mechanism, and DA, DOPAC, and HVA enhancing capabilities in the sequence of efficacy CUR > DMC > BDMC. Further, curcuminoids may have potential utility in treatment of many more oxidative stress-induced neurodegenerative disorders.

  6. Behavioral and Neurochemical Effects of Alpha-Lipoic Acid in the Model of Parkinson's Disease Induced by Unilateral Stereotaxic Injection of 6-Ohda in Rat

    Science.gov (United States)

    de Araújo, Dayane Pessoa; De Sousa, Caren Nádia Soares; Araújo, Paulo Victor Pontes; Menezes, Carlos Eduardo de Souza; Sousa Rodrigues, Francisca Taciana; Escudeiro, Sarah Souza; Lima, Nicole Brito Cortez; Patrocínio, Manoel Claúdio Azevedo; Aguiar, Lissiana Magna Vasconcelos; Viana, Glauce Socorro de Barros; Vasconcelos, Silvânia Maria Mendes

    2013-01-01

    This study aimed to investigate behavioral and neurochemical effects of α-lipoic acid (100 mg/kg or 200 mg/kg) alone or associated with L-DOPA using an animal model of Parkinson's disease induced by stereotaxic injection of 6-hydroxydopamine (6-OHDA) in rat striatum. Motor behavior was assessed by monitoring body rotations induced by apomorphine, open field test and cylinder test. Oxidative stress was accessed by determination of lipid peroxidation using the TBARS method, concentration of nitrite and evaluation of catalase activity. α-Lipoic acid decreased body rotations induced by apomorphine, as well as caused an improvement in motor performance by increasing locomotor activity in the open field test and use of contralateral paw (in the opposite side of the lesion produced by 6-OHDA) at cylinder test. α-lipoic acid showed antioxidant effects, decreasing lipid peroxidation and nitrite levels and interacting with antioxidant system by decreasing of endogenous catalase activity. Therefore, α-lipoic acid prevented the damage induced by 6-OHDA or by chronic use of L-DOPA in dopaminergic neurons, suggesting that α-lipoic could be a new therapeutic target for Parkinson's disease prevention and treatment. PMID:24023579

  7. Anti-dyskinetic mechanisms of amantadine and dextromethorphan in the 6-OHDA rat model of Parkinson’s disease: role of NMDA vs. 5-HT1A receptors

    Science.gov (United States)

    Paquette, Melanie A.; Martinez, Alex A.; Macheda, Teresa; Meshul, Charles K.; Johnson, Steven W.; Berger, S. Paul; Giuffrida, Andrea

    2013-01-01

    Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia (LID) in patients with Parkinson’s disease (PD) and abnormal involuntary movements (AIMs) in the unilateral 6-hydroxydopamine (6-OHDA) rat model. These effects have been attributed to N-methyl-d-aspartate (NMDA) antagonism. However, amantadine and dextromethorphan are also thought to block serotonin (5-HT) uptake and cause 5-HT overflow, leading to stimulation of 5-HT1A receptors, which has been shown to reduce LID. We undertook a study in 6-OHDA rats to determine whether the anti-dyskinetic effects of these two compounds are mediated by NMDA antagonism and/or 5-HT1A agonism. In addition, we assessed the sensorimotor effects of these drugs using the Vibrissae-Stimulated Forelimb Placement and Cylinder tests. Our data show that the AIM-suppressing effect of amantadine was not affected by the 5-HT1A antagonist WAY-100635, but was partially reversed by the NMDA agonist d-cycloserine. Conversely, the AIM-suppressing effect of dextromethorphan was prevented by WAY-100635 but not by d-cycloserine. Neither amantadine nor dextromethorphan affected the therapeutic effects of L-DOPA in sensorimotor tests. We conclude that the anti-dyskinetic effect of amantadine is partially dependent on NMDA antagonism, while dextromethorphan suppresses AIMs via indirect 5-HT1A agonism. Combined with previous work from our group, our results support the investigation of 5-HT1A agonists as pharmacotherapies for LID in PD patients. PMID:22861201

  8. Unprecedented therapeutic potential with a combination of A2A/NR2B receptor antagonists as observed in the 6-OHDA lesioned rat model of Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Anne Michel

    Full Text Available In Parkinson's disease, the long-term use of dopamine replacing agents is associated with the development of motor complications; therefore, there is a need for non-dopaminergic drugs. This study evaluated the potential therapeutic impact of six different NR2B and A2A receptor antagonists given either alone or in combination in unilateral 6-OHDA-lesioned rats without (monotherapy or with (add-on therapy the co-administration of L-Dopa: Sch-58261+ Merck 22; Sch-58261+Co-101244; Preladenant + Merck 22; Preladenant + Radiprodil; Tozadenant + Radiprodil; Istradefylline + Co-101244. Animals given monotherapy were assessed on distance traveled and rearing, whereas those given add-on therapy were assessed on contralateral rotations. Three-way mixed ANOVA were conducted to assess the main effect of each drug separately and to determine whether any interaction between two drugs was additive or synergistic. Additional post hoc analyses were conducted to compare the effect of the combination with the effect of the drugs alone. Motor activity improved significantly and was sustained for longer when the drugs were given in combination than when administered separately at the same dose. Similarly, when tested as add-on treatment to L-Dopa, the combinations resulted in higher levels of contralateral rotation in comparison to the single drugs. Of special interest, the activity observed with some combinations could not be described by a simplistic additive effect and involved more subtle synergistic pharmacological interactions. The combined administration of A2A/NR2B-receptor antagonists improved motor behaviour in 6-OHDA rats. Given the proven translatability of this model such a combination may be expected to be effective in improving motor symptoms in patients.

  9. Treadmill Exercise Prevents Increase of Neuroinflammation Markers Involved in the Dopaminergic Damage of the 6-OHDA Parkinson's Disease Model.

    Science.gov (United States)

    Real, Caroline Cristiano; Garcia, Priscila Crespo; Britto, Luiz R G

    2017-08-11

    Parkinson's disease (PD) involves loss of dopaminergic neurons in the substantia nigra (SN), which can be correlated to neuroinflammatory changes with the aging of the nervous system. On the other hand, exercise can reduce the deleterious effects promoted by age, but the mechanism involved is still unclear. This study investigated the preventive exercise-induced changes on neuroinflammatory processes in a rat model of PD induced by unilateral striatal injections of 6-hydroxydopamine (6-OHDA). Adult male Wistar rats were divided into two groups: (1) sedentary (SED) or (2) exercised (EX), animals that did treadmill exercise three times per week, every other day, for 4 weeks prior to 6-OHDA or saline injection. The rats were then divided into four sub-groups: (1) sedentary saline (SED), (2) sedentary 6-OHDA (SED + 6-OHDA), (3) exercised saline (EX), and (4) exercised 6-OHDA (EX + 6-OHDA). Seven and 30 days after surgery, brains were collected for immunohistochemistry and immunoblotting for dopaminergic and neuroinflammatory markers into SN and striatum. The SED + 6-OHDA animals presented an increase in the astrocyte, microglial, and oxidative species activation. On the other hand, EX + 6-OHDA animals did not present neuroinflammatory responses and performed better apormorphine test. Our data suggest that treadmill exercise throughout life can markedly reduce the chances of dopamine decrease, reinforcing studies that showed a lower incidence of Parkinson's disease in patients who were active during life.

  10. 6-羟基多巴胺致帕金森病大鼠模型的建立与评价%The Establishment and Evaluation of Rats Model of the Parkinson's Disease Cased by 6-OHDA

    Institute of Scientific and Technical Information of China (English)

    李泽鸿; 陶英楠; 刘继阳; 张帆

    2012-01-01

    应用6-羟基多巴胺(6-hydroxydopamine,6-OHDA)制造帕金森病(Parkinson,s disease,PD)大鼠模型,建模成功后采用组织化学方法检测模型黑质多巴胺能神经元变化,并从行为学及黑质多巴胺能神经元数目的变化对模型进行综合评价.取Wistar大鼠,采用立体定向法,进行右侧纹状体区6-OHDA双点注射.结果表明,6-OHDA纹状体注射可成功的诱导帕金森大鼠模型.%Appplicate the 6-hydroxydopanine (6-OHDA) to manufacture the rat's model of Parkinson's disease (PD), through the organizations of chemical method could dectect and evaluate the model comprehensivly from the changes of the behaviour and the number changes of dopaminergic neurons of nigra after the model succeed. Fetch Wistar rat by using stereotac-tic method, and then inject right striatum 6-OHDA into two-point. This study showed that 6-OHDA injection striatum could induce the rat model of Parkinson's sucessfully.

  11. Antagonism of quercetin against tremor induced by unilateral striatal lesion of 6-OHDA in rats.

    Science.gov (United States)

    Mu, Xin; Yuan, Xia; Du, Li-Da; He, Guo-Rong; Du, Guan-Hua

    2016-01-01

    Quercetin, a flavonoid present in many plants, is reported to be effective in models of neurodegenerative diseases. The aim of the present study was to evaluate the anti-tremor effects of quercetin in 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease. In rats, quercetin had no effect on apomorphine-induced rotations, but it could significantly attenuate muscle tremor of 6-OHDA lesioned rats. Interestingly, quercetin could decrease the burst frequency in a dose- and time-dependent manner. These results suggest that quercetin may have a protective effect on models to mimic muscle tremors of Parkinson's disease. This effect of quercetin may be associated with serotonergic system, but further study is needed.

  12. Neuroprotective effect of Spirulina fusiform and amantadine in the 6-OHDA induced Parkinsonism in rats

    OpenAIRE

    Chattopadhyaya, I; Gupta, Sumeet; Mohammed, Asad; Mushtaq, N; Chauhan, S.; Ghosh, Saikant

    2015-01-01

    Background Multi-factorial etiology exists in pathophysiology of neurodegenerative diseases. The imbalance of anti-oxidant enzymes and dopamine level leads to Parkinsonism. The objective of this study was to assess the protective effect of Spirulina fusiform alone and in combination with amantadine against Parkinsonism effect in 6-hydroxydopamine (6-OHDA) induced rat model. Methods S. fusiform was administered in different groups (500 mg/kg, once daily and twice daily) and a combination of sp...

  13. Bilobalide inhibits 6-OHDA-induced activation of NF-κB and loss of dopaminergic neurons in rat substantia nigra

    Institute of Scientific and Technical Information of China (English)

    Ling-yun LI; Xi-lin ZHAO; Xi-feng FEI; Zhen-lun GU; Zheng-hong QIN; Zhong-qin LIANG

    2008-01-01

    Aim: To investigate the offect of bilobalide on the activation of NF-κB, and apoptasis of dopaminergic neurons induced by 6-hydroxydopamine (6-OHDA). Methods: A rat model of Parkinson's disease was produced with a unilateral infu-sion of 6-OHDA (8 μg) into the substantia nigra par compact. Bilobalide was administered 5, 10, and 20 mg/kg (ip) once a day for 7 d, starting 6 d prior to the 6-OHDA infusion. The rats were subjected to locomotor activity and rotational behavior testing 2 or 3 weeks after the 6-OHDA infusion. The expressions of tyrosine hydroxylase (TH) and NF-κB p65 were examined by immunofluorescence. The loss of dopaminergic neurons was detected by Nissl's staining. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling was used to iden-tify apoptosis. ResUltS; Tho behavioral changes due to 6-OHDA were signifi-cantly restored by bilobalide pretreatment. Bilobalide inhibited the 6-OHDA-induced loss of TH-positive neurons, decreased the activation of NF-κB, and protected dopaminergic neurons from apoptosis remarkably. Conclusion: NF-κB activation contributes to the 6-OHDA-induced loss of dopaminergic neurons, and the inhibition of the NF-κB pathway is likely to be involved in the neuroprotective effect of bilobalide.

  14. Protective Effect of GSH on PD Model Induced by 6-OHDA In Vitro

    Institute of Scientific and Technical Information of China (English)

    徐岩; 孙圣刚; 曹学兵; 童萼塘

    2002-01-01

    Summary: To study the effects of 6-hydroxydopamine (6-OHDA) and reduced glutathione (GSH)on the nigral dopaminergic neurons in brain slices in vitro, immolunohistochemical technique wasused to observe the changes of TH-stained neurons, including cell bodies and the dendrites, in thesubstantia nigra (SN) of midbrain slices of rats after incubation for 1 h in the presence of GSH 15min before and during the period of incubation with 6-OHDA. The results showed that cell bodiesremained intact but dendrites were fragmented and truncated after treatment with 6-OHDA. Theantioxidant GSH alone did not significantly affect the dendrites of SN neurons but prevented 6-O-HDA-induced damage of dendrites. It was concluded that glutathione may prevent 6-OHDA-in-duced dopaminergic neurodegeneration and play a protective role in dopaminergic neurons.

  15. Decreased synaptic plasticity in the medial prefrontal cortex underlies short-term memory deficits in 6-OHDA-lesioned rats.

    Science.gov (United States)

    Matheus, Filipe C; Rial, Daniel; Real, Joana I; Lemos, Cristina; Ben, Juliana; Guaita, Gisele O; Pita, Inês R; Sequeira, Ana C; Pereira, Frederico C; Walz, Roger; Takahashi, Reinaldo N; Bertoglio, Leandro J; Da Cunha, Cláudio; Cunha, Rodrigo A; Prediger, Rui D

    2016-03-15

    Parkinson's disease (PD) is characterized by motor dysfunction associated with dopaminergic degeneration in the dorsolateral striatum (DLS). However, motor symptoms in PD are often preceded by short-term memory deficits, which have been argued to involve deregulation of medial prefrontal cortex (mPFC). We now used a 6-hydroxydopamine (6-OHDA) rat PD model to explore if alterations of synaptic plasticity in DLS and mPFC underlie short-term memory impairments in PD prodrome. The bilateral injection of 6-OHDA (20μg/hemisphere) in the DLS caused a marked loss of dopaminergic neurons in the substantia nigra (>80%) and decreased monoamine levels in the striatum and PFC, accompanied by motor deficits evaluated after 21 days in the open field and accelerated rotarod. A lower dose of 6-OHDA (10μg/hemisphere) only induced a partial degeneration (about 60%) of dopaminergic neurons in the substantia nigra with no gross motor impairments, thus mimicking an early premotor stage of PD. Notably, 6-OHDA (10μg)-lesioned rats displayed decreased monoamine levels in the PFC as well as short-term memory deficits evaluated in the novel object discrimination and in the modified Y-maze tasks; this was accompanied by a selective decrease in the amplitude of long-term potentiation in the mPFC, but not in DLS, without changes of synaptic transmission in either brain regions. These results indicate that the short-term memory dysfunction predating the motor alterations in the 6-OHDA model of PD is associated with selective changes of information processing in PFC circuits, typified by persistent changes of synaptic plasticity.

  16. Targeted inhibition of RAGE in substantia nigra of rats blocks 6-OHDA-induced dopaminergic denervation.

    Science.gov (United States)

    Gasparotto, Juciano; Ribeiro, Camila Tiefensee; Bortolin, Rafael Calixto; Somensi, Nauana; Rabelo, Thallita Kelly; Kunzler, Alice; Souza, Natália Cabral; Pasquali, Matheus Augusto de Bittencourt; Moreira, José Claudio Fonseca; Gelain, Daniel Pens

    2017-08-18

    The receptor for advanced glycation endproducts (RAGE) is a pattern-recognition receptor associated with inflammation in most cell types. RAGE up-regulates the expression of proinflammatory mediators and its own expression via activation of NF-kB. Recent works have proposed a role for RAGE in Parkinson's disease (PD). In this study, we used the multimodal blocker of RAGE FPS-ZM1, which has become available recently, to selectively inhibit RAGE in the substantia nigra (SN) of rats intracranially injected with 6-hydroxydopamine (6-OHDA). FPS-ZM1 (40 μg per rat), injected concomitantly with 6-OHDA (10 μg per rat) into the SN, inhibited the increase in RAGE, activation of ERK1/2, Src and nuclear translocation of NF-kB p65 subunit in the SN. RAGE inhibition blocked glial fibrillary acidic protein and Iba-1 upregulation as well as associated astrocyte and microglia activation. Circulating cytokines in serum and CSF were also decreased by FPS-ZM1 injection. The loss of tyrosine hydroxylase and NeuN-positive neurons was significantly inhibited by RAGE blocking. Finally, FPS-ZM1 attenuated locomotory and exploratory deficits induced by 6-OHDA. Our results demonstrate that RAGE is an essential component in the neuroinflammation and dopaminergic denervation induced by 6-OHDA in the SN. Selective inhibition of RAGE may offer perspectives for therapeutic approaches.

  17. 黑质致密部和内侧前脑束注射6-OHDA 制备的帕金森病大鼠模型纹状体中 DA 含量比较%Effects of 6-OHDA-lesioned Parkinson’s disease rat model in substantia nigra compacta and medial forebrain bundle on DA level in the striatum

    Institute of Scientific and Technical Information of China (English)

    韩玲娜; 常永丽; 郭晓姝; 张翠英

    2016-01-01

    Objective:To study the effects of substantia nigra compacta (SNc)lesioned and medial forebrain bundle (MFB)lesion Parkinson’s disease(PD)rat models by 6-hydroxydopamine (6-OHDA)on the dopamine (DA)level in the striatum.Methods:Rats were randomly divided into sham-operated (n = 12),SNc-lesioned(n = 1 5 )and MFB-lesioned (n =14)groups.Changes of the DA level in the striatum were observed by the high performance liquid chromatography with elec-trochemical detection in 3 groups rats.Results:Compared to sham-operated rats,the DA levels of the SNc-lesioned and MFB-lesioned rats decreased significantly.And compared to the SNc-lesioned rats,the degree of DA levels in the MFB-lesioned rats docreased more serious (P =0.005).Conclusion:The lesioned range of DA neurons of MFB-lesioned PD rat model is wider than that of SNc-lesion,which provides a theory basis for the choice of modeling methods in different researches.%目的::比较黑质致密部(SNc)损毁和内侧前脑束(MFB)损毁2种方法制备的帕金森病(PD)大鼠模型对纹状体中多巴胺(DA)递质含量的影响。方法:将大鼠随机分为假手术组(n=12)、SNc 损毁组(n=15)和 MFB 损毁组(n=14)。采用高效液相色谱-电化学检测法,观察3组大鼠损毁侧纹状体中 DA的含量。结果:与假手术组相比较,SNc 损毁组(P <0.001)和 MFB 损毁组(P <0.001)大鼠纹状体中 DA含量均显著降低,与 SNc 损毁组相比较,MFB 损毁组大鼠纹状体中 DA 含量下降更为显著(P =0.005)。结论:MFB 损毁制备的 PD 大鼠模型对 DA 能神经元的损伤范围较 SNc 损毁有所扩大,为不同研究选择制备模型的方法提供一定的理论依据。

  18. Neuroprotective effect of Spirulina fusiform and amantadine in the 6-OHDA induced Parkinsonism in rats.

    Science.gov (United States)

    Chattopadhyaya, I; Gupta, Sumeet; Mohammed, Asad; Mushtaq, N; Chauhan, S; Ghosh, Saikat; Ghosh, Saikant

    2015-08-25

    Multi-factorial etiology exists in pathophysiology of neurodegenerative diseases. The imbalance of anti-oxidant enzymes and dopamine level leads to Parkinsonism. The objective of this study was to assess the protective effect of Spirulina fusiform alone and in combination with amantadine against Parkinsonism effect in 6-hydroxydopamine (6-OHDA) induced rat model. S. fusiform was administered in different groups (500 mg/kg, once daily and twice daily) and a combination of spirulina (500 mg/kg, once daily) with amantadine (20 mg/kg once daily) for 30 days before and 14 days after a single injection of 6-OHDA into the dorsal striatum. Post lesion produced rotational behavior which was measured at two week intervals (37th and 44th day). Locomotors activity was also done at 44th and muscle coordination at 48th day. Dorsal striatum was isolated from rat brain for evaluating the antioxidant assays and dopamine content at 49th day. Both the body rotations (ipsilateral and contralateral) were found to have a statistically significant (pspirulina (Twice a day) in spirulina treated lesioned group. A higher percentage of improvement was shown in the reduction of ipsilateral (57.34%) and contralateral (78.3%) rotations in combination of spirulina with amantadine treated lesioned group rather than spirulina alone treated lesioned groups when compared with positive control lesioned group. Body movements and locomotor activity were improved statistically (pspirulina with amantadine and spirulina twice daily). Similar results were also seen in anti-oxidant levels which later on reached to the normal value. The levels of dopamine content had a statistically significant (pspirulina with amantadine treated lesioned group. Spirulina is a potent nutraceutical supplement all over the world, so my preclinical study may contribute to give an additional adjuvant drug therapy in aging related disorders (Neurodegenerative as well as diabetes associated neurodegenerative disorders).

  19. 应用6-羟基多巴胺建立帕金森病大鼠模型的稳定性评价%Reliability of a 6-OHDA rat model of Parkinson's disease

    Institute of Scientific and Technical Information of China (English)

    周厚广; 鲍远程; 陆建明

    2004-01-01

    背景:应用6-羟基多巴胺(6-Hydroxydopamine,6-OHDA)损毁黑质多巴胺神经元(nigral dopaminergic neuron,NDN)制作的大鼠模型,在目前帕金森病的研究中应用最广,但由于黑质致密部体积狭小,技术难度大,故模型制备成功率一般仅为30%~40%左右.目的:探讨提高6-羟基多巴胺帕金森病大鼠模型成功率的方法,并对模型进行评价.设计:完全随机的实验研究.地点和材料:实验在安徽中医学院第一附属医院中心实验室完成,实验材料包括SD大鼠,6-OHDA,阿朴吗啡,兔抗TH血清,ABC试剂盒,SR-6N大鼠脑立体定向仪,JEM-100CX电镜.干预:取SD大鼠90只,将6-OHDA立体定向微量注射于左侧黑质区及黑质纹状体通路,观察大鼠行为及黑质细胞形态学变化.主要观察指标:旋转行为,免疫组织化学观察多巴胺能神经元数量,电镜观察多巴胺能神经元形态改变.结果:90只大鼠中经阿朴吗啡诱导后有64只(占71%)恒定转向右侧且结果稳定,旋转圈数30 min>210 r,被视为成功大鼠模型;免疫组化观察发现注射侧黑质区多巴胺能神经元较对侧明显减少,电镜观察发现其普遍存在凋亡及坏死样改变.结论:应用本方法可较快建立稳定的成功率较高的大鼠模型,但在病理和行为学等方面同自然患者仍有较多差异.%BACKGROUND: The most commonly used animal model of Parkinson's disease is created by lesion of nigral dopaminergic neuron (NDN) resulted from intrastriatial injection of 6-hydroxydopamine (6-OHDA) . However, the success rate is as low as 30% - 40% because of the tiny size of the striate.OBJECTIVES: To investigate the feasibility of a new method using 6-OHDA to create Parkinson model in rats with a higher success rate.DESIGN: Full-randomized experimental study.SETTING AND MATERIALS: The experiment was finished in the Central Laboratory, the First Affiliated Hospital of Anhui College of Traditional Chinese Medicine. SD rats, 6-OHDA

  20. Effect of potassium channel blocker 4-aminopyridine pretreatment on the 6-OHDA-induced Parkinson's disease in rats

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    M. Sofiabadi

    2015-06-01

    Full Text Available Background: Nuclease and caspase enzymes activities which promote death signals and lead to apoptosis are dependent to potassium ions. Objective: The aim of this study was to determine the effect of 4-aminopyridine (4-AP potassium channel blocker on the animal model of Parkinson's disease. Methods: This experimental study was performed in Qazvin University of Medical Sciences, 2013. Male Rats were received different doses of 4-AP twice daily from half an hour before injection of 6-hydroxydopamine (6-OHDA to 7 or 15 days after that. 6-OHDA was injected into medial forebrain bundle (MFB in acute model groups and into striatum in chronic model groups. The severity of Parkinsonism was assessed by standard behavioral methods. Data were analyzed using Kruskal-Wallis and Mann Whitney U tests. Findings: In acute model groups, administration of 0.5 mg/kg 4-AP (n=9 had no remarkable effect on behavioral symptoms, but 1 mg/kg 4-AP (n=8 significantly reduced the severity of apomorphine-induced rotations and improved motor learning in rotarod test. In chronic model groups, although 1 mg/kg 4-AP (n=7 significantly reduced the severity of rotations and improved motor learning, but 0.5 mg/kg 4-AP (n=8 was more effective. Conclusion: Pretreatment with 4-AP can reduce 6-OHDA-induced dopaminergic neuron death. Since the chronic model of 6-OHDA is more similar to Parkinson's disease in human, the low dose of 4-AP is recommended for treatment of this disease.

  1. The nonsteroidal antiinflammatory drug piroxicam reverses the onset of depressive-like behavior in 6-OHDA animal model of Parkinson's disease.

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    Santiago, R M; Tonin, F S; Barbiero, J; Zaminelli, T; Boschen, S L; Andreatini, R; Da Cunha, C; Lima, M M S; Vital, M A B F

    2015-08-06

    Depression is one of the most common psychiatric symptoms in patients with Parkinson's disease (PD). Some authors have reported that depression is characterized by activation of the inflammatory response. Animal models of PD also present with depressive-like behavior, such as increased immobility time in the modified forced swim test and anhedonia-like behavior in the sucrose preference test. Considering the potential neuroprotective effect of nonsteroidal antiinflammatory drugs in neurodegenerative diseases, the objective of the present study was to investigate the effects of piroxicam on depressive-like behavior in male Wistar rats lesioned with 6-hydroxydopamine (6-OHDA) in the substantia nigra (SN). Antidepressant-like effects were observed after prolonged administration of piroxicam for 21days. In the forced swim test, the 6-OHDA+saline group exhibited significant reductions in swimming time and increased immobility time compared with the sham+saline. In the sucrose preference test, the 6-OHDA+piroxicam group exhibited no reduction of sucrose preference compared with the sham+saline, with significant effects of treatment and time and a significant treatment×time interaction. 5-Hydroxytryptamine (5-HT) levels significantly decreased in the hippocampus in the 6-OHDA+saline group and not changed in the 6-OHDA+piroxicam group when compared with the sham+saline on day 21. In conclusion, 21-day treatment with piroxicam reversed the onset of depressive-like behavior and prevented the reduction of hippocampal 5-HT levels.

  2. Polysomnographic Features of Sleep Disturbances and REM Sleep Behavior Disorder in the Unilateral 6-OHDA Lesioned Hemiparkinsonian Rat

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    Quynh Vo

    2014-01-01

    Full Text Available Sleep pattern disruption, specifically REM sleep behavior disorder (RBD, is a major nonmotor cause of disability in PD. Understanding the pathophysiology of these sleep pattern disturbances is critical to find effective treatments. 24-hour polysomnography (PSG, the gold standard for sleep studies, has never been used to test sleep dysfunction in the standard 6-OHDA lesioned hemiparkinsonian (HP rat PD model. In this study, we recorded 24-hour PSG from normal and HP rats. Recordings were scored into wake, rapid eye movement (REM, and non-REM (NREM. We then examined EEG to identify REM periods and EMG to check muscle activity during REM. Normal rats showed higher wakefulness (70–80% during the dark phase and lower wakefulness (20% during the light phase. HP rats showed 30–50% sleep in both phases, less modulation and synchronization to the light schedule (P<0.0001, and more long run lengths of wakefulness (P<0.05. HP rats also had more REM epochs with muscle activity than control rats (P<0.05. Our findings that the sleep architecture in the HP rat resembles that of PD patients demonstrate the value of this model in studying the pathophysiological basis of PD sleep disturbances and preclinical therapeutics for PD related sleep disorders including RBD.

  3. Effect of potassium channel blocker Tetraethylammonium pretreatment on prevention of the 6-OHDA-induced chronic Parkinson's disease in rats

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    H. Haghdoost-Yazdi

    2016-06-01

    Full Text Available Background: Nuclease and caspase activities that promote death signals and cause apoptosis are dependent to potassium ion. Objective: The aim of this study was to investigate the effect of potassium channel blocker tetraethylammonium (TEA on prevention of Parkinson's disease in rats. Methods: This experimental study was conducted on 33 male rats in Qazvin University of Medical Sciences, 2014. 6-hydroxydopamine (6-OHDA was injected into the striatum of the brain. The rats received different doses of TEA twice daily the day before the 6-OHDA injection till 15 days after the injection. The severity of Parkinsonism was assessed by the apomorphine-induced rotational behavior, the elevated body swing test (EBST, and the rotarod test. Data were analyzed using Kruskal Wallis and Mann Whitney U tests. Findings: Pretreatment with 5 mg/kg TEA significantly reduced the severity of rotations compared to the saline group. TEA did not reduce the swings in the EBST. In the rotarod test, TEA caused significant improvement in the motor performance of the rats. Conclusion: With regards to the results, it seems that pretreatment with TEA can partly reduce the severity of behavioral symptoms in the 6-OHDA-induced chronic Parkinson's disease. The higher the TEA dose, the more significant the reduction in the severity of symptoms.

  4. Behavioural Assessment of the A2a/NR2B Combination in the Unilateral 6-OHDA-Lesioned Rat Model: A New Method to Examine the Therapeutic Potential of Non-Dopaminergic Drugs.

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    Anne Michel

    Full Text Available In Parkinson's disease (PD, dopaminergic therapies are often associated with the development of motor complications. Attention has therefore been focused on the use of non-dopaminergic drugs. This study developed a new behavioural method capable of demonstrating the added value of combining adenosinergic and glutamatergic receptor antagonists in unilateral 6-OHDA lesioned rats. Rats were dosed orally with Tozadenant, a selective A2A receptor antagonist, and three different doses of Radiprodil, an NR2B-selective NMDA receptor antagonist. The drugs were given alone or in combination and rats were placed in an open-field for behavioural monitoring. Video recordings were automatically analysed. Five different behaviours were scored: distance traveled, ipsi- and contraversive turns, body position, and space occupancy. The results show that A2A or NR2B receptor antagonists given alone or in combination did not produce enhanced turning as observed with an active dose of L-Dopa/benserazide. Instead the treated rats maintained a straight body position, were able to shift from one direction to the other and occupied a significantly larger space in the arena. The highest "Tozadenant/Radiprodil" dose combination significantly increased all five behavioural parameters recorded compared to rats treated with vehicle or the same doses of the drugs alone. Our data suggest that the A2A/NR2B antagonist combination may be able to stimulate motor activity to a similar level as that achieved by L-Dopa but in the absence of the side-effects that are associated with dopaminergic hyperstimulation. If these results translate into the clinic, this combination could represent an alternative symptomatic treatment option for PD.

  5. EGCG Protects against 6-OHDA-Induced Neurotoxicity in a Cell Culture Model

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    Dan Chen

    2015-01-01

    Full Text Available Background. Parkinson’s disease (PD is a progressive neurodegenerative disease that causes severe brain dopamine depletion. Disruption of iron metabolism may be involved in the PD progression. Objective. To test the protective effect of (−-epigallocatechin-3-gallate (EGCG against 6-hydroxydopamine- (6-OHDA- induced neurotoxicity by regulating iron metabolism in N27 cells. Methods. Protection by EGCG in N27 cells was assessed by SYTOX green assay, MTT, and caspase-3 activity. Iron regulatory gene and protein expression were measured by RT-PCR and Western blotting. Intracellular iron uptake was measured using 55Fe. The EGCG protection was further tested in primary mesencephalic dopaminergic neurons by immunocytochemistry. Results. EGCG protected against 6-OHDA-induced cell toxicity. 6-OHDA treatment significantly (p<0.05 increased divalent metal transporter-1 (DMT1 and hepcidin and decreased ferroportin 1 (Fpn1 level, whereas pretreatment with EGCG counteracted the effects. The increased 55Fe (by 96%, p<0.01 cell uptake confirmed the iron burden by 6-OHDA and was reduced by EGCG by 27% (p<0.05, supporting the DMT1 results. Pretreatment with EGCG and 6-OHDA significantly increased (p<0.0001 TH+ cell count (~3-fold and neurite length (~12-fold compared to 6-OHDA alone in primary mesencephalic neurons. Conclusions. Pretreatment with EGCG protected against 6-OHDA-induced neurotoxicity by regulating genes and proteins involved in brain iron homeostasis, especially modulating hepcidin levels.

  6. Progressive impairment in motor skill learning at 12 and 20 weeks post 6-OHDA- SNc lesion in rats.

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    Gambhir, Hardeep; Mathur, Rashmi; Behari, Madhuri

    2011-07-01

    Deficiency in skilled motor activity is primarily attributed to the loss of dopaminergic neurons in the pars compacta of substantia nigra (SNc), which can be detected by performance of the rotarod test. Previous reports have demonstrated impaired skilled motor behavior in rats during the pre-motor stage of Parkinson's disease (PD) (3-8 weeks post 6-OHDA lesion of striatum). We studied skilled motor learning in 6-hydroxydopamine (6-OHDA) SNc lesion rats at 12 and 20 weeks by rotarod task after providing sufficient training to give allowance for ageing (3 sessions/day for 14 consecutive days). On each day, the stay duration on rotarod was noted and compared between the groups (Group 1 = Control, Group 2 = Post lesion (PL) week 12, Group 3 = PL week 20). In Group 2 rats, the duration of stay on rotarod gradually increased from day 1 through 7 {day 7 = 193.1 (81.8-247.4) vs. control group day 7 = 202.1 (87.7-279.8), p = 0.771} and declined thereafter. While, the stay duration in Group 3 rats remained lower {day 7 = 32.5 (20.4-52.1), p = 0.011} than that of the control rats throughout the study period. The results of our study suggest a slower brief learning of skilled motor tasks at post lesion week 12 whereas no learning at all at post-lesion week 20.

  7. Neuroprotective Properties of the Standardized Extract from Camellia sinensis (Green Tea) and Its Main Bioactive Components, Epicatechin and Epigallocatechin Gallate, in the 6-OHDA Model of Parkinson's Disease

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    Bitu Pinto, Natália; da Silva Alexandre, Bruno; Neves, Kelly Rose Tavares; Silva, Aline Holanda; Leal, Luzia Kalyne A. M.; Viana, Glauce S. B.

    2015-01-01

    Camellia sinensis (green tea) is largely consumed, mainly in Asia. It possesses several biological effects such as antioxidant and anti-inflammatory properties. The objectives were to investigate the neuroprotective actions of the standardized extract (CS), epicatechin (EC) and epigallocatechin gallate (EGCG), on a model of Parkinson's disease. Male Wistar rats were divided into SO (sham-operated controls), untreated 6-OHDA-lesioned and 6-OHDA-lesioned treated for 2 weeks with CS (25, 50, or 100 mg/kg), EC (10 mg/kg), or EGCG (10 mg/kg) groups. One hour after the last administration, animals were submitted to behavioral tests and euthanized and their striata and hippocampi were dissected for neurochemical (DA, DOPAC, and HVA) and antioxidant activity determinations, as well as immunohistochemistry evaluations (TH, COX-2, and iNOS). The results showed that CS and catechins reverted behavioral changes, indicating neuroprotection manifested as decreased rotational behavior, increased locomotor activity, antidepressive effects, and improvement of cognitive dysfunction, as compared to the untreated 6-OHDA-lesioned group. Besides, CS, EP, and EGCG reversed the striatal oxidative stress and immunohistochemistry alterations. These results show that the neuroprotective effects of CS and its catechins are probably and in great part due to its powerful antioxidant and anti-inflammatory properties, pointing out their potential for the prevention and treatment of PD. PMID:26167188

  8. Neuroprotective effects of aqueous extracts of Uncaria tomentosa: Insights from 6-OHDA induced cell damage and transgenic Caenorhabditis elegans model.

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    Shi, Zhenhua; Lu, Zhongbing; Zhao, Yashuo; Wang, Yueqi; Zhao-Wilson, Xi; Guan, Peng; Duan, Xianglin; Chang, Yan-Zhong; Zhao, Baolu

    2013-06-01

    Previous pharmacological studies have indicated that AC11 (a standardized aqueous extract of Uncaria tomentosa) has beneficial effects on DNA repair and immune function. However, its benefits go beyond this. The present study utilized electron spin resonance (ESR) and spin trapping technique, as well as the 6-OHDA-induced cell damage and transgenic Caenorhabditis elegans models, towards exploring the antioxidant and neuroprotective ability of AC11. Our results showed that AC11 could scavenge several types of free radicals, especially hydroxyl radicals (60% of hydroxyl radicals were scavenged by 30 μg/ml of AC11). In SH-SY5Y cells, we found that AC11 could dose dependently protect 6-OHDA induced cell damage by increase cell viability and mitochondrial membrane potential. AC11 pretreatment also significantly decreased the level of lipid peroxidation, intracellular reactive oxygen species and nitric oxide in 6-OHDA treated cells. In NL5901 C. elegans, 10 μg/ml AC11 could reduce the aggregation of α-synuclein by 40%. These findings encourage further investigation on AC11 and its active constituent compounds, as possible therapeutic intervention against Parkinson's disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. [Effects of hypothalamic microinjections of 6-hydroxydopamine (6-OHDA) on estral cycle and morphology of the genital tract in the female rat (author's transl)].

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    Sala, M A; Oteui, J T; Benedetti, W I

    1975-01-01

    To determine whether central catecholaminergic pathways are involved in the neural contral of gonadotrophin secretion, they were interrupted at the hypothalamic level by microinjections of 6-hydroxydopamine (6-OHDA). The effects on ovulation, estral cycle and ovarian and uterine histology were studied. Microinjections of 50 mug of 6-OHDA hydrobromyde were made bilaterally into the anterolateral hypothalamus in a group of rats. Another group was injected with 25 mug of 6-OHDA, while a control group recieved an equivalent volume (5 mul) of saline with ascorbic acid. Animals injected with 50 mug of 6-OHDA showed blockade of ovulation, vaginal cytology characteristics of persistent estrous, polyfollicular ovaries and enlarged uteri with hypertrophic endometrial glands. In the group injected with 25 mug, similiar effects were demonstrated, but the number of affected animals was smaller than that in the 50 mug group. Control animals dit not show modifications, either in estral cycle or in ovarian and uterine histology. These results suggest that 6-OHDA injected into the anterolateral hypothalmus interferes with catecholaminergic pathways that participate in the neural control of ovulation.

  10. The 6-OHDA mouse model of Parkinson's disease - Terminal striatal lesions provide a superior measure of neuronal loss and replacement than median forebrain bundle lesions.

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    Bagga, V; Dunnett, S B; Fricker, R A

    2015-07-15

    Unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway produce side-biased motor impairments that reflect the motor deficits seen in Parkinson's disease (PD). This toxin-induced model in the rat has been used widely, to evaluate possible therapeutic strategies, but has not been well established in mice. With the advancements in mouse stem cell research we believe the requirement for a mouse model is essential for the therapeutic potential of these and other mouse-derived cells to be efficiently assessed. This aim of this study focused on developing a mouse model of PD using the 129 P2/OLA Hsd mouse strain as this is widely used in the generation of mouse embryonic stem cells. Both unilateral 6-OHDA medial forebrain bundle (MFB) and striatal lesion protocols were compared, with mice analysed for appropriate drug-induced rotational bias. Results demonstrated that lesioned mice responded to d-amphetamine with peak rotation dose at 5mg/kg and 10mg/kg for MFB and striatal lesions respectively. Apomorphine stimulation produced no significant rotational responses, at any dose, in either the MFB or striatal 6-OHDA lesioned mice. Analysis of dopamine neuron loss revealed that the MFB lesion was unreliable with little correlation between dopamine neuron loss and rotational asymmetry. Striatal lesions however were more reliable, with a strong correlation between dopamine neuron loss and rotational asymmetry. Functional recovery of d-amphetamine-induced rotational bias was shown following transplantation of E13 mouse VM tissue into the lesioned striatum; confirming the validity of this mouse model.

  11. Anti-Inflammatory Modulation of Microglia via CD163-Targeted Glucocorticoids Protects Dopaminergic Neurons in the 6-OHDA Parkinson's Disease Model.

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    Tentillier, Noemie; Etzerodt, Anders; Olesen, Mads N; Rizalar, F Sila; Jacobsen, Jan; Bender, Dirk; Moestrup, Søren K; Romero-Ramos, Marina

    2016-09-07

    Increasing evidence supports a decisive role for inflammation in the neurodegenerative process of Parkinson's disease (PD). The immune response in PD seems to involve, not only microglia, but also other immune cells infiltrated into the brain. Indeed, we observed here the infiltration of macrophages, specifically CD163+ macrophages, into the area of neurodegeneration in the 6-hydroxydopamine (6-OHDA) PD model. Therefore, we investigated the therapeutic potential of the infiltrated CD163+ macrophages to modulate local microglia in the brain to achieve neuroprotection. To do so, we designed liposomes targeted for the CD163 receptor to deliver dexamethasone (Dexa) into the CD163+ macrophages in the 6-OHDA PD model. Our data show that a fraction of the CD163-targeted liposomes were carried into the brain after peripheral intravenous injection. The 6-OHDA-lesioned rats that received repeated intravenous CD163-targeted liposomes with Dexa for 3 weeks exhibited better motor performance than the control groups and had minimal glucocorticoid-driven side effects. Furthermore, these animals showed better survival of dopaminergic neurons in substantia nigra and an increased number of microglia expressing major histocompatibility complex II. Therefore, rats receiving CD163-targeted liposomes with Dexa were partially protected against 6-OHDA-induced dopaminergic neurodegeneration, which correlated with a distinctive microglia response. Altogether, our data support the use of macrophages for the modulation of brain neurodegeneration and specifically highlight the potential of CD163-targeted liposomes as a therapeutic tool in PD. The immune response now evident in the progression of Parkinson's disease comprises both local microglia and other immune cells. We provide evidence that CD163+ macrophages can be a target to modulate brain immune response to achieve neuroprotection in the 6-hydroxydopamine model. To do so, we targeted the CD163+ population, which to a low but significant

  12. Squamosamide derivative FLZ protected dopaminergic neuron by activating Akt signaling pathway in 6-OHDA-induced in vivo and in vitro Parkinson's disease models.

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    Bao, Xiu-Qi; Kong, Xiang-Chen; Kong, Li-Bing; Wu, Liang-Yu; Sun, Hua; Zhang, Dan

    2014-02-14

    Parkinson's disease (PD) is a neurodegenerative disease affecting up to 80% of dopaminergic neurons in the nigrostriatal pathway. FLZ, a novel synthetic squamosamide derivative from a Chinese herb, has been shown to have neuroprotective effects in experimental PD models. In this study, we carried out a set of in vitro and in vivo experiments to address the neuroprotective effect of FLZ and related mechanism. The results showed that FLZ significantly improved motor dysfunction and dopaminergic neuronal loss of rats injured by 6-hydroxydopamine (6-OHDA). The beneficial effects of FLZ attributed to the elevation of dopaminergic neuron number, dopamine level and tyrosine hydroxylase (TH) activity. Mechanistic study showed that FLZ protected TH activity and dopaminergic neurons through decreasing α-synuclein (α-Syn) expression and the interaction between α-Syn and TH. Further studies indicated the involvement of phosphoinositide 3-kinases (PI3K)/Akt signaling pathway in the protective effect of FLZ since it showed that blocking PI3K/Akt signaling pathway prevented the expression of α-Syn and attenuated the neuroprotection of FLZ. In addition, FLZ treatment reduced the expression of RTP801, an important protein involved in the pathogenesis of PD. Taken together, these results revealed that FLZ suppressed α-Syn expression and elevated TH activity in dopaminergic neuron through activating Akt survival pathway in 6-OHDA-induced PD models. The data also provided evidence that FLZ had potent neuroprotecive effects and might become a new promising agent for PD treatment.

  13. The CB1 cannabinoid receptor agonist reduces L-DOPA-induced motor fluctuation and ERK1/2 phosphorylation in 6-OHDA-lesioned rats.

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    Song, Lu; Yang, Xinxin; Ma, Yaping; Wu, Na; Liu, Zhenguo

    2014-01-01

    The dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) has been used as an effective drug for treating dopamine depletion-induced Parkinson's disease (PD). However, long-term administration of L-DOPA produces motor complications. L-DOPA has also been found to modify the two key signaling cascades, protein kinase A/dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) and extracellular signal-regulated kinases 1 and 2 (ERK1/2), in striatal neurons, which are thought to play a pivotal role in forming motor complications. In the present study, we tested the possible effect of a CB1 cannabinoid receptor agonist on L-DOPA-stimulated abnormal behavioral and signaling responses in vivo. Intermittent L-DOPA administration for 3 weeks induced motor fluctuation in a rat model of PD induced by intrastriatal infusion of dopamine-depleting neurotoxin 6-hydroxydopamine (6-OHDA). A single injection of a CB1 cannabinoid receptor agonist WIN-55,212-2 had no effect on L-DOPA-induced motor fluctuation. However, chronic injections of WIN-55,212-2 significantly attenuated abnormal behavioral responses to L-DOPA in 6-OHDA-lesioned rats. Similarly, chronic injections of WIN-55,212-2 influence the L-DOPA-induced alteration of DARPP-32 and ERK1/2 phosphorylation status in striatal neurons. These data provide evidence for the active involvement of CB1 cannabinoid receptors in the regulation of L-DOPA action during PD therapy.

  14. Dopaminergic neurotoxicant 6-OHDA induces oxidative damage through proteolytic activation of PKC{delta} in cell culture and animal models of Parkinson's disease

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    Latchoumycandane, Calivarathan; Anantharam, Vellareddy; Jin, Huajun; Kanthasamy, Anumantha; Kanthasamy, Arthi, E-mail: arthik@iastate.edu

    2011-11-15

    The neurotoxicant 6-hydroxydopamine (6-OHDA) is used to investigate the cellular and molecular mechanisms underlying selective degeneration of dopaminergic neurons in Parkinson's disease (PD). Oxidative stress and caspase activation contribute to the 6-OHDA-induced apoptotic cell death of dopaminergic neurons. In the present study, we sought to systematically characterize the key downstream signaling molecule involved in 6-OHDA-induced dopaminergic degeneration in cell culture and animal models of PD. Treatment of mesencephalic dopaminergic neuronal N27 cells with 6-OHDA (100 {mu}M) for 24 h significantly reduced mitochondrial activity and increased cytosolic cytochrome c, followed by sequential activation of caspase-9 and caspase-3. Co-treatment with the free radical scavenger MnTBAP (10 {mu}M) significantly attenuated 6-OHDA-induced caspase activities. Interestingly, 6-OHDA induced proteolytic cleavage and activation of protein kinase C delta (PKC{delta}) was completely suppressed by treatment with a caspase-3-specific inhibitor, Z-DEVD-FMK (50 {mu}M). Furthermore, expression of caspase-3 cleavage site-resistant mutant PKC{delta}{sup D327A} and kinase dead PKC{delta}{sup K376R} or siRNA-mediated knockdown of PKC{delta} protected against 6-OHDA-induced neuronal cell death, suggesting that caspase-3-dependent PKC{delta} promotes oxidative stress-induced dopaminergic degeneration. Suppression of PKC{delta} expression by siRNA also effectively protected N27 cells from 6-OHDA-induced apoptotic cell death. PKC{delta} cleavage was also observed in the substantia nigra of 6-OHDA-injected C57 black mice but not in control animals. Viral-mediated delivery of PKC{delta}{sup D327A} protein protected against 6-OHDA-induced PKC{delta} activation in mouse substantia nigra. Collectively, these results strongly suggest that proteolytic activation of PKC{delta} is a key downstream event in dopaminergic degeneration, and these results may have important translational value for

  15. ORALLY ACTIVE CARBAMATE PRODRUGS OF THE SELECTIVE DOPAMINE AGONIST N-0437 - INVIVO ACTIVITIES IN THE 6-OHDA TURNING MODEL AND INVITRO ACTIVITIES

    NARCIS (Netherlands)

    DENDAAS, [No Value; DEBOER, P; TEPPER, PG; ROLLEMA, H; HORN, AS

    The in-vivo activities of eight carbamate prodrugs of the D2-agonist N-0437 were determined by examining the effects of the prodrugs, after their oral administration in rats with unilateral 6-OHDA lesions of the striatum. The resulting contralateral turning was used as an index of the activity of

  16. Hepcidin Plays a Key Role in 6-OHDA Induced Iron Overload and Apoptotic Cell Death in a Cell Culture Model of Parkinson’s Disease

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    Qi Xu

    2016-01-01

    Full Text Available Background. Elevated brain iron levels have been implicated in the pathogenesis of Parkinson’s disease (PD. However, the precise mechanism underlying abnormal iron accumulation in PD is not clear. Hepcidin, a hormone primarily produced by hepatocytes, acts as a key regulator in both systemic and cellular iron homeostasis. Objective. We investigated the role of hepcidin in 6-hydroxydopamine (6-OHDA induced apoptosis in a cell culture model of PD. Methods. We downregulated hepcidin using siRNA interference in N27 dopaminergic neuronal cells and made a comparison with control siRNA transfected cells to investigate the role of hepcidin in 6-OHDA induced neurodegeneration. Results. Hepcidin knockdown (32.3%, P<0.0001 upregulated ferroportin 1 expression and significantly (P<0.05 decreased intracellular iron by 25%. Hepcidin knockdown also reduced 6-OHDA induced caspase-3 activity by 42% (P<0.05 and DNA fragmentation by 29% (P=0.086 and increased cell viability by 22% (P<0.05. In addition, hepcidin knockdown significantly attenuated 6-OHDA induced protein carbonyls by 52% (P<0.05 and intracellular iron by 28% (P<0.01, indicating the role of hepcidin in oxidative stress. Conclusions. Our results demonstrate that hepcidin knockdown protected N27 cells from 6-OHDA induced apoptosis and that hepcidin plays a major role in reducing cellular iron burden and oxidative damage by possibly regulating cellular iron export mediated by ferroportin 1.

  17. Dopaminergic neurons derived from human induced pluripotent stem cells survive and integrate into 6-OHDA-lesioned rats.

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    Cai, Jingli; Yang, Ming; Poremsky, Elizabeth; Kidd, Sarah; Schneider, Jay S; Iacovitti, Lorraine

    2010-07-01

    Cell replacement therapy could be an important treatment strategy for Parkinson's disease (PD), which is caused by the degeneration of dopamine neurons in the midbrain (mDA). The success of this approach greatly relies on the discovery of an abundant source of cells capable of mDAergic function in the brain. With the paucity of available human fetal tissue, efforts have increasingly focused on renewable stem cells. Human induced pluripotent stem (hiPS) cells offer great promise in this regard. If hiPS cells can be differentiated into authentic mDA neuron, hiPS could provide a potential autologous source of transplant tissue when generated from PD patients, a clear advantage over human embryonic stem (hES) cells. Here, we report that mDA neurons can be derived from a commercially available hiPS cell line, IMR90 clone 4, using a modified hES differentiation protocol established in our lab. These cells express all the markers (Lmx1a, Aldh1a1, TH, TrkB), follow the same mDA lineage pathway as H9 hES cells, and have similar expression levels of DA and DOPAC. Moreover, when hiPS mDA progenitor cells are transplanted into 6-OHDA-lesioned PD rats, they survive long term and many develop into bona fide mDA neurons. Despite their differentiation and integration into the brain, many Nestin+ tumor-like cells remain at the site of the graft. Our data suggest that as with hES cells, selecting the appropriate population of mDA lineage cells and eliminating actively dividing hiPS cells before transplantation will be critical for the future success of hiPS cell replacement therapy in PD patients.

  18. Neuroprotective Properties of the Standardized Extract from Camellia sinensis (Green Tea and Its Main Bioactive Components, Epicatechin and Epigallocatechin Gallate, in the 6-OHDA Model of Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Natália Bitu Pinto

    2015-01-01

    Full Text Available Camellia sinensis (green tea is largely consumed, mainly in Asia. It possesses several biological effects such as antioxidant and anti-inflammatory properties. The objectives were to investigate the neuroprotective actions of the standardized extract (CS, epicatechin (EC and epigallocatechin gallate (EGCG, on a model of Parkinson’s disease. Male Wistar rats were divided into SO (sham-operated controls, untreated 6-OHDA-lesioned and 6-OHDA-lesioned treated for 2 weeks with CS (25, 50, or 100 mg/kg, EC (10 mg/kg, or EGCG (10 mg/kg groups. One hour after the last administration, animals were submitted to behavioral tests and euthanized and their striata and hippocampi were dissected for neurochemical (DA, DOPAC, and HVA and antioxidant activity determinations, as well as immunohistochemistry evaluations (TH, COX-2, and iNOS. The results showed that CS and catechins reverted behavioral changes, indicating neuroprotection manifested as decreased rotational behavior, increased locomotor activity, antidepressive effects, and improvement of cognitive dysfunction, as compared to the untreated 6-OHDA-lesioned group. Besides, CS, EP, and EGCG reversed the striatal oxidative stress and immunohistochemistry alterations. These results show that the neuroprotective effects of CS and its catechins are probably and in great part due to its powerful antioxidant and anti-inflammatory properties, pointing out their potential for the prevention and treatment of PD.

  19. Genetic, temporal and diurnal influences on L-dopa-induced dyskinesia in the 6-OHDA model.

    Science.gov (United States)

    Monville, Christelle; Torres, Eduardo M; Pekarik, Vladimir; Lane, Emma L; Dunnett, Stephen B

    2009-03-16

    Current treatments for Parkinson's disease rely on a dopamine replacement strategy and are reasonably effective, particularly in the early stages of the disease. However, chronic dopaminergic therapy is limited by the development of a range of side effects, including the onset of abnormal movements ('dyskinesia'). The neural mechanisms that underlie dyskinesia are far from clear but they have been associated with pulsatile stimulation of dopamine receptors, downstream changes in proteins and genes, and abnormalities in non-dopamine transmitter systems. However, there has been no pathophysiological explanation for the worsening motor symptoms in the afternoon and evening reported by Parkinsonian patients in long-term L-dopa therapy, and no direct relationship has been found with the pharmacokinetics of the drug. Moreover, there continues to be a debate about whether the development of dyskinesias in patients is dependent upon the duration of L-dopa treatment or on the degree of denervation/advanced stage of the disease, both factors that are difficult to resolve experimentally in the human disease. The objective of this study was to characterise, in an animal model, factors that predispose some individuals to develop dyskinesia after a prolonged treatment with L-dopa, whereas others continue to exhibit symptom alleviation without the side effects. We report that none of the parameters studied--genetic variation within and between strains, delay of treatment onset after lesion, or time of day of the drug treatment--were found to influence directly the formation of dyskinesias after L-dopa treatment. We conclude that a complex combination of individual factors are likely to interact to regulate the onset and development of abnormal movements in some animals but not others.

  20. Formation and Metabolism of Catecholamine Isoquinolines in the 6-OHDA Lesion rat Model Brains%帕金森模型大鼠脑内儿茶酚胺异喹啉类化合物的形成与代谢

    Institute of Scientific and Technical Information of China (English)

    牟晓玲; 李丽莉; 朱勇; 邓玉林

    2008-01-01

      帕金森(PD)是一种常见的神经退行性疾病,确切的致病机理尚不清楚,其中环境因素引起的神经毒素假说受到广泛关注。本文提出了关于内源性神经毒素恶性循环导致PD的假说,为了验证该假说,建立了定位注射6-OHDA单侧损毁黑质-纹状体的PD Wistar大鼠模型,并采用HPLC-ESI-TOF分别检测了PD模型大鼠和对照组大鼠脑健侧和受损侧的黑质、纹状体中Sal和NMSal的含量。结果表明,PD模型大鼠受损侧黑质-纹状体中Sal和NMSal的含量都比健侧及其他对照组高,说明PD模型受损侧内源性儿茶酚胺异喹啉类神经毒素导致的恶性循环严重,对假说的验证提供了依据。%  Parkinson’s disease (PD) is progressive neurodegenerative disorder and the exactly mechanism is still unknown. The extregenous and endogenous neurotoxin provoked by environmental factors may contribute to the development of PD and drew more and more attention. Based on our research data, a hypothesis of PD pathogenesis that CAIQs and related enzymes were involved in the dopaminergic neurons death had been proposed. In order to verify this hypothesis, the 6-OHDA lesion rat model was established and a method based on HPLC-ESI-TOF was developed for the determination of Sal and NMSal in nigra-striatum. Data showed that the Sal and NMSal in damaged regions of PD significantly raised (P﹤0.05) compared to the control group, which firmly support the suggested hypothesis.

  1. The H3 receptor agonist immepip does not affect l-dopa-induced abnormal involuntary movements in 6-OHDA-lesioned rats.

    Science.gov (United States)

    Papathanou, Maria; Jenner, Peter; Iravani, Mahmoud; Jackson, Michael; Stockwell, Kim; Strang, Isabel; Zeng, Bai-Yun; McCreary, Andrew C; Rose, Sarah

    2014-10-15

    The treatment of dyskinesia in Parkinson׳s disease remains poor but H3 receptor agonists have been suggested as a novel pharmacological approach. We examined the effects of the H3 agonist, immepip, in 6-OHDA-lesioned rats exhibiting AIMs (abnormal involuntary movements), a rat analogue of dyskinesia, in response to l-dopa compared to the known anti-dyskinetic agents amantadine, MK-801 and 8-OHDPAT. We then attempted to extend these studies in to dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated common marmosets. Amantadine, MK-801 and 8-OHDPAT all dose-dependently reduced l-dopa-induced axial, lingual and oral (ALO) AIMs in 6-OHDA-lesioned animals accompanied by a reduction in contralateral rotation with higher doses of amantadine and MK-801. By contrast, immepip had no effect on AIMs expression or contralateral rotation. In the MPTP-treated common marmoset exhibiting dyskinesia to l-dopa, immepip alone induced retching and in combination with l-dopa administered subcutaneously or orally induced the rapid onset of retching and vomiting which was not controlled by pretreatment with domperidone. Administration of the unrelated H3 agonist, imetit had the same effect. Despite causing negative side-effects, it appears that both agonists reduced the antiparkinsonian response to l-dopa resulting in reduced dyskinesia. H3 agonists appear unlikely candidates for the treatment of dyskinesia in PD based on lack of evidence of efficacy and potential adverse effects.

  2. Neuroprotection of inositol hexaphosphate and changes of mitochondrion mediated apoptotic pathway and α-synuclein aggregation in 6-OHDA induced parkinson's disease cell model.

    Science.gov (United States)

    Zhang, Zheng; Hou, Lin; Li, Xianghong; Ju, Chuanxia; Zhang, Jinyu; Li, Xin; Wang, Xiuli; Liu, Cun; Lv, Yuqiang; Wang, Yuehua

    2016-02-15

    Animal and cell experiments showed that inositol hexaphosphate (IP6) was protective on neurons in parkinson's disease (PD) model, but the underlying mechanism of this action was not extensively elucidated. To address this question, we established 6-hydroxydopamine (6-OHDA) induced human dopaminergic cell line SH-SY5Y as PD cell model and testified the neuroprotection of IP6. Through hoechst nuclear stain method and flow cytometric analysis, apoptosis induced by 6-OHDA was blocked by IP6 pretreatment. Significant protection against reactive oxygen species (ROS) and lipid peroxidation product malondialdehyde (MDA) was observed in 6-OHDA induced cells pretreated with IP6. To further investigate the mechanism of anti-apoptotic effect of IP6, expression of mediators in mitochondrion dependent apoptotic pathway was detected. Results indicated that loss of mitochondrial membrane potential, cytochrome c releasing, upregulation of Bcl-2-associated X protein (Bax), downregulation of B-cell CLL/lymphoma 2 (Bcl-2) and caspases activation were reversed by IP6. In addition, using flow cytometric method and western blot approach, our data showed that IP6 attenuated the rise of calcium and α-synuclein aggregation in cytosol. Collectively, IP6 exerted its neuroprotection on dopaminergic cells in PD cell model and the mechanism may be associated with changes of mitochondrion mediated apoptotic pathway and α-synuclein aggregation.

  3. The mitochondria-targeted anti-oxidant MitoQ reduces aspects of mitochondrial fission in the 6-OHDA cell model of Parkinson's disease.

    Science.gov (United States)

    Solesio, María E; Prime, Tracy A; Logan, Angela; Murphy, Michael P; Del Mar Arroyo-Jimenez, María; Jordán, Joaquín; Galindo, María F

    2013-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder for which available treatments provide symptom relief but do not stop disease progression. Mitochondria, and in particular mitochondrial dynamics, have been postulated as plausible pharmacological targets. Mitochondria-targeted antioxidants have been developed to prevent mitochondrial oxidative damage, and to alter the involvement of reactive oxygen species (ROS) in signaling pathways. In this study, we have dissected the effect of MitoQ, which is produced by covalent attachment of ubiquinone to a triphenylphosphonium lipophilic cation by a ten carbon alkyl chain. MitoQ was tested in an in vitro PD model which involves addition of 6-hydroxydopamine (6-OHDA) to SH-SY5Y cell cultures. At sublethal concentrations of 50μM, 6-OHDA did not induce increases in protein carbonyl, mitochondrial lipid peroxidation or mitochondrial DNA damage. However, after 3h of treatment, 6-OHDA disrupts the mitochondrial morphology and activates the machinery of mitochondrial fission, but not fusion. Addition of 6-OHDA did not increase the levels of fission 1, mitofusins 1 and 2 or optic atrophy 1 proteins, but does lead to the translocation of dynamin related protein 1 from the cytosol to the mitochondria. Pre-treatment with MitoQ (50nM, 30min) results in the inhibition of the mitochondrial translocation of Drp1. Furthermore, MitoQ also inhibited the translocation of the pro-apoptotic protein Bax to the mitochondria. These findings provide mechanistic evidence for a role for redox events contributing to mitochondrial fission and suggest the potential of mitochondria-targeted therapeutics in diseases that involve mitochondrial fragmentation due to oxidative stress.

  4. Chronic pramipexole treatment induces compulsive behavior in rats with 6-OHDA lesions of the substantia nigra and ventral tegmental area.

    Science.gov (United States)

    Dardou, D; Reyrolle, L; Chassain, C; Durif, F

    2017-08-14

    Dopamine replacement therapy (DRT) reduces motor symptoms in Parkinson's disease (PD), but also induces impulsive-compulsive behavior (ICB) in up to 25% of PD patients. These non-motor side effects of DRT generally follow a gradual transition from impulsive to compulsive-like-i.e. repetitive, compelled, and non-pleasurable-behavior. Here, we investigated the effect of chronic pramipexole (PPX) treatment on the onset of compulsive-like behavior, measured via the post-training signal attenuation (PTSA) procedure, in rats with dopaminergic lesions. Accordingly, we aimed to mimic chronic DRT in a PD context, and obtain data on the brain regions that potentially sustain this type of compulsive behavior pattern in rats. We observed that the lesion or treatment alone did not induce compulsive lever pressing in rats. However, rats with lesions of the substantia nigra and ventral tegmental area as well as with chronic PPX treatment developed strong compulsive lever-pressing behavior, as measured via PTSA. Furthermore, when chronic PPX treatment was discontinued before the PTSA test, the lesioned rats showed the same level of compulsive behavior as sham-operated rats. In fact, lesioned, treated, and compulsive-like rats showed significantly higher Fos expression in the orbitofrontal cortex and dorsal striatum. Thus, chronic PPX treatment in PD rats induced a strong compulsive-like behavior. Furthermore, Fos expression mapping suggests that the behavior was sustained via the activation of the orbitofrontal cortex and dorsal striatum. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Early L-dopa, but not pramipexole, restores basal ganglia activity in partially 6-OHDA-lesioned rats.

    Science.gov (United States)

    Marin, C; Bonastre, M; Mengod, G; Cortés, R; Giralt, A; Obeso, J A; Schapira, A H

    2014-04-01

    The most appropriate time for the initiation of dopaminergic symptomatic therapy in Parkinson's disease remains debatable. It has been suggested that early correction of basal ganglia pathophysiological abnormalities may have long-term beneficial effects. To test this hypothesis, we investigated the early and delayed actions of L-dopa and pramipexole, using a delayed-start protocol of treatment. The effects of early and delayed administration of these drugs on motor response, development of dyskinesias, neurogenesis and molecular markers in basal ganglia were studied in rats with a unilateral and partial 6-hydroxydopamine-induced nigrostriatal lesion. Ten days after lesioning, rats received treatment with: a) L-dopa methyl ester (25mg/kg with 6.25mg/kg of benserazide, i.p., twice a day); b) pramipexole (0.5mg/kg, sc, twice a day) or c) saline for 4weeks. Four weeks after treatment initiation, rats from the saline group were distributed in three groups that then received the following treatments: d) L-dopa, e) pramipexole or f) saline, for 4weeks more. Three animals in each treatment arm received 5-bromo-2-deoxyuridine injections (200mg/kg) 3days before starting treatment. When compared with delayed-start L-dopa, early-start L-dopa treatment induced a lower rotational response (ppramipexole, early-start pramipexole induced a higher rotational response (ppramipexole treatments. Our data support a possible restoration of basal ganglia physiological mechanisms by early-start L-dopa therapy.

  6. The effects of Nanog gene transfer on NF-κB expression in rats with Parkinson's disease induced by 6-OHDA%转Nanog基因对6-羟基多巴胺帕金森病大鼠脑核因子-κB表达的影响

    Institute of Scientific and Technical Information of China (English)

    陈施艳; 冯飞阳; 张志坚; 周海涛; 吴秀丽

    2014-01-01

    目的:探讨转Nanog基因对6-羟多巴胺(6-OHDA)诱导的帕金森病(PD)大鼠A脑内核因子(NF)-κB表达的影响。方法取SD大鼠随机分成正常对照组、6-OHDA+磷酸盐缓冲液( PBS)组、6-OHDA+PNL组与6-OHDA+Nanog组,各组又分注射后1、14 d亚组。除正常对照组外,采用脑立体定向注射技术,6-OHDA+PBS组注入PBS,6-OHDA+PNL组注入空载体,6-OHDA+Nanog组注入转Nanog基因载体。各组动物注射阿朴吗啡(APO)后观察各时间点大鼠的旋转行为改变;行脑免疫组织化学染色,观察黑质多巴胺(DA)能神经元数量变化、纹状体NF-κBp65的表达改变;激光扫描共聚焦显微镜技术检测NF-κBp65表达的定位。结果注射后14 d,6-OHDA+Nanog组大鼠APO诱发的旋转效应明显低于6-OHDA+PNL组与6-OHDA+PBS组(P<0.05);除正常对照组外,其他各组大鼠注射后14 d黑质TH阳性细胞数普遍较注射后1 d减少(P<0.01),但6-OHDA+Nanog组损毁侧黑质存活的TH阳性细胞数明显高于6-OHDA+PNL组与6-OHDA+PBS组(P<0.01),且其注射侧纹状体 NF-κBp65阳性细胞数低于注射后1 d组(P<0.05)、注射后14 d的6-OHDA+PNL与6-OHDA+PBS组(P<0.05)。除正常对照组外,注射后各组各时程均可见 NF-κBp65的阳性表达,并呈现核内转移现象。结论转Nanog基因可抑制6-OHDA诱导的PD大鼠模型脑内NF-κB的活化,同时具有神经元保护作用。%Objective To observe the effects of Nanog on NF-κB expression in Parkinson's disease ( PD) model.Methods SD rats were randomly divided into control ,6-OHDA+PBS,6-OHDA+PNL and 6-OHDA+Nanog groups.Rats were given a brain injection of phos-phate buffered saline (PBS), PLNCX (PLN) and Nanog gene vector respectively , and were divided into post injection 1 st, 14 th day sub-groups.The Apomorphine ( APO) was injected in each

  7. Serotonergic modulation of receptor occupancy in rats treated with L-DOPA after unilateral 6-OHDA lesioning

    DEFF Research Database (Denmark)

    Nahimi, Adjmal; Høltzermann, Mette; Landau, Anne M.

    2012-01-01

    Recent studies suggest that l-3,4 dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), a severe complication of conventional L-DOPA therapy of Parkinson's disease, may be caused by dopamine (DA) release originating in serotonergic neurons. To evaluate the in vivo effect of a 5-HT(1A) agonist...... [(±)-8-hydroxy-2-(dipropylamino) tetralin hydrobromide, 8-OHDPAT] on the L-DOPA-induced increase in extracellular DA and decrease in [(11) C]raclopride binding in an animal model of advanced Parkinson's disease and LID, we measured extracellular DA in response to L-DOPA or a combination of L...

  8. Effects of prolonged neuronal nitric oxide synthase inhibition on the development and expression of L-DOPA-induced dyskinesia in 6-OHDA-lesioned rats.

    Science.gov (United States)

    Padovan-Neto, Fernando Eduardo; Cavalcanti-Kiwiatkoviski, Roberta; Carolino, Ruither Oliveira Gomes; Anselmo-Franci, Janete; Del Bel, Elaine

    2015-02-01

    It is well known that nitric oxide (NO) interacts with dopamine (DA) within the striatal circuitry. The anti-dyskinetic properties of NO synthase (NOS) inhibitors demonstrate the importance of NO in L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID). Here, we investigated the ability of a daily co-treatment of the preferential neuronal NOS (nNOS) inhibitor, 7-nitroindazole (7-NI, 30 mg/kg), with L-DOPA (30 mg/kg) to counteract LID in unilaterally 6-OHDA-lesioned rats. We analyzed striatal nNOS-expressing interneurons, DA and 5-HT neurochemistry in the striatum and alterations of the Fos-B/ΔFosB expression in the corticostriatal, nigrostriatal and mesolimbic pathways. Prolonged administration of 7-NI inhibited the manifestation of chronic L-DOPA treatment-induced abnormal involuntary movements (AIMs). LID was associated with an up-regulation in the number of nNOS-expressing interneurons in the lateral but not medial striatum. nNOS inhibition reduced the number of nNOS-expressing interneurons. The anti-dyskinetic effects of 7-NI correlated with a reduction in DA and 5-HT turnover in the striatum. At postsynaptic striatal sites, 7-NI prevented L-DOPA-induced Fos-B/ΔFosB up-regulation in the motor cortex, nucleus accumbens and striatum. Finally, 7-NI blocked Fos-B/ΔFosB expression in nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d)-positive interneurons in the striatum. These results provide further evidence of the molecular mechanisms by which NOS-inhibiting compounds attenuate LID. The involvement of NO with DA and 5-HT neurochemistry may contribute to the understanding of this new, non-dopaminergic therapy for the management of LID. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Effects of unilateral 6-OHDA lesions on [3H]-N-propylnorapomorphine binding in striatum ex vivo and vulnerability to amphetamine-evoked dopamine release in rat

    DEFF Research Database (Denmark)

    Palner, Mikael; Kjaerby, Celia; Knudsen, Gitte M;

    2011-01-01

    ligands should likewise be fitter than antagonists for detecting responses to denervation in positron emission tomography studies of idiopathic Parkinson's disease. Agonist binding increases in vivo are likely to reflect the composite of a sensitization-like phenomenon, and relatively less competition...... from endogenous dopamine, as seen in the lesioned side of 6-OHDA induced hemi-parkinsonism....

  10. Effects of unilateral 6-OHDA lesions on [3H]-N-propylnorapomorphine binding in striatum ex vivo and vulnerability to amphetamine-evoked dopamine release in rat

    DEFF Research Database (Denmark)

    Palner, Mikael; Kjaerby, Celia; Knudsen, Gitte M

    2011-01-01

    It has been argued that agonist ligands for dopamine D(2/3) receptors recognize a privileged subset of the receptors in living striatum, those which are functionally coupled to intracellular G-proteins. In support of this claim, the D(2/3) agonist [(3)H]-N-propylnorapomorphine ([(3)H]NPA) proved ...... from endogenous dopamine, as seen in the lesioned side of 6-OHDA induced hemi-parkinsonism....

  11. Levodopa/benserazide microspheres reduced levodopa-induced dyskinesia by downregulating phosphorylated GluR1 expression in 6-OHDA-lesioned rats

    Directory of Open Access Journals (Sweden)

    Song L,Yuan W

    2012-11-01

    Full Text Available Xinxin Yang,1,* Yinghui Chen,2,* Xiaoyun Hong,3 Na Wu,1 Lu Song,1 Weien Yuan,3 Zhenguo Liu11Department of Neurology, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China; 2Department of Neurology, Jinshan Hospital, Fudan University, JinShan District, Shanghai, China; 3School of Pharmacy, Shanghai Jiaotong University, Shanghai, China*These authors contributed equally to this workBackground: Levodopa is the gold standard in the treatment of Parkinson’s disease (PD. However, long-term levodopa replacement therapy is accompanied by abnormal involuntary movements (AIMs, known as levodopa-induced dyskinesia (LID. Until now, the precise mechanisms of LID were only partially understood. Previous studies have shown that continuous dopamine stimulation was helpful in reducing the expression of LID. In addition to dopamine D1 receptor, glutamatergic receptors such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA receptor also contribute to the expression of LID. The current authors have previously reported that levodopa/benserazide-loaded microspheres could ameliorate the expression of LID by reducing the protein kinase A signaling pathway in dyskinetic rats. However, whether AMPA receptor is involved in the mechanism by which levodopa/benserazide-loaded microspheres ameliorate the expression of LID in dyskinetic rats was unknown.Methods: In the present study, as reported previously, levodopa and benserazide were loaded by poly(lactic-co-glycolic acid microspheres, which can release levodopa and benserazide in a sustained manner. 6-Hydroxydopamine was injected into the right medial forebrain bundle to produce a rat model of PD. Then valid PD rats were treated with levodopa plus benserazide for 3 weeks to induce a rat model of LID. Dyskinetic rats were treated with levodopa/beserazide-loaded microspheres containing levodopa (6 mg/kg plus benserazide (15 mg/kg or same dose of levodopa plus benserazide

  12. High frequency electro-acupuncture enhances striatum DAT and D1 receptor expression, but decreases D2 receptor level in 6-OHDA lesioned rats.

    Science.gov (United States)

    Rui, Gao; Guangjian, Zhang; Yong, Wang; Jie, Feng; Yanchao, Cui; Xi, Jia; Fen, Li

    2013-01-15

    The direct effects of electro-acupuncture (EA) on the dopaminergic neurotransmitter system in Parkinson's disease (PD) patients remain elusive. In the present study, 0, 2 or 100Hz EA was applied to acupoints Sanyinjiao (SP6), Yanglingquan (GB34) and Zusanli (ST36) in a rat model unilaterally lesioned by 6-hydroxydopamine. Rotational behavior tests were performed and the animals were then decapitated. Levels of striatal dopamine (DA), dopamine transporter, and D1- and D2-like DA receptors were subsequently evaluated. EA at 100 Hz was shown to significantly enhance survival of dopaminergic neurons in the substantia nigra (52.10 ± 11.41% of the level on the non-lesioned rats vs. 21.22 ± 5.52% in the non-EA group, P0.05 vs. the non-EA group). There was a 253.78% increase in dopamine transporter protein expression in the striatum in the 100 Hz EA group (P0.05 vs. the sham operation group). These findings suggest that high-frequency EA might work by acting on presynaptic dopamine transporter and postsynaptic dopamine receptors simultaneously to achieve a therapeutic effect in PD patients and models. This might shed some light on the mechanism by which EA affects the DA neurotransmitter system.

  13. Prostaglandin receptor EP2 protects dopaminergic neurons against 6-OHDA-mediated low oxidative stress.

    Science.gov (United States)

    Carrasco, Emilce; Werner, Peter; Casper, Diana

    2008-08-15

    Dopaminergic neurons in the substantia nigra (SN) selectively die in Parkinson's disease (PD), but it is unclear how and why this occurs. Recent findings implicate prostaglandin E(2) (PGE(2)) and two of its four receptors, namely EP1 and EP2, as mediators of degenerative and protective events in situations of acute and chronic neuronal death. EP1 activation can exacerbate excitotoxic damage in stroke models and our recent study showed that EP1 activation may explain the selective sensitivity of dopaminergic neurons to oxidative stress. Conversely, EP2 activation may be neuroprotective, although toxic effects have also been demonstrated. Here we investigated if and how EP2 activation might alter the survival of dopaminergic neurons following selective low-level oxidative injury evoked by the neurotoxin 6-hydroxydopamine (6-OHDA) in primary neuronal cultures prepared from embryonic rat midbrain. We found that cultured dopaminergic neurons displayed EP2 receptors. Butaprost, a selective EP2 agonist, significantly reduced 6-OHDA neurotoxicity. EP2 receptors are coupled to stimulatory G-proteins (Gs), which activate adenylate cyclase, increasing cAMP synthesis, which then activates protein kinase A (PKA). Both dibutyryl cAMP and forskolin reduced dopaminergic cell loss after 6-OHDA exposure. Conversely, KT5720 and H-89, two structurally distinct high-affinity PKA inhibitors, abolished the protective effect of butaprost, implicating cAMP-dependent PKA activity in the neuroprotection by EP2 activation. Finally, we show that melanized dopaminergic neurons in the human SN express EP2. This pathway warrants consideration as a neuroprotective strategy for PD.

  14. Temporal changes of CB1 cannabinoid receptor in the basal ganglia as a possible structure-specific plasticity process in 6-OHDA lesioned rats.

    Directory of Open Access Journals (Sweden)

    Gabriela P Chaves-Kirsten

    Full Text Available The endocannabinoid system has been implicated in several neurobiological processes, including neurodegeneration, neuroprotection and neuronal plasticity. The CB1 cannabinoid receptors are abundantly expressed in the basal ganglia, the circuitry that is mostly affected in Parkinson's Disease (PD. Some studies show variation of CB1 expression in basal ganglia in different animal models of PD, however the results are quite controversial, due to the differences in the procedures employed to induce the parkinsonism and the periods analyzed after the lesion. The present study evaluated the CB1 expression in four basal ganglia structures, namely striatum, external globus pallidus (EGP, internal globus pallidus (IGP and substantia nigra pars reticulata (SNpr of rats 1, 5, 10, 20, and 60 days after unilateral intrastriatal 6-hydroxydopamine injections, that causes retrograde dopaminergic degeneration. We also investigated tyrosine hydroxylase (TH, parvalbumin, calbindin and glutamic acid decarboxylase (GAD expression to verify the status of dopaminergic and GABAergic systems. We observed a structure-specific modulation of CB1 expression at different periods after lesions. In general, there were no changes in the striatum, decreased CB1 in IGP and SNpr and increased CB1 in EGP, but this increase was not sustained over time. No changes in GAD and parvalbumin expression were observed in basal ganglia, whereas TH levels were decreased and the calbindin increased in striatum in short periods after lesion. We believe that the structure-specific variation of CB1 in basal ganglia in the 6-hydroxydopamine PD model could be related to a compensatory process involving the GABAergic transmission, which is impaired due to the lack of dopamine. Our data, therefore, suggest that the changes of CB1 and calbindin expression may represent a plasticity process in this PD model.

  15. Effect and mechanism of homocysteine on Parkinson's disease induced by 6-OHDA

    Institute of Scientific and Technical Information of China (English)

    Hongxia Xing; Hai Peng; Xuebing Cao; Shenggang Sun

    2008-01-01

    Objective: To study the effects and mechanism of homocysteine(Hey) on Parkinson's disease(PD) induced by 6-hydroxydopamine (6-OHDA) in vivo. Methods:Forty rats were divided into 4 groups. 6-OHDA or the solvent of 6-OHDA was focally administrated to induce PD, 2 h later Hey or 0.9% sodium chloride was administrated in the ipsolateral substantial nigra(SN). We used behavioral testing, Immolunohistochemical techniques, biochemistry techniques to detect the injury of SN. Results:The rotary turns of PD rats induced by 6-OHDA showed significant increase after treatment with Hey compared with the controls(P < 0.05). Also the numbers of tyrosine hydroxylase(TH)-stained neurons were decreased, and dendrites were fragmented and truncated. Free radicals were increased and antioxidant enzymes decreased. Conclusion:Focal infusion of Hey into the SN increased the vulnerability of the dopaminergic neurons to 6-OHDA-induced degeneration, it seems that the endangering effect of Hey is due to exacerbating oxidative stress.

  16. Intrastriatal grafts of fetal ventral mesencephalon improve allodynia-like withdrawal response to mechanical stimulation in a rat model of Parkinson's disease.

    Science.gov (United States)

    Takeda, Ryuichiro; Ishida, Yasushi; Ebihara, Kosuke; Abe, Hiroshi; Matsuo, Hisae; Ikeda, Tetsuya; Koganemaru, Go; Kuramashi, Aki; Funahashi, Hideki; Magata, Yasuhiro; Kawai, Keiichi; Nishimori, Toshikazu

    2014-06-24

    We previously reported that a unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease showed allodynia-like withdrawal response to mechanical stimulation of the ipsilateral side of the rat hindpaw. The goal of this study was to investigate the effect of intrastriatal grafts of fetal ventral mesencephalon (VM) on the withdrawal response in 6-OHDA rats. The withdrawal threshold in response to the mechanical stimulation of the rat hindpaw was measured using von Frey filaments. In the ipsilateral side of the 6-OHDA lesions, the withdrawal threshold in response to mechanical stimulation significantly increased in 6-OHDA rats with VM grafts compared with those with sham grafts, but did not change in the contralateral side at 5 weeks after transplantation. The present results suggest that the intrastriatal grafts of fetal VM may relieve pain sensation induced by mechanical stimulation in 6-OHDA rats. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  17. 6-OHDA Induces Cycle Reentry and Apoetosis of PC12 Cells through Activation of ERK1/2 Signaling Pathway

    Institute of Scientific and Technical Information of China (English)

    Zhentao ZHANG; Tao WANG; Xuebing CAO; Shenggang SUN; Lan WANG

    2009-01-01

    This study investigated the effect and mechanism of cell cycle reentry induced by 6-hydrodopamine (6-OHDA) in PCI2 cells.By using neural differentiated PCI2 cells treated with 6-OHDA,the apoptosis model of dopaminergic neurons was established.Cell viability was measured by MTT.Cell apoptosis and the distribution of cell cycle were assessed by flow cytometry.Western blot was used to detect the activation of extracellular regulator kinasel/2 (ERK1/2) pathway and the phosphorylation of retinoblastoma protein (RB).Our results showed that after PC12 cells were treated wtih 6-OHDA,the viability of PC12 cells was declined in a concentration-dependent manner.Flow cytometry revealed that 6-OHDA could increase the apoptosis ratio of PC12 cells in a time-dependent manner.The percentage of cells in G0/G1 phase of cell cycle was decreased and that in S phase and G2/M phase increased.Simultaneously,ERK1/2 pathway was activated and phos- phorylated RB increased.It was concluded that 6-OHDA could induce cell cycle reentry of dopa-minergic neurons through the activation of ERK1/2 pathway and RB phosphorylation.The aberrant cell cycle reentry contributes to the apoptosis of dopaminergic neurons.

  18. Early expression of the receptor for advanced glycation end products in a toxic model produced by 6-hydroxydopamine in the rat striatum.

    Science.gov (United States)

    Serratos, Iris N; Castellanos, Pilar; Pastor, Nina; Millán-Pacheco, César; Colín-González, Ana Laura; Rembao, Daniel; Pérez-Montfort, Ruy; Cabrera, Nallely; Sánchez-García, Aurora; Gómez, Isabel; Rangel-López, Edgar; Santamaria, Abel

    2016-04-05

    The receptor for advanced glycation end products (RAGE) is commonly involved in different neurodegenerative and inflammatory disorders. The cellular signaling associated to RAGE activation may occur upon binding to different ligands. In this study we investigated whether the toxic model produced by 6-hydroxydopamine (6-OHDA) in rats comprises early noxious responses related to RAGE-mediated signaling cascades. In order to explore a possible interaction between 6-OHDA and RAGE, affinity parameters of RAGE with 6-OHDA were estimated by different means. The possible binding sites of 6-OHDA with the VC1 homodimer for both rat and human RAGE were also modeled. Our results show that the striatal infusion of 6-OHDA recruits RAGE upregulation, as evidenced by an early expression of the receptor. 6-OHDA was also found to bind the VC1 homodimer, although its affinity was moderate when compared to other ligands. This work contributes to the understanding of the role of RAGE activation for 6-OHDA-induced neurotoxicity.

  19. Intranasal Administration of GDNF Protects Against Neural Apoptosis in a Rat Model of Parkinson's Disease Through PI3K/Akt/GSK3β Pathway.

    Science.gov (United States)

    Yue, Peijian; Gao, Lin; Wang, Xuejing; Ding, Xuebing; Teng, Junfang

    2017-02-28

    Glial cell line-derived neurotrophic factor (GDNF) plays important roles in protecting the damaged or dying dopamine neurons in the animal models of Parkinson's disease (PD). This study was to determine the effect and mechanisms of GDNF on the apoptosis of neurons in 6-hydroxydopamine (6-OHDA) induced Parkinson's disease model of rats. Healthy male Sprague-Dawley rats (220-240 g) were randomly divided into six groups (n = 10). 6-OHDA was used to establish the PD rat model. Tyrosine hydroxylase (TH) immunohistochemistry was used to assess the neuron loss in 6-OHDA-lesioned rats. TUNEL and western blot were used to identify the effects and mechanisms of GDNF in the rat model of PD. The numbers of TH-positive neurons in the 6-OHDA-injected lesioned substantia nigra (SN) decreased significantly compared with the Sham group. GDNF treatment effectively ameliorated the apoptosis of neuronal cells in SN induced by 6-OHDA. In addition, GDNF significantly increased serine protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK3β) phosphorylation induced by 6-OHDA. In contrast, application of LY294002 or triciribine reversed the roles of GDNF in PD models. The results implicated that the anti-apoptosis effects of GDNF in neurons might be mediated through PI3K/Akt/GSK3β pathway. Therefore, GDNF may be a promising agent for PD treatment.

  20. MODELING OPERANT BEHAVIOR IN THE PARKINSONIAN RAT

    OpenAIRE

    Avila, Irene; Reilly, Mark P; Sanabria, Federico; Posadas-Sánchez, Diana; Chavez, Claudia L.; Banerjee, Nikhil; Killeen, Peter; Castañeda, Edward

    2008-01-01

    Mathematical principles of reinforcement (MPR; Killeen, 1994) is a quantitative model of operant behavior that contains 3 parameters representing motor capacity (δ), motivation (a), and short term memory (λ). The present study applied MPR to characterize the effects of bilateral infusions of 6-OHDA into the substantia nigra pars compacta in the rat, a model of Parkinson’s disease. Rats were trained to lever press under a 5-component fixed ratio (5, 15, 30, 60, and 100) schedule of food reinfo...

  1. The high-affinity D2/D3 agonist D512 protects PC12 cells from 6-OHDA-induced apoptotic cell death and rescues dopaminergic neurons in the MPTP mouse model of Parkinson's disease.

    Science.gov (United States)

    Shah, Mrudang; Rajagopalan, Subramanian; Xu, Liping; Voshavar, Chandrashekhar; Shurubor, Yevgeniya; Beal, Flint; Andersen, Julie K; Dutta, Aloke K

    2014-10-01

    In this study, in vitro and in vivo experiments were carried out with the high-affinity multifunctional D2/D3 agonist D-512 to explore its potential neuroprotective effects in models of Parkinson's disease and the potential mechanism(s) underlying such properties. Pre-treatment with D-512 in vitro was found to rescue rat adrenal Pheochromocytoma PC12 cells from toxicity induced by 6-hydroxydopamine administration in a dose-dependent manner. Neuroprotection was found to coincide with reductions in intracellular reactive oxygen species, lipid peroxidation, and DNA damage. In vivo, pre-treatment with 0.5 mg/kg D-512 was protective against neurodegenerative phenotypes associated with systemic administration of MPTP, including losses in striatal dopamine, reductions in numbers of DAergic neurons in the substantia nigra (SN), and locomotor dysfunction. These observations strongly suggest that the multifunctional drug D-512 may constitute a novel viable therapy for Parkinson's disease.

  2. Curcumin protects nigral dopaminergic neurons by iron-chelation in the 6-hydroxydopamine rat model of Parkinson's disease

    Institute of Scientific and Technical Information of China (English)

    Xi-Xun Du; Hua-Min Xu; Hong Jiang; Ning Song; Jun Wang; Jun-Xia Xie

    2012-01-01

    [Objective] Curcumin is a plant polyphenolic compound and a major component of spice turmeric (Curcuma longa).It has been reported to possess free radical-scavenging,iron-chelating,and anti-inflammatory properties in different tissues.Our previous study showed that curcumin protects MES23.5 dopaminergic cells from 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in vitro.The present study aimed to explore this neuroprotective effect in the 6-OHDAlesioned rat model of Parkinson's disease in vivo.[Methods] Rats were given intragastric curcumin for 24 days.6-OHDA lesioning was conducted on day 4 of curcumin treatment.Dopamine content was assessed by high-performance liquid chromatography with electrochemical detection,tyrosine hydroxylase (TH)-containing neurons by immunohistochemistry,and iron-containing cells by Perls' iron staining.[Results] The dopamine content in the striatum and the number of THimmunoreactive neurons decreased after 6-OHDA treatment.Curcumin pretreatment reversed these changes.Further studies demonstrated that 6-OHDA treatment increased the number of iron-staining cells,which was dramatically decreased by curcumin pretreatment.[Conclusion]The protective effects of curcumin against 6-OHDA may be attributable to the ironchelating activity of curcumin to suppress the iron-induced degeneration of nigral dopaminergic neurons.

  3. Effects of GDNF pretreatment on function and survival of transplanted fetal ventral mesencephalic cells in the 6-OHDA rat model of Parkinson's disease

    DEFF Research Database (Denmark)

    Andereggen, Lukas; Meyer, Morten; Guzman, Raphael

    2009-01-01

    Transplantation of fetal dopaminergic (DA) neurons offers an experimental therapy for Parkinson's disease (PD). The low availability and the poor survival and integration of transplanted cells in the host brain are major obstacles in this approach. Glial cell line-derived neurotrophic factor (GDNF...

  4. Partial neurorescue effects of DHA following a 6-OHDA lesion of the mouse dopaminergic system.

    Science.gov (United States)

    Coulombe, Katherine; Saint-Pierre, Martine; Cisbani, Giulia; St-Amour, Isabelle; Gibrat, Claire; Giguère-Rancourt, Ariane; Calon, Frédéric; Cicchetti, Francesca

    2016-04-01

    Pre-clinical data collected in mouse models of Parkinson's disease (PD) support the neuroprotective potential of omega-3 polyunsaturated fatty acids (n-3 PUFA)-enriched diet on the dopaminergic (DAergic) system. In this study, we investigated the effects of an n-3 PUFA-rich diet using a neurorescue/neurorestorative paradigm. C57BL/6 adult mice were submitted to a striatal stereotaxic injection of the neurotoxin 6-hydroxydopamine (6-OHDA) to induce striatal DAergic denervation and subsequent nigral DAergic cell loss. Three weeks post-lesion, mice received either a docosahexaenoic acid (DHA)-enriched or a control diet for a period of 6 weeks. HPLC analyses revealed a 111% post-lesion increase in striatal dopamine levels in the DHA-fed animals compared to controls (ctrl, PDHA treatment led to a 89% rise in tyrosine-hydroxylase (TH)-immunoreactive terminals within the striatum (PDHA did not change the number of TH+ neurons in the substantia nigra pars compacta (SNpc), morphological analyses revealed an increased in perimeters (+7%) and areas (+21%) of DAergic cell bodies in treated animals. Collectively, our results suggest that DHA induces a partial neurorescue/neurorestoration of the DAergic system and support further studies to investigate the potential of a diet-based intervention, or at least the combination of such approach, to current treatments in PD.

  5. Subtle Cardiovascular Dysfunction in the Unilateral 6-Hydroxydopamine-Lesioned Rat

    Directory of Open Access Journals (Sweden)

    K. Slack

    2010-01-01

    Full Text Available The present study evaluated whether the unilateral 6-hydroxydopamine (6-OHDA model of Parkinson's disease produces autonomic deficits. Autonomic parameters were assessed by implanting a small radiofrequency telemetry device which measured heart rate variability (HRV, diurnal rhythms of heart rate (HR, core body temperature (cBT and locomotor activity (LA. Rats then received 6-OHDA lesion or sham surgery. 6-OHDA lesioned rats exhibited head and body axis biases, defective sensorimotor function (“disengage” test, and prominent apomorphine rotation (all P<.05 versus controls. Diurnal rhythm of HR was lower for 6-OHDA lesioned rats (n=8 versus controls (n=6; P<.05. Whilst HR decreased similarly in both groups during the day, there was a greater decrease in HR for the 6-OHDA lesioned rats at night (by 38 b.p.m. relative to 17 b.p.m. for controls. LA and cBT did not differ between surgery groups. This study indicates the unilateral 6-OHDA model of PD shows subtle signs of cardiovascular autonomic dysfunction.

  6. Resveratrol Protects PC12 Cell against 6-OHDA Damage via CXCR4 Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Jing Zhang

    2015-01-01

    Full Text Available Resveratrol, herbal nonflavonoid polyphenolic compound naturally derived from grapes, has long been acknowledged to possess extensive biological and pharmacological properties including antioxidant and anti-inflammatory ones and may exert a neuroprotective effect on neuronal damage in neurodegenerative diseases. However, the underlying molecular mechanisms remain undefined. In the present study, we intended to investigate the neuroprotective effects of resveratrol against 6-OHDA-induced neurotoxicity of PC12 cells and further explore the possible mechanisms involved. For this purpose, PC12 cells were exposed to 6-OHDA in the presence of resveratrol (0, 12.5, 25, and 50 μM. The results showed that resveratrol increased cell viability, alleviated the MMP reduction, and reduced the number of apoptotic cells as measured by MTT assay, JC-1 staining, and Hoechst/PI double staining (all p<0.01. Immunofluorescent staining and Western blotting revealed that resveratrol averts 6-OHDA induced CXCR4 upregulation (p<0.01. Our results demonstrated that resveratrol could effectively protect PC12 cells from 6-OHDA-induced oxidative stress and apoptosis via CXCR4 signaling pathway.

  7. Both Creatine and Its Product Phosphocreatine Reduce Oxidative Stress and Afford Neuroprotection in an In Vitro Parkinson’s Model

    Science.gov (United States)

    Martín-de-Saavedra, Maria D.; Romero, Alejandro; Egea, Javier; Ludka, Fabiana K.; Tasca, Carla I.; Farina, Marcelo; Rodrigues, Ana Lúcia S.; López, Manuela G.

    2014-01-01

    Creatine is the substrate for creatine kinase in the synthesis of phosphocreatine (PCr). This energetic system is endowed of antioxidant and neuroprotective properties and plays a pivotal role in brain energy homeostasis. The purpose of this study was to investigate the neuroprotective effect of creatine and PCr against 6-hydroxydopamine (6-OHDA)-induced mitochondrial dysfunction and cell death in rat striatal slices, used as an in vitro Parkinson’s model. The possible involvement of the signaling pathway mediated by phosphatidylinositol-3 kinase (PI3K), protein kinase B (Akt), and glycogen synthase kinase-3β (GSK3β) was also evaluated. Exposure of striatal slices to 6-OHDA caused a significant disruption of the cellular homeostasis measured as 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide reduction, lactate dehydrogenase release, and tyrosine hydroxylase levels. 6-OHDA exposure increased the levels of reactive oxygen species and thiobarbituric acid reactive substances production and decreased mitochondrial membrane potential in rat striatal slices. Furthermore, 6-OHDA decreased the phosphorylation of Akt (Serine473) and GSK3β (Serine9). Coincubation with 6-OHDA and creatine or PCr reduced the effects of 6-OHDA toxicity. The protective effect afforded by creatine or PCr against 6-OHDA-induced toxicity was reversed by the PI3K inhibitor LY294002. In conclusion, creatine and PCr minimize oxidative stress in striatum to afford neuroprotection of dopaminergic neurons. PMID:25424428

  8. Both creatine and its product phosphocreatine reduce oxidative stress and afford neuroprotection in an in vitro Parkinson's model.

    Science.gov (United States)

    Cunha, Mauricio Peña; Martín-de-Saavedra, Maria D; Romero, Alejandro; Egea, Javier; Ludka, Fabiana K; Tasca, Carla I; Farina, Marcelo; Rodrigues, Ana Lúcia S; López, Manuela G

    2014-01-01

    Creatine is the substrate for creatine kinase in the synthesis of phosphocreatine (PCr). This energetic system is endowed of antioxidant and neuroprotective properties and plays a pivotal role in brain energy homeostasis. The purpose of this study was to investigate the neuroprotective effect of creatine and PCr against 6-hydroxydopamine (6-OHDA)-induced mitochondrial dysfunction and cell death in rat striatal slices, used as an in vitro Parkinson's model. The possible involvement of the signaling pathway mediated by phosphatidylinositol-3 kinase (PI3K), protein kinase B (Akt), and glycogen synthase kinase-3β (GSK3β) was also evaluated. Exposure of striatal slices to 6-OHDA caused a significant disruption of the cellular homeostasis measured as 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide reduction, lactate dehydrogenase release, and tyrosine hydroxylase levels. 6-OHDA exposure increased the levels of reactive oxygen species and thiobarbituric acid reactive substances production and decreased mitochondrial membrane potential in rat striatal slices. Furthermore, 6-OHDA decreased the phosphorylation of Akt (Serine(473)) and GSK3β (Serine(9)). Coincubation with 6-OHDA and creatine or PCr reduced the effects of 6-OHDA toxicity. The protective effect afforded by creatine or PCr against 6-OHDA-induced toxicity was reversed by the PI3K inhibitor LY294002. In conclusion, creatine and PCr minimize oxidative stress in striatum to afford neuroprotection of dopaminergic neurons.

  9. Tetramethylpyrazine Analogue CXC195 Protects Against Dopaminergic Neuronal Apoptosis via Activation of PI3K/Akt/GSK3β Signaling Pathway in 6-OHDA-Induced Parkinson's Disease Mice.

    Science.gov (United States)

    Chen, Lin; Cheng, Li; Wei, Xinbing; Yuan, Zheng; Wu, Yanmei; Wang, Shuaishuai; Ren, Zhiping; Liu, Xinyong; Liu, Huiqing

    2016-12-22

    Parkinson's disease (PD) is a progressive neurodegenerative disorder and characterized by motor system disorders resulting in loss of dopaminergic (DA) neurons. CXC195, a novel tetramethylpyrazine derivative, has been shown strongest neuroprotective effects due to its anti-apoptotic activity. However, whether CXC195 protects against DA neuronal damage in PD and the mechanisms underlying its beneficial effects are unknown. The purpose of our study was to investigate the potential neuroprotective role of CXC195 and to elucidate its mechanism of action against 6-hydroxydopamine (6-OHDA)-induced mouse model of PD. CXC195 administration improved DA neurodegeneration in PD mice induced by 6-OHDA. Our further findings confirmed treatment of CXC195 at the dose of 10 mg/kg significantly inhibited the apoptosis by decreasing the level of cleaved caspase-3 and Bax, and increasing the level of Bcl-2 in 6-OHDA-lesioned mice. Meanwhile, 6-OHDA also decreased the amount of phosphorylated Akt while increased GSK-3β activity (the amount of phosphorylated GSK-3β at Ser9 was decreased) which was prevented by CXC195. Wortmannin, a specific PI3K inhibitor, dramatically abolished the changes induced by CXC195. Our study firstly demonstrated that CXC195 protected against DA neurodegeneration in 6-OHDA-induced PD model by its anti-apoptotic properties and PI3K/Akt/GSK3β signaling pathway was involved in it.

  10. Effects of (-)-sesamin on 6-hydroxydopamine-induced neurotoxicity in PC12 cells and dopaminergic neuronal cells of Parkinson's disease rat models.

    Science.gov (United States)

    Park, Hyun Jin; Zhao, Ting Ting; Lee, Kyung Sook; Lee, Seung Ho; Shin, Keon Sung; Park, Keun Hong; Choi, Hyun Sook; Lee, Myung Koo

    2015-01-01

    The present study investigated the effects of (-)-sesamin on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity using PC12 cells and dopaminergic neuronal cells of 6-OHDA-lesioned rat model of Parkinson's disease (PD). In PC12 cells, treatment with (-)-sesamin (25 µM) reduced 6-OHDA (100 µM)-induced cell death and induced transient extracellular signal-regulated kinase (ERK1/2) phosphorylation and Bad phosphorylation at Ser112 (BadSer112). In contrast, sustained ERK1/2 phosphorylation, p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK1/2) phosphorylation, and cleaved-caspase-3 activity, all of which were induced by 6-OHDA (100 µM), were inhibited by treatment with (-)-sesamin (25 µM). Furthermore, co-treatment with (-)-sesamin (30 mg/kg, p.o.) once a day for 28 days significantly increased the number of tyrosine hydroxylase-immunopositive neuronal cells and the levels of dopamine, norepinephrine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the substantia nigra-striatum of 6-OHDA-lesioned rat model of PD with or without L-DOPA treatment. These results suggest that (-)-sesamin protects 6-OHDA-induced cytotoxicity via the activation of transient ERK1/2-BadSer112 system and the inhibition of sustained ERK-p38MAPK-JNK1/2-caspase-3 system in PC12 cells. (-)-Sesamin also shows protective effects on long-term L-DOPA therapy in dopaminergic neuronal cells of PD rat models. (-)-Sesamin may serve as adjuvant therapeutics in PD.

  11. Changes of norepinephrine and tumor necrosis factor in submandibular gland of rats with sympathetic nerve injury and the protective effect of 17 beta-estradiol

    Institute of Scientific and Technical Information of China (English)

    Yagao Feng; Suya Deng; Zhenqi Liu; Min Hu; Houjun Yan; Qiusheng Wang

    2006-01-01

    BACKGROUND: Recent researches have indicated that estrogen has extensive neuroprotective effects. So some studies designed ovariectomized animal models and administrated with estrogen, so as to verify its neuroprotective effects.OBJECTIVE: To observe the effect of 17 beta-estradiol on the content of norepinephrine (NE) and level of tumor necrosis factor (TNF) in submandibular glands of rats with sympathetic nerve injury, and analyze the dose-dependence and pathway of action.DESIGN: A randomized control animal study.SETTINGS: Department of Hand Surgery, the 252 Hospital of Chinese PLA; Department of Hand Surgery,Union Hospital affiliated to Tongji Medical College, Huazhong University of Science and Technology.MATERIALS: Fifty healthy female Wistar rats were randomly divided into 5 groups with 10 rats in each group: sham-operated group, ovariectomy+6-OHDA+saline group, ovariectomy+6-OHDA+17β-estradiol 50,200 and 500 μg/kg groups.METHODS: The experiments were carried out in Tongji Medical College, Huazhong University of Science and Technology between October 2005 and March 2006. Bilateral ovaries were only exposed but not resected for the rats in the sham-operated group, but bilateral ovaries were resected in all the other groups. In the ovariectomy+6-OHDA+17β-estradiol 50, 200 and 500 μg/kg groups, the rats were administrated with intraperitoneal injection of 6-OHDA (8 mg/kg), and then immediately given 17β-estradiol of corresponding dosages respectively, once a day for 10 days continuously. Rats in the sham-operated group and ovariectomy+6-OHDA+saline group were administrated with saline of the same volume. After administration, 5 rats in each group were killed to determine the NE contents in bilateral submandibular glands with high performance liquid chromatography-electrochemical detector (HPLC-ECD), and the other 5 rats were used to determine the TNF levels in submandibular glands with enzyme-linked immunosorbant assay.MATN OUTCOME MEASURES: The NE contents

  12. Pituitary adenylate cyclase-activating polypeptide (PACAP has a neuroprotective function in dopamine-based neurodegeneration in rat and snail parkinsonian models

    Directory of Open Access Journals (Sweden)

    Gabor Maasz

    2017-02-01

    Full Text Available Pituitary adenylate cyclase-activating polypeptide (PACAP rescues dopaminergic neurons from neurodegeneration and improves motor changes induced by 6-hydroxy-dopamine (6-OHDA in rat parkinsonian models. Recently, we investigated the molecular background of the neuroprotective effect of PACAP in dopamine (DA-based neurodegeneration using rotenone-induced snail and 6-OHDA-induced rat models of Parkinson's disease. Behavioural activity, monoamine (DA and serotonin, metabolic enzyme (S-COMT, MB-COMT and MAO-B and PARK7 protein concentrations were measured before and after PACAP treatment in both models. Locomotion and feeding activity were decreased in rotenone-treated snails, which corresponded well to findings obtained in 6-OHDA-induced rat experiments. PACAP was able to prevent the behavioural malfunctions caused by the toxins. Monoamine levels decreased in both models and the decreased DA level induced by toxins was attenuated by ∼50% in the PACAP-treated animals. In contrast, PACAP had no effect on the decreased serotonin (5HT levels. S-COMT metabolic enzyme was also reduced but a protective effect of PACAP was not observed in either of the models. Following toxin treatment, a significant increase in MB-COMT was observed in both models and was restored to normal levels by PACAP. A decrease in PARK7 was also observed in both toxin-induced models; however, PACAP had a beneficial effect only on 6-OHDA-treated animals. The neuroprotective effect of PACAP in different animal models of Parkinson's disease is thus well correlated with neurotransmitter, enzyme and protein levels. The models successfully mimic several, but not all etiological properties of the disease, allowing us to study the mechanisms of neurodegeneration as well as testing new drugs. The rotenone and 6-OHDA rat and snail in vivo parkinsonian models offer an alternative method for investigation of the molecular mechanisms of neuroprotective agents, including PACAP.

  13. Pituitary adenylate cyclase-activating polypeptide (PACAP) has a neuroprotective function in dopamine-based neurodegeneration in rat and snail parkinsonian models

    Science.gov (United States)

    Kiss, Tibor; Jungling, Adel

    2017-01-01

    ABSTRACT Pituitary adenylate cyclase-activating polypeptide (PACAP) rescues dopaminergic neurons from neurodegeneration and improves motor changes induced by 6-hydroxy-dopamine (6-OHDA) in rat parkinsonian models. Recently, we investigated the molecular background of the neuroprotective effect of PACAP in dopamine (DA)-based neurodegeneration using rotenone-induced snail and 6-OHDA-induced rat models of Parkinson's disease. Behavioural activity, monoamine (DA and serotonin), metabolic enzyme (S-COMT, MB-COMT and MAO-B) and PARK7 protein concentrations were measured before and after PACAP treatment in both models. Locomotion and feeding activity were decreased in rotenone-treated snails, which corresponded well to findings obtained in 6-OHDA-induced rat experiments. PACAP was able to prevent the behavioural malfunctions caused by the toxins. Monoamine levels decreased in both models and the decreased DA level induced by toxins was attenuated by ∼50% in the PACAP-treated animals. In contrast, PACAP had no effect on the decreased serotonin (5HT) levels. S-COMT metabolic enzyme was also reduced but a protective effect of PACAP was not observed in either of the models. Following toxin treatment, a significant increase in MB-COMT was observed in both models and was restored to normal levels by PACAP. A decrease in PARK7 was also observed in both toxin-induced models; however, PACAP had a beneficial effect only on 6-OHDA-treated animals. The neuroprotective effect of PACAP in different animal models of Parkinson's disease is thus well correlated with neurotransmitter, enzyme and protein levels. The models successfully mimic several, but not all etiological properties of the disease, allowing us to study the mechanisms of neurodegeneration as well as testing new drugs. The rotenone and 6-OHDA rat and snail in vivo parkinsonian models offer an alternative method for investigation of the molecular mechanisms of neuroprotective agents, including PACAP. PMID:28067625

  14. Pituitary adenylate cyclase-activating polypeptide (PACAP) has a neuroprotective function in dopamine-based neurodegeneration in rat and snail parkinsonian models.

    Science.gov (United States)

    Maasz, Gabor; Zrinyi, Zita; Reglodi, Dora; Petrovics, Dora; Rivnyak, Adam; Kiss, Tibor; Jungling, Adel; Tamas, Andrea; Pirger, Zsolt

    2017-02-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) rescues dopaminergic neurons from neurodegeneration and improves motor changes induced by 6-hydroxy-dopamine (6-OHDA) in rat parkinsonian models. Recently, we investigated the molecular background of the neuroprotective effect of PACAP in dopamine (DA)-based neurodegeneration using rotenone-induced snail and 6-OHDA-induced rat models of Parkinson's disease. Behavioural activity, monoamine (DA and serotonin), metabolic enzyme (S-COMT, MB-COMT and MAO-B) and PARK7 protein concentrations were measured before and after PACAP treatment in both models. Locomotion and feeding activity were decreased in rotenone-treated snails, which corresponded well to findings obtained in 6-OHDA-induced rat experiments. PACAP was able to prevent the behavioural malfunctions caused by the toxins. Monoamine levels decreased in both models and the decreased DA level induced by toxins was attenuated by ∼50% in the PACAP-treated animals. In contrast, PACAP had no effect on the decreased serotonin (5HT) levels. S-COMT metabolic enzyme was also reduced but a protective effect of PACAP was not observed in either of the models. Following toxin treatment, a significant increase in MB-COMT was observed in both models and was restored to normal levels by PACAP. A decrease in PARK7 was also observed in both toxin-induced models; however, PACAP had a beneficial effect only on 6-OHDA-treated animals. The neuroprotective effect of PACAP in different animal models of Parkinson's disease is thus well correlated with neurotransmitter, enzyme and protein levels. The models successfully mimic several, but not all etiological properties of the disease, allowing us to study the mechanisms of neurodegeneration as well as testing new drugs. The rotenone and 6-OHDA rat and snail in vivo parkinsonian models offer an alternative method for investigation of the molecular mechanisms of neuroprotective agents, including PACAP.

  15. Neuroprotective Effects of Sulphated Agaran from Marine Alga Gracilaria cornea in Rat 6-Hydroxydopamine Parkinson's Disease Model: Behavioural, Neurochemical and Transcriptional Alterations.

    Science.gov (United States)

    Souza, Ricardo Basto; Frota, Annyta Fernandes; Sousa, Rayane Siqueira; Cezario, Nayara Araújo; Santos, Tarcizio Brito; Souza, Luziana Mara Frota; Coura, Chistiane Oliveira; Monteiro, Valdécio Silvano; Cristino Filho, Gerardo; Vasconcelos, Silvânia Maria Mendes; da Cunha, Rodrigo Maranguape Silva; Aguiar, Lissiana Magna Vasconcelos; Benevides, Norma Maria Barros

    2017-02-01

    Parkinson's disease (PD) is a multifactorial disease associated with the degeneration of dopaminergic neurons and behavioural alterations. Natural bioactive compounds may provide new therapeutic alternatives for neurodegenerative disorders, such as PD. The sulphated polysaccharides isolated from marine algae are heterogenic molecules that show different biological activities. The red marine alga Gracilaria cornea has a sulphated polysaccharide (SA-Gc) with structure and anti-inflammatory and antinociceptive activities reported in the literature. Therefore, this study aimed to evaluate the neuroprotective effects of SA-Gc in rat model PD induced by 6-hydroxydopamine (6-OHDA). Firstly, we established the PD model in rats, induced by an intrastriatal injection (int.) of 6-OHDA, followed by a single administration of SA-Gc (15, 30 or 60 μg; int.). On the 14th day, behavioural tests were performed. After killing, brain areas were dissected and used for neurochemical and/or transcriptional analyses. The results showed that SA-Gc (60 μg, int.) promoted neuroprotective effects in vivo through reducing the oxidative/nitroactive stress and through alterations in the monoamine contents induced by 6-OHDA. Furthermore, SA-Gc modulated the transcription of neuroprotective and inflammatory genes, as well as returning behavioural activities and weight gain to normal conditions. Thus, this study reports the neuroprotective effects of SA-Gc against 6-OHDA in rats.

  16. The ameliorative effect of Monascus purpureus NTU 568-fermented rice extracts on 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells and the rat model of Parkinson's disease.

    Science.gov (United States)

    Tseng, Wei-Ting; Hsu, Ya-Wen; Pan, Tzu-Ming

    2016-02-01

    Oxidative stress and neuroinflammation underlie the major pathogenesis in Parkinson's disease (PD). Antioxidants are known to protect against the degeneration of dopaminergic neurons. Monascus purpureus-fermented rice, a traditional Chinese medicine as well as a health food, includes multifunctional metabolites. The present study was designed to investigate the effects of the antioxidant-containing M. purpureus NTU 568-fermented rice extract (extracted with 50% ethanol, so called R50E) in 6-hydrodopamine (6-OHDA)-induced neurotoxicity in vitro and in vivo. In vitro, treatment with R50E reduced 6-OHDA-induced SH-SY5Y cell death. In vivo, two doses of R50E (5.5 and 11.0 mg kg(-1)) were administered for a period of 28 days following 6-OHDA-induced lesioning. The administration of R50E reduced parkinsonian motor dysfunction and the number of tyrosine hydroxylase (TH)-immunoreactive neurons present in 6-OHDA-induced lesioned rats. Moreover, the administration of R50E reversed the elevation of reactive oxygen species (ROS) and malondialdehyde (MDA) levels and promoted the activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione reductase, and glutathione peroxidase via down-regulation of p47 phox, NOX1, and NOX2 expression in the 6-OHDA-lesion rats. Furthermore, treatment with R50E attenuated nitric oxide (NO) and tumor necrosis factor (TNF-α) levels in the 6-OHDA-lesion rats. In conclusion, R50E may prevent neurodegeneration via anti-oxidative and anti-inflammatory mechanisms, suggesting its potential therapeutic value for PD treatment. This is the first study for evaluating the neuroprotective effects of red mold fermented products in PD models.

  17. Hematological disorders in 6-hydroxydopamine-induced rat model of Parkinson’s disease

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    Lucian Hritcu

    2008-09-01

    Full Text Available Objective: The present work was undertaken in order to investigate the effects of right-unilateral lesion of substantia nigra neurons by means of 6- hydroxydopamine (6-OHDA, a dopaminergic-selective neurotoxin, on hematological parameters in rats. The primary reason for the using of rat model of Parkinson’s disease was the interest regarding the role of the central dopaminergic system in hematopoiesis regulation because some neurological diseases like Parkinson’s disease are well-correlated with anemia associated with autonomic dysfunction in rats.Material and Methods: Thirty male Wistar rats weighing 200 ± 50 g at the start of the experiment were used. The substantia nigra was right-unilateral lesioned by stereotaxic microinjections of 8 micrograms (free base 6-OHDA, dissolved in 4 µl physiological saline containing 0.1% ascorbic acid, administered through the Hamilton microsyringe over 4.50 minutes. 7 days after neurosurgery, we assessed the total number of white blood cells (WBC, the total number of red blood cells (RBC, hemoglobin level and the erythrocyte indexes (mean cell volume, MCV and mean cell hemoglobin, MCH.Hematological parameters were assayed by a COULTER® Ac◊T 5diff CP-precision instruments for hematology research.Results: 6-OHDA treatment induced a significantly decrease of white blood cells (p<0.03, red blood cells (p<0.01, hemoglobin level (p<0.02 comparative with sham-operated rats. By contrast, in the 6-OHDA-lesioned rats the erythrocyte indexes (mean cell volume, MCV (p<0.04; mean cell hemoglobin, MCH (p<0.01 were significantly enhanced comparative with sham-operated rats.Conclusion: On the whole, the obtained data indicate the important role of the central dopaminergic system in the regulation of erythrocyte dynamics.

  18. Tetraspanin (TSP-17 protects dopaminergic neurons against 6-OHDA-induced neurodegeneration in C. elegans.

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    Neda Masoudi

    2014-12-01

    Full Text Available Parkinson's disease (PD, the second most prevalent neurodegenerative disease after Alzheimer's disease, is linked to the gradual loss of dopaminergic neurons in the substantia nigra. Disease loci causing hereditary forms of PD are known, but most cases are attributable to a combination of genetic and environmental risk factors. Increased incidence of PD is associated with rural living and pesticide exposure, and dopaminergic neurodegeneration can be triggered by neurotoxins such as 6-hydroxydopamine (6-OHDA. In C. elegans, this drug is taken up by the presynaptic dopamine reuptake transporter (DAT-1 and causes selective death of the eight dopaminergic neurons of the adult hermaphrodite. Using a forward genetic approach to find genes that protect against 6-OHDA-mediated neurodegeneration, we identified tsp-17, which encodes a member of the tetraspanin family of membrane proteins. We show that TSP-17 is expressed in dopaminergic neurons and provide genetic, pharmacological and biochemical evidence that it inhibits DAT-1, thus leading to increased 6-OHDA uptake in tsp-17 loss-of-function mutants. TSP-17 also protects against toxicity conferred by excessive intracellular dopamine. We provide genetic and biochemical evidence that TSP-17 acts partly via the DOP-2 dopamine receptor to negatively regulate DAT-1. tsp-17 mutants also have subtle behavioral phenotypes, some of which are conferred by aberrant dopamine signaling. Incubating mutant worms in liquid medium leads to swimming-induced paralysis. In the L1 larval stage, this phenotype is linked to lethality and cannot be rescued by a dop-3 null mutant. In contrast, mild paralysis occurring in the L4 larval stage is suppressed by dop-3, suggesting defects in dopaminergic signaling. In summary, we show that TSP-17 protects against neurodegeneration and has a role in modulating behaviors linked to dopamine signaling.

  19. Effects of 6-OHDA lesion of hippocampal CA3 dopaminergic system on conditioned fear memory in rats%损毁海马CA3区多巴胺能系统对大鼠条件性恐惧记忆的影响

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    文加玲; 时燕薇; 赵虎

    2012-01-01

    目的 研究大鼠海马CA3区多巴胺(DA)能系统在条件性恐惧记忆形成与保持中的作用.方法 条件性恐惧训练前2周向双侧海马CA3区注入6-羟基多巴胺(6-OHDA)进行损毁,训练后用Western blotting检测前额叶皮层、CA1、杏仁体GluR1及NR2B的表达变化.结果 (1)与生理盐水组[(66.44±16.58)%,(73.43±23.57)%,(55.27±20.57)%]比较,6-OHDA损毁组恐惧记忆获得的僵住反应[ (65.58±5.33)%]差异无统计学意义(P>0.05),短时恐惧记忆的僵住反应[(39.24±12.83)%]与长时恐惧记忆的僵住反应[(31.15±6.51)%]明显减少(P<0.05).(2)与生理盐水组比较,6-OHDA损毁组大鼠前额叶皮层,海马CA1区的GluR1蛋白表达差异无统计学意义(P>0.05),杏仁体BLA区的GluR1蛋白表达升高(P<0.01).与生理盐水组比较,6-OHDA损毁组大鼠前额叶皮层的NR2B蛋白表达升高(P<0.01),海马CA1区的NR2B蛋白表达差异无统计学意义(P>0.05),杏仁体BLA区的NR2B蛋白表达降低(P<0.01).结论 大鼠海马CA3区多巴胺能系统功能下调能损害恐惧记忆的巩固但不影响其获得,还可以调节其他脑区记忆相关蛋白的表达.%Objective To investigate the effects of hippocampal CA3 dopaminergic system in acquisition and consolidation of Pavlovian fear conditioning,and expression of GluR1 and NR2B in medial prefrontal cortex (mPFC),CA1 and basolateral amygdala (BLA) after fear conditioning training.Methods Bilateral injection 6-OHDA into hippocampal CA3 to lesion dopaminergic fibers 2 weeks before fear conditioning training.The change of GluR1 and NR2B were analyzed by western blot after training.Results Compared with the saline group ( (66.44 ± 16.58)% ),there were significant decreases ( (39.24 ± 12.83)%,(31.15 ±6.51 )% ) in the consolidation of short- and long- term fear memory (P < 0.05 ) but not the acquisition ( ( 65.58 ± 5.33 ) %,P > 0.05).The expression of GluR1 protein was significantly increased in BLA

  20. Neurokinin receptor 3 peptide exacerbates 6-hydroxydopamine-induced dopaminergic degeneration in rats through JNK pathway.

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    Chu, John Man Tak; Chan, Ying Shing; Chen, Liang Wei; Yung, Ken Kin Lam

    2012-11-01

    Neurokinin 3 (NK3) receptor is predominantly expressed in striatum and substantia nigra (SN). Evidences have indicated the roles of NK3 receptor in the pathogenesis of Parkinson's disease. By administrating NK3 receptor agonist senktide into 6-hydroxydopamine (6-OHDA)-lesioned rats, exacerbation of dopaminergic degeneration was found in striatum and substantia nigra pars compacta. From apomorphine rotation test, significant increase of contralateral rotation number was detected in 6-OHDA-lesioned rats with senktide injection. Furthermore, tyrosine hydroxylase expression in striatum and substantia nigra pars compacta were examined by immunohistochemistry and Western blotting. Further reduction of tyrosine hydroxylase immunoreactivities was found in 6-OHDA-lesioned rats that received senktide treatment. Also, phosphorylation of N-methyl-D-aspartate receptor 1 subunit was investigated in SN region and significant up-regulation was revealed in senktide-treated 6-OHDA-lesioned rats. Finally, phosphorylation of mitogen-activated protein kinase c-Jun N-terminal kinase (JNK) and c-Jun were examined in nigral region. Up-regulation of phosphorylated JNK molecules was shown in SN region after senktide injection. In line with this evidence, phosphorylation of c-Jun at Ser 63 and Ser 73 was also up-regulated by senktide treatment, thus presenting new aspects that NK3 peptide could exacerbate 6-OHDA toxicity in in vivo models and the possible mechanism may be contributed by the modulation of N-methyl-D-aspartate receptor 1 subunit and JNK pathway activities.

  1. PGE2 EP1 receptor deletion attenuates 6-OHDA-induced Parkinsonism in mice: old switch, new target.

    Science.gov (United States)

    Ahmad, Abdullah Shafique; Maruyama, Takayuki; Narumiya, Shuh; Doré, Sylvain

    2013-04-01

    Recent experimental data on Parkinson's disease (PD) predicts the critical role of inflammation in the progression of neurodegeneration and the promising preventive effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Previous studies suggest that NSAIDs minimize cyclooxygenase-2 (COX-2) activity and thereby attenuate free radical generation. Prostaglandin E2 (PGE2) is an important product of COX activity and plays an important role in various physiologic and pathophysiologic conditions through its EP receptors (EP1-EP4). Part of the toxic effect of PGE2 in the central nervous system has been reported to be through the EP1 receptor; however, the effect of the EP1 receptor in PD remains elusive. Therefore, in our pursuit to determine if deletion of the PGE2 EP1 receptor will attenuate 6-hydroxy dopamine (6-OHDA)-induced Parkinsonism, mice were given a unilateral 6-OHDA injection into the medial forebrain bundle. We found that apomorphine-induced contralateral rotations were significantly attenuated in the 6-OHDA-lesioned EP1(-/-) mice compared with the 6-OHDA-lesioned WT mice. Quantitative analysis showed significant protection of dopaminergic neurons in the substantia nigra pars compacta of the 6-OHDA-lesioned EP1(-/-) mice. To the best of our knowledge, this is the first in vivo study to implicate the PGE2 EP1 receptor in toxin-induced Parkinsonism. We propose the PGE2 EP1 receptor as a new target to better understand some of the mechanisms leading to PD.

  2. Neuroprotective effect of ketamine/xylazine on two rat models of Parkinson's disease

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    M.M. Ferro

    2007-01-01

    Full Text Available There is a great concern in the literature for the development of neuroprotectant drugs to treat Parkinson's disease. Since anesthetic drugs have hyperpolarizing properties, they can possibly act as neuroprotectants. In the present study, we have investigated the neuroprotective effect of a mixture of ketamine (85 mg/kg and xylazine (3 mg/kg (K/X on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP or 6-hydroxydopamine (6-OHDA rat models of Parkinson's disease. The bilateral infusion of MPTP (100 µg/side or 6-OHDA (10 µg/side into the substantia nigra pars compacta of adult male Wistar rats under thiopental anesthesia caused a modest (~67% or severe (~91% loss of tyrosine hydroxylase-immunostained cells, respectively. On the other hand, an apparent neuroprotective effect was observed when the rats were anesthetized with K/X, infused 5 min before surgery. This treatment caused loss of only 33% of the nigral tyrosine hydroxylase-immunostained cells due to the MPTP infusion and 51% due to the 6-OHDA infusion. This neuroprotective effect of K/X was also suggested by a less severe reduction of striatal dopamine levels in animals treated with these neurotoxins. In the working memory version of the Morris water maze task, both MPTP- and 6-OHDA-lesioned animals spent nearly 10 s longer to find the hidden platform in the groups where the neurotoxins were infused under thiopental anesthesia, compared to control animals. This amnestic effect was not observed in rats infused with the neurotoxins under K/X anesthesia. These results suggest that drugs with a pharmacological profile similar to that of K/X may be useful to delay the progression of Parkinson's disease.

  3. Effect of pre- and postnatal manganese exposure on brain histamine content in a rodent model of Parkinson's disease.

    Science.gov (United States)

    Brus, Ryszard; Jochem, Jerzy; Nowak, Przemysław; Adwent, Marta; Boroń, Dariusz; Brus, Halina; Kostrzewa, Richard M

    2012-02-01

    Rats lesioned shortly after birth with 6-hydroxydopamine (6-OHDA; 134 μg icv) represent a near-ideal model of severe Parkinson's disease because of the near-total destruction of nigrostriatal dopaminergic fibers. There are scarce data that in Parkinson's disease, activity of the central histaminergic system is increased. The element manganese, an essential cofactor for many enzymatic reactions, itself in toxic amount, replicates some clinical features similar to those of Parkinson's disease. The aim of this study was to examine the effect of neonatal manganese exposure on 6-OHDA modeling of Parkinson's disease in rats, and to determine effects on histamine content in the brain of these rats in adulthood. Manganese (MnCl₂·4H₂O; 10,000 ppm) was included in the drinking water of pregnant Wistar rats from the time of conception until the 21st day after delivery, the age when neonatal rats were weaned. Control rats consumed tap water. Other groups of neonatal rat pups, on the 3rd day after birth, were pretreated with desipramine (20 mg/kg ip 1 h) prior to bilateral icv administration of 6-OHDA (60 or 134 μg) or its vehicle saline-ascorbic (0.1%) (control). At 2 months after birth, in rats lesioned with 60 or 134 μg 6-OHDA, endogenous striatal dopamine (DA) content was reduced, respectively, by 92 and 98% (HPLC/ED), while co-exposure of these groups to perinatal manganese did not magnify the DA depletion. However, there was prominent enhancement of histamine content in frontal cortex, hippocampus, hypothalamus, and medulla oblongata of adult rat brain after 6-OHDA (60 and 134 μg) injection on the day 3rd postnatal day. These findings indicate that histamine and the central histaminergic system are altered in the brain of rats lesioned to model Parkinson's disease, and that manganese enhances effects of 6-OHDA on histamine in brain.

  4. Neuronal Entropy-Rate Feature of Entopeduncular Nucleus in Rat Model of Parkinson's Disease.

    Science.gov (United States)

    Darbin, Olivier; Jin, Xingxing; Von Wrangel, Christof; Schwabe, Kerstin; Nambu, Atsushi; Naritoku, Dean K; Krauss, Joachim K; Alam, Mesbah

    2016-03-01

    The function of the nigro-striatal pathway on neuronal entropy in the basal ganglia (BG) output nucleus, i.e. the entopeduncular nucleus (EPN) was investigated in the unilaterally 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD). In both control subjects and subjects with 6-OHDA lesion of dopamine (DA) the nigro-striatal pathway, a histological hallmark for parkinsonism, neuronal entropy in EPN was maximal in neurons with firing rates ranging between 15 and 25 Hz. In 6-OHDA lesioned rats, neuronal entropy in the EPN was specifically higher in neurons with firing rates above 25 Hz. Our data establishes that the nigro-striatal pathway controls neuronal entropy in motor circuitry and that the parkinsonian condition is associated with abnormal relationship between firing rate and neuronal entropy in BG output nuclei. The neuronal firing rates and entropy relationship provide putative relevant electrophysiological information to investigate the sensory-motor processing in normal condition and conditions such as movement disorders.

  5. Nrf2 signaling contributes to the neuroprotective effects of urate against 6-OHDA toxicity.

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    Ning Zhang

    Full Text Available BACKGROUND: Mounting evidence shows that urate may become a biomarker of Parkinson's disease (PD diagnosis and prognosis and a neuroprotectant candidate for PD therapy. However, the cellular and molecular mechanisms underlying its neuroprotective actions remain poorly understood. RESULTS: In this study, we showed that urate pretreatment protected dopaminergic cell line (SH-SY5Y and MES23.5 against 6-hydroxydopamine (6-OHDA- and hydrogen peroxide- induced cell damage. Urate was found to be accumulated into SH-SY5Y cells after 30 min treatment. Moreover, urate induced NF-E2-related factor 2 (Nrf2 accumulation by inhibiting its ubiquitinationa and degradation, and also promoted its nuclear translocation; however, it did not modulate Nrf2 mRNA level or Kelch-like ECH-associated protein 1 (Keap1 expression. In addition, urate markedly up-regulated the transcription and protein expression of γ-glutamate-cysteine ligase catalytic subunit (γ-GCLC and heme oxygenase-1 (HO-1, both of which are controlled by Nrf2 activity. Furthermore, Nrf2 knockdown by siRNA abolished the intracellular glutathione augmentation and the protection exerted by urate pretreatment. CONCLUSION: Our findings demonstrated that urate treatment may result in Nrf2-targeted anti-oxidant genes transcription and expression by reducing Nrf2 ubiquitination and degradation and promoting its nuclear translocation, and thus offer neuroprotection on dopaminergic cells against oxidative stresses.

  6. Ontogenetic exposure of rats to pre- and post-natal manganese enhances behavioral impairments produced by perinatal 6-hydroxydopamine.

    Science.gov (United States)

    Nowak, Przemysław; Bojanek, Kamila; Szkilnik, Ryszard; Jośko, Jadwiga; Boroń, Dariusz; Adwent, Marta; Gorczyca, Piotr; Kostrzewa, Richard M; Brus, Ryszard

    2011-05-01

    Rats lesioned shortly after birth with 6-hydroxydopamine (6-OHDA; 134 μg icv) represent a near-ideal model of severe Parkinson's disease because of the near-total destruction of nigrostriatal dopaminergic fibers. The element manganese, an essential cofactor for many enzymatic reactions, itself in toxic amount, replicates some clinical features similar to those of Parkinson's disease. The aim of this study was to examine the effect of neonatal manganese exposure on 6-OHDA modeling of Parkinson's disease in rats. Manganese (MnCl(2)·4H(2)O) 10,000 ppm was included in the drinking water of pregnant Wistar rats from the time of conception until the 21st day after delivery, the age when neonatal rats were weaned. Control rats consumed tap water. Other groups of neonatal rat pups, on the 3rd day after birth, were pretreated with desipramine (20 mg/kg ip 1 h) prior to bilateral icv administration of 6-OHDA (30, 60, or 137 μg) or its vehicle saline-ascorbic (0.1%) (control). At 2 months after birth, in rats lesioned with 30, 60, or 134 μg 6-OHDA, endogenous striatal dopamine (DA) content was reduced, respectively, by 66, 92, and 98% (HPLC/ED), while co-exposure of these groups to perinatal manganese did not magnify the DA depletion. However, there was prominent enhancement of DA D(1) agonist (i.e., SKF 38393)-induced oral activity in the group of rats exposed perinatally to manganese and also treated neonatally with the 30 mg/kg dose of 6-OHDA. The 30 mg/kg 6-OHDA group, demonstrating cataleptogenic responses to SCH 23390 (0.5 mg/kg) and haloperidol (0.5 mg/kg ip), developed resistance if co-exposed to perinatal manganese. In the group exposed to manganese and lesioned with the 60 mg/kg dose of 6-OHDA, there was a reduction in D(2) agonist (i.e., quinpirole, 0.1 mg/kg)-induced yawning. The series of findings demonstrate that ontogenetic exposure to manganese results in an enhancement of behavioral toxicity to a moderate dose of 6-OHDA, despite the fact that

  7. Metabolic-dopaminergic mapping of the 6-hydroxydopamine rat model for Parkinson's disease

    Energy Technology Data Exchange (ETDEWEB)

    Casteels, Cindy [KU Leuven and University Hospital Leuven, Division of Nuclear Medicine, Leuven (Belgium); KU Leuven, Molecular Small Animal Imaging Center (MOSAIC), Leuven (Belgium); KU Leuven and University Hospital Gasthuisberg, Division of Nuclear Medicine, Leuven (Belgium); Lauwers, Erwin; Baekelandt, Veerle [KU Leuven, Laboratory for Neurobiology and Gene Therapy, Leuven (Belgium); Bormans, Guy [KU Leuven, Molecular Small Animal Imaging Center (MOSAIC), Leuven (Belgium); KU Leuven, Laboratory for Radiopharmacy, Leuven (Belgium); Laere, Koen van [KU Leuven and University Hospital Leuven, Division of Nuclear Medicine, Leuven (Belgium); KU Leuven, Molecular Small Animal Imaging Center (MOSAIC), Leuven (Belgium)

    2008-01-15

    The unilateral 6-hydroxydopamine (6-OHDA) lesion rat model is a well-known acute model for Parkinson's disease (PD). Its validity has been supported by invasive histology, behavioral studies and electrophysiology. Here, we have characterized this model in vivo by multitracer imaging [glucose metabolism and dopamine transporter (DAT)] in relation to behavioral and histological parameters. Eighteen female adult Wistar rats (eight 6-OHDA-lesioned, ten controls) were investigated using multitracer [{sup 18}F]-fluoro-2-deoxy-D-glucose (FDG) and [{sup 18}F]-FECT 2'-[{sup 18}F]-fluoroethyl-(1R-2-exo-3-exe)-8-methyl-3-(4-chlorophenyl)-8-azabicyclo(3.2.1)-octane-2-carboxylate small animal positron emission tomography (PET). Relative glucose metabolism and parametric DAT binding images were anatomically standardized to Paxinos space and analyzed on a voxel-basis using SPM2, supplemented by a template-based predefined volumes-of-interest approach. Behavior was characterized by the limb-use asymmetry test; dopaminergic innervation was validated by in vitro tyrosine hydroxylase staining. In the 6-OHDA model, significant glucose hypometabolism is present in the ipsilateral sensory-motor cortex (-6.3%; p = 4 x 10 {sup -6}). DAT binding was severely decreased in the ipsilateral caudate-putamen, nucleus accumbens and substantia nigra (all p < 5 x 10 {sup -9}), as confirmed by the behavioral and histological outcomes. Correlation analysis revealed a positive relationship between the degree of DAT impairment and the change in glucose metabolism in the ipsilateral hippocampus (p = 3 x 10 {sup -5}), while cerebellar glucose metabolism was inversely correlated to the level of DAT impairment (p < 3 x 10 {sup -4}). In vivo cerebral mapping of 6-OHDA-lesioned rats using [ {sup 18}F ]-FDG and [ {sup 18}F ]-FECT small animal PET shows molecular-functional correspondence to the cortico-subcortical network impairments observed in PD patients. This provides a further molecular

  8. Characterization of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in rat partial and full nigral 6-hydroxydopamine lesion models of Parkinson's disease

    DEFF Research Database (Denmark)

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille;

    2016-01-01

    Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, have been demonstrated to promote neuroprotection in the rat 6-hydroxydopamine (6-OHDA) neurotoxin model of Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive nigrostriatal dopaminergic neuron loss...... model setting. In conclusion, liraglutide showed no neuroprotective effects in the context of moderate or substantial midbrain dopaminergic neuronal loss and associated functional motor deficits in the rat 6-OHDA lesion model of PD....... weeks starting three weeks pre-lesion, or administered for three weeks starting on the lesion day. Quantitative stereology was applied to assess the total number of midbrain tyrosine hydroxylase (TH) positive dopaminergic neurons. As compared to vehicle controls, liraglutide had no effect...

  9. Characterization of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in rat partial and full nigral 6-hydroxydopamine lesion models of Parkinson's disease.

    Science.gov (United States)

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Mikkelsen, Jens D; Jelsing, Jacob; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-09-01

    Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, have been demonstrated to promote neuroprotection in the rat 6-hydroxydopamine (6-OHDA) neurotoxin model of Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive nigrostriatal dopaminergic neuron loss. In this report, we characterized the effect of a long-acting GLP-1 receptor agonist, liraglutide (500µg/kg/day, s.c.) in the context of a partial or advanced (full) 6-OHDA induced nigral lesion in the rat. Rats received a low (3µg, partial lesion) or high (13.5µg, full lesion) 6-OHDA dose stereotaxically injected into the right medial forebrain bundle (n=17-20 rats per experimental group). Six weeks after induction of a partial nigral dopaminergic lesion, vehicle or liraglutide was administered for four weeks. In the full lesion model, vehicle dosing or liraglutide treatment was applied for a total of six weeks starting three weeks pre-lesion, or administered for three weeks starting on the lesion day. Quantitative stereology was applied to assess the total number of midbrain tyrosine hydroxylase (TH) positive dopaminergic neurons. As compared to vehicle controls, liraglutide had no effect on the rotational responsiveness to d-amphetamine or apomorphine, respectively. In correspondence, while numbers of TH-positive nigral neurons were significantly reduced in the lesion side (partial lesion ≈55%; full lesion ≈90%) liraglutide administration had no influence dopaminergic neuronal loss in either PD model setting. In conclusion, liraglutide showed no neuroprotective effects in the context of moderate or substantial midbrain dopaminergic neuronal loss and associated functional motor deficits in the rat 6-OHDA lesion model of PD.

  10. Berberine protects against 6-OHDA-induced neurotoxicity in PC12 cells and zebrafish through hormetic mechanisms involving PI3K/AKT/Bcl-2 and Nrf2/HO-1 pathways

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    Chao Zhang

    2017-04-01

    Full Text Available Berberine (BBR is a renowned natural compound that exhibits potent neuroprotective activities. However, the cellular and molecular mechanisms are still unclear. Hormesis is an adaptive mechanism generally activated by mild oxidative stress to protect the cells from further damage. Many phytochemicals have been shown to induce hormesis. This study aims to investigate whether the neuroprotective activity of BBR is mediated by hormesis and the related signaling pathways in 6-OHDA-induced PC12 cells and zebrafish neurotoxic models. Our results demonstrated that BBR induced a typical hormetic response in PC12 cells, i.e. low dose BBR significantly increased the cell viability, while high dose BBR inhibited the cell viability. Moreover, low dose BBR protected the PC12 cells from 6-OHDA-induced cytotoxicity and apoptosis, whereas relatively high dose BBR did not show neuroprotective activity. The hormetic and neuroprotective effects of BBR were confirmed to be mediated by up-regulated PI3K/AKT/Bcl-2 cell survival and Nrf2/HO-1 antioxidative signaling pathways. In addition, low dose BBR markedly mitigated the 6-OHDA-induced dopaminergic neuron loss and behavior movement deficiency in zebrafish, while high dose BBR only slightly exhibited neuroprotective activities. These results strongly suggested that the neuroprotection of BBR were attributable to the hormetic mechanisms via activating cell survival and antioxidative signaling pathways.

  11. Amphetamine-induced perseverative behavior in a radial arm maze following DSP4 or 6-OHDA pretreatment.

    Science.gov (United States)

    Bruto, V; Beauchamp, C; Zacharko, R M; Anisman, H

    1984-01-01

    Mice permitted to explore an 8-arm radial maze tended to visit those arms least recently entered. Treatment with D-amphetamine engendered a perseverative tendency, wherein mice repeatedly visited two arms of the maze. Administration of the norepinephrine (NE) neurotoxin, N-2-chloroethyl-N-ethyl-2-bromo-benzylamine (DSP4), appreciably reduced NE in the hippocampus and cortex, moderately reduced NE in the locus coeruleus, and had only a small effect on hypothalamic NE. The DSP4 treatment resulted in a decrease of locomotor activity among amphetamine-treated mice, coupled with an increase of stereotyped response patterns. Although the NE depletion did not affect the pattern of exploration that mice ordinarily displayed, DSP4 appreciably increased the perseverative tendency provoked by amphetamine. Reduction of dopamine (DA) and NE by intraventricular administration of the catecholamine neurotoxin, 6-hydroxydopamine (6-OHDA), antagonized the effects of amphetamine, such that the frequency of alternation responses was increased and the proportion of perseverative responses was reduced. The effectiveness of the 6-OHDA treatment in antagonizing the amphetamine-induced perseveration was not reduced among mice that were pretreated with desmethylimipramine, which resulted in partial prevention of the NE reduction by 6-OHDA administration. It is suggested that DA neuronal activity contributes to the amphetamine -provoked perseveration , whereas NE stimulation modifies the perseverative tendency by influencing exploration or habituation.

  12. 6-OHDA lesions to amygdala and hippocampus attenuate memory-enhancing effect of the 3-7 fragment of angiotensin II.

    Science.gov (United States)

    Winnicka, M M; Braszko, J J; Wiśniewski, K

    1998-05-01

    We have previously shown that facilitatory effect of angiotensin II (AII) on the retrieval of memory is mediated by the dopaminergic system. In the present study, we searched for the influence of the 3-7 fragment of angiotensin II [AII(3-7)] on the retrieval processes in a passive avoidance situation after bilateral 6-OHDA lesions to the central amygdala (CA) and the CA4 field of the hippocampus (HI). AII(3-7) given 15 min before the retention testing, at the intracerebroventricular dose of 1 nmol, significantly prolonged avoidance latencies in sham-operated rats (i.e. improved retrieval of memory for the electric footshock experienced during the learning trial). Bilateral lesions to CA totally abolished, and to HI significantly diminished, this facilitatory effect. An increase of spontaneous locomotor activity in rats lesioned to CA and a decrease in rats lesioned to HI were unlikely to interfere with the cognitive effect of AII (3-7). These results suggest that the anatomical substrate of facilitating retrieval of information activity of AII(3-7) is closely related to the dopaminergic projection from the ventral tegmental area and substantia nigra to CA and HI.

  13. Restoring Spinal Noradrenergic Inhibitory Tone Attenuates Pain Hypersensitivity in a Rat Model of Parkinson's Disease

    Science.gov (United States)

    Wang, Bing; Chen, Li-Hua

    2016-01-01

    In the present study, we investigated whether restoring descending noradrenergic inhibitory tone can attenuate pain in a PD rat model, which was established by stereotaxic infusion of 6-hydroxydopamine (6-OHDA) into the bilateral striatum (CPu). PD rats developed thermal and mechanical hypersensitivity at the 4th week after surgery. HPLC analysis showed that NE content, but not dopamine or 5-HT, significantly decreased in lumbar spinal cord in PD rats. Additional noradrenergic depletion by injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) aggravated pain hypersensitivity in PD rats. At the 5th week after injection of 6-OHDA, systemic treatment with pharmacological norepinephrine (NE) precursor droxidopa (L-DOPS) or α2 adrenoceptor agonist clonidine significantly attenuated thermal and mechanical pain hypersensitivity in PD rats. Furthermore, application of norepinephrine (NE) and 5-hydroxytryptamine (5-HT) reuptake inhibitors duloxetine, but not 5-HT selective reuptake inhibitors sertraline, significantly inhibited thermal and mechanical pain hypersensitivity in PD rats. Systemic administration of Madopar (L-DOPA) or the D2/D3 agonist pramipexole slightly inhibited the thermal, but not mechanical, hypersensitivity in PD rats. Thus, our study revealed that impairment of descending noradrenergic system may play a key role in PD-associated pain and restoring spinal noradrenergic inhibitory tone may serve as a novel strategy to manage PD-associated pain. PMID:27747105

  14. Alterations of BDNF and trkB mRNA Expression in the 6-Hydroxydopamine-Induced Model of Preclinical Stages of Parkinson’s Disease: An Influence of Chronic Pramipexole in Rats

    OpenAIRE

    Klemencja Berghauzen-Maciejewska; Jadwiga Wardas; Barbara Kosmowska; Urszula Głowacka; Katarzyna Kuter; Krystyna Ossowska

    2015-01-01

    Our recent study has indicated that a moderate lesion of the mesostriatal and mesolimbic pathways in rats, modelling preclinical stages of Parkinson's disease, induces a depressive-like behaviour which is reversed by chronic treatment with pramipexole. The purpose of the present study was to examine the role of brain derived neurotrophic factor (BDNF) signalling in the aforementioned model of depression. Therefore, we investigated the influence of 6-hydoxydopamine (6-OHDA) administration into...

  15. Neuroprotective potentials of neurotrophin rich olfactory ensheathing cell's conditioned media against 6OHDA-induced oxidative damage.

    Science.gov (United States)

    Shukla, A; Mohapatra, T M; Parmar, D; Seth, K

    2014-05-01

    On the basis of recent reports, we propose that impaired neurotrophin signaling (PI3k/Akt), low antioxidant levels, and generation of reactive oxygen species (ROS) conjointly participate in the progressive events responsible for the dopaminergic cell loss in Parkinson's disease (PD). In the present study we tried to target these deficits collectively through multiple neurotrophic factors (NTFs) support in the form of Olfactory Ensheathing Cell's Conditioned Media (OEC CM) using human SH-SY5Y neuroblastoma cell line exposed to 6 hydroxydopamine (6OHDA). 6OHDA exposure induced, oxidative stress-mediated apoptotic cell death viz. enhanced ROS generation, diffused cytosolic cytochrome c (cyt c), impaired Bcl-2: Bax levels along with decrease in GSH content. These changes were accompanied by loss in Akt phosphorylation and TH levels in SH-SY5Y cells. OEC CM significantly checked apoptotic cell death by preserving pAkt levels which coincided with enhanced GSH and suppressed oxidative injury. Functional integrity of OEC CM supported cells was evident by maintained tyrosine hydroxylase (TH) expression. Intercepting Akt signaling by specific inhibitor LY294002 blocked the protective effect. Taken together our findings provide important evidence that the key to protective effect of multiple NTF support via OEC CM is enhanced Akt survival signaling which promotes antioxidant defense leading to suppression of oxidative damage.

  16. Neuroprotective Effect of the Marine-Derived Compound 11-Dehydrosinulariolide through DJ-1-Related Pathway in In Vitro and In Vivo Models of Parkinson’s Disease

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    Chien-Wei Feng

    2016-10-01

    Full Text Available Parkinson’s disease (PD is a neurodegenerative disorder characterized by tremor, rigidity, bradykinesia, and gait impairment. In a previous study, we found that the marine-derived compound 11-dehydrosinulariolide (11-de upregulates the Akt/PI3K pathway to protect cells against 6-hydroxydopamine (6-OHDA-mediated damage. In the present study, SH-SY5Y, zebrafish and rats were used to examine the therapeutic effect of 11-de. The results revealed the mechanism by which 11-de exerts its therapeutic effect: the compound increases cytosolic or mitochondrial DJ-1 expression, and then activates the downstream Akt/PI3K, p-CREB, and Nrf2/HO-1 pathways. Additionally, we found that 11-de could reverse the 6-OHDA-induced downregulation of total swimming distance in a zebrafish model of PD. Using a rat model of PD, we showed that a 6-OHDA-induced increase in the number of turns, and increased time spent by rats on the beam, could be reversed by 11-de treatment. Lastly, we showed that 6-OHDA-induced attenuation in tyrosine hydroxylase (TH, a dopaminergic neuronal marker, in zebrafish and rat models of PD could also be reversed by treatment with 11-de. Moreover, the patterns of DJ-1 expression observed in this study in the zebrafish and rat models of PD corroborated the trend noted in previous in vitro studies.

  17. Neuroprotective Effect of the Marine-Derived Compound 11-Dehydrosinulariolide through DJ-1-Related Pathway in In Vitro and In Vivo Models of Parkinson’s Disease

    Science.gov (United States)

    Feng, Chien-Wei; Hung, Han-Chun; Huang, Shi-Ying; Chen, Chun-Hong; Chen, Yun-Ru; Chen, Chun-Yu; Yang, San-Nan; Wang, Hui-Min David; Sung, Ping-Jyun; Sheu, Jyh-Horng; Tsui, Kuan-Hao; Chen, Wu-Fu; Wen, Zhi-Hong

    2016-01-01

    Parkinson’s disease (PD) is a neurodegenerative disorder characterized by tremor, rigidity, bradykinesia, and gait impairment. In a previous study, we found that the marine-derived compound 11-dehydrosinulariolide (11-de) upregulates the Akt/PI3K pathway to protect cells against 6-hydroxydopamine (6-OHDA)-mediated damage. In the present study, SH-SY5Y, zebrafish and rats were used to examine the therapeutic effect of 11-de. The results revealed the mechanism by which 11-de exerts its therapeutic effect: the compound increases cytosolic or mitochondrial DJ-1 expression, and then activates the downstream Akt/PI3K, p-CREB, and Nrf2/HO-1 pathways. Additionally, we found that 11-de could reverse the 6-OHDA-induced downregulation of total swimming distance in a zebrafish model of PD. Using a rat model of PD, we showed that a 6-OHDA-induced increase in the number of turns, and increased time spent by rats on the beam, could be reversed by 11-de treatment. Lastly, we showed that 6-OHDA-induced attenuation in tyrosine hydroxylase (TH), a dopaminergic neuronal marker, in zebrafish and rat models of PD could also be reversed by treatment with 11-de. Moreover, the patterns of DJ-1 expression observed in this study in the zebrafish and rat models of PD corroborated the trend noted in previous in vitro studies. PMID:27763504

  18. Simultaneous transplantation of fetal ventral mesencephalic tissue and encapsulated genetically modified cells releasing GDNF in a hemi-parkinsonian rat model of Parkinson's disease

    DEFF Research Database (Denmark)

    Perez-Bouza, Alberto; Di Santo, Stefano; Seiler, Stefanie

    2017-01-01

    Transplantation of fetal ventral mesencephalic (VM) neurons for Parkinson's disease (PD) is limited by poor survival and suboptimal integration of grafted tissue into the host brain. In a 6-OHDA rat model of PD we investigated the feasibility of simultaneous transplantation of rat fetal VM tissue...... and polymer-encapsulated C2C12 myoblasts genetically modified to produce glial cell line-derived neurotrophic factor or mocktransfected myoblasts on graft function. Amphetamine-induced rotations were assessed prior and 2, 4, 6 and 9 weeks post-transplantation. We found that rats grafted with VM transplants...

  19. Restoring Spinal Noradrenergic Inhibitory Tone Attenuates Pain Hypersensitivity in a Rat Model of Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Lei-Fang Cao

    2016-01-01

    Full Text Available In the present study, we investigated whether restoring descending noradrenergic inhibitory tone can attenuate pain in a PD rat model, which was established by stereotaxic infusion of 6-hydroxydopamine (6-OHDA into the bilateral striatum (CPu. PD rats developed thermal and mechanical hypersensitivity at the 4th week after surgery. HPLC analysis showed that NE content, but not dopamine or 5-HT, significantly decreased in lumbar spinal cord in PD rats. Additional noradrenergic depletion by injection of N-(2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP-4 aggravated pain hypersensitivity in PD rats. At the 5th week after injection of 6-OHDA, systemic treatment with pharmacological norepinephrine (NE precursor droxidopa (L-DOPS or α2 adrenoceptor agonist clonidine significantly attenuated thermal and mechanical pain hypersensitivity in PD rats. Furthermore, application of norepinephrine (NE and 5-hydroxytryptamine (5-HT reuptake inhibitors duloxetine, but not 5-HT selective reuptake inhibitors sertraline, significantly inhibited thermal and mechanical pain hypersensitivity in PD rats. Systemic administration of Madopar (L-DOPA or the D2/D3 agonist pramipexole slightly inhibited the thermal, but not mechanical, hypersensitivity in PD rats. Thus, our study revealed that impairment of descending noradrenergic system may play a key role in PD-associated pain and restoring spinal noradrenergic inhibitory tone may serve as a novel strategy to manage PD-associated pain.

  20. Involvement of activation of the Nrf2/ARE pathway in protection against 6-OHDA-induced SH-SY5Y cell death by α-iso-cubebenol.

    Science.gov (United States)

    Park, Sun Young; Kim, Do Yeon; Kang, Jong-Koo; Park, Geuntae; Choi, Young-Whan

    2014-09-01

    Free radical-mediated neurodegeneration is one of the many causes of Parkinson's disease (PD). As part of our ongoing studies on the identification of biologically active Schisandra chinensis components, we have isolated and structurally elucidated α-iso-cubebenol. This study was carried out in an attempt to clarify the neuroprotective effect of α-iso-cubebenol on toxin-insulted dopaminergic neuronal death using 6-hydroxy-dopamine (6-OHDA)-induced dopaminergic SH-SY5Y cells. α-iso-cubebenol significantly attenuated the loss of mitochondrial function (MTT assay) and membrane integrity (lactate dehydrogenase assay) associated with 6-OHDA-induced neurotoxicity. Pretreatment of the cells with α-iso-cubebenol diminished the intracellular accumulation of reactive oxygen species (ROS) and calcium in response to 6-OHDA. Moreover, α-iso-cubebenol protected against 6-OHDA-induced neurotoxicity through inhibition of SH-SY5Y cell apoptosis. In addition, JC-1 staining, which is a well-established measure of mitochondrial damage, was decreased after treatment with α-iso-cubebenol. Notably, α-iso-cubebenol inhibited the release of mitochondrial flavoprotein apoptosis inducing factor (AIF) from the mitochondria to the cytosol and nucleus following 6-OHDA treatment. In addition, α-iso-cubebenol reduced the 6-OHDA-induced phosphorylation of ERK and induced the phosphorylation of PKA, PKB, and CREB in a dose-dependent manner. Moreover, α-iso-cubebenol stimulated the activation of Nrf2, a downstream target of CREB. Furthermore, α-iso-cubebenol stimulated the expression of multiple antioxidant response genes (NQO-1 and HO-1). Finally, CREB and Nrf2 siRNA transfection diminished α-iso-cubebenol-mediated neuroprotection.

  1. Neuroprotective Properties of a Standardized Extract from Myracrodruon urundeuva Fr. All. (Aroeira-Do-Sertão, as Evaluated by a Parkinson’s Disease Model in Rats

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    Iana Calou

    2014-01-01

    Full Text Available Myracrodruon urundeuva Fr. All. (Anacardiaceae is a Brazilian medicinal species, which is common to the Northeastern Brazilian semiarid region, whose stem-bark is widely used in folk medicine. It is an endangered species, presenting as main bioactive components tannins and chalcones. In this work, we studied the neuroprotective effects of a standardized extract from cultivated M. urundeuva (SEMU, in a model of Parkinson’s disease. Thus, a unilateral injection of 6-OHDA was done into the rat right stratum. The animals were submitted to stereotaxic surgery, then treated with SEMU (5, 10, 20, or 40 mg/kg, p.o. for 2 weeks, subjected to behavioral tests, and euthanized for striata dissections and neurochemical, histological, and immunohistochemical analyses. We showed, for the first time, that SEMU reverted behavioral alterations seen in the 6-OHDA-lesioned group and partially blocked the decrease in DA and DOPAC contents. The numbers of viable neurons and TH immunopositive cells were increased by SEMU. In addition, the SEMU-treated 6-OHDA groups showed lower numbers of GFAP and OX-42 immunopositive cells. The neuroprotective action of SEMU is possibly related to the antioxidant and anti-inflammatory properties of M. urundeuva, pointing out to its potential use in the prevention or treatment of neurodegenerative conditions, such as Parkinson’s disease.

  2. Adaptive down-regulation of the serotonin transporter in the 6-hydroxydopamine-induced rat model of preclinical stages of Parkinson's disease and after chronic pramipexole treatment.

    Science.gov (United States)

    Berghauzen-Maciejewska, K; Wardas, J; Kosmowska, B; Domin, H; Śmiałowska, M; Głowacka, U; Ossowska, K

    2016-02-09

    Our recent study has indicated that a moderate lesion induced by bilateral 6-hydroxydopamine (6-OHDA) injections into the ventrolateral region of the caudate-putamen (CP) in rats, modeling preclinical stages of Parkinson's disease, induces a "depressive-like" behavior which is reversed by chronic treatment with pramipexole (PRA). The aim of the present study was to examine the influence of the above lesion and chronic PRA treatment on binding to the serotonin transporter (SERT) in different brain regions. As before, 6-OHDA (15 μg/2.5 μl) was administered bilaterally into the CP. PRA (1mg/kg) was injected subcutaneously twice a day for 2 weeks. Serotonergic and dopaminergic neurons of the dorsal raphe (DR) were immunostained for tryptophan hydroxylase and tyrosine hydroxylase, respectively, and were counted stereologically. Binding of [(3)H]GBR 12,935 to the dopamine transporter (DAT) and [(3)H]citalopram to SERT was analyzed autoradiographically. Intrastriatal 6-OHDA injections decreased the number of dopaminergic, but not serotonergic neurons in the DR. 6-OHDA reduced the DAT binding in the CP, and SERT binding in the nigrostriatal system (CP, substantia nigra (SN)), limbic system (ventral tegmental area (VTA), nucleus accumbens (NAC), amygdala, prefrontal cortex (PFCX), habenula, hippocampus) and DR. A significant positive correlation was found between DAT and SERT binding in the CP. Chronic PRA did not influence DAT binding but reduced SERT binding in the above structures, and deepened the lesion-induced losses in the core region of the NAC, SN, VTA and PFCX. The present study indicates that both the lesion of dopaminergic neurons and chronic PRA administration induce adaptive down-regulation of SERT binding. Moreover, although involvement of stimulation of dopaminergic transmission by chronic PRA in its "antidepressant" effect seems to be prevalent, additional contribution of SERT inhibition cannot be excluded. Copyright © 2015 IBRO. Published by Elsevier

  3. Polylysine-modified polyethylenimine (PEI-PLL) mediated VEGF gene delivery protects dopaminergic neurons in cell culture and in rat models of Parkinson's Disease (PD).

    Science.gov (United States)

    Sheikh, Muhammad Abid; Malik, Yousra Saeed; Xing, Zhenkai; Guo, Zhaopei; Tian, Huayu; Zhu, Xiaojuan; Chen, Xuesi

    2017-05-01

    Parkinson's Disease (PD) is a chronic neurodegenerative disorder characterized by motor deficits which result from the progressive loss of dopaminergic neurons. Gene therapy using growth factors such as VEGF seems to be a viable approach for potential therapeutic treatment of PD. In this study, we utilized a novel non-viral gene carrier designated as PEI-PLL synthesized by our laboratory to deliver VEGF gene to study its effect by using both cell culture as well as animal models of PD. For cell culture experiments, we utilized 6-hydroxydopamine (6-OHDA) mediated cell death model of MN9D cells following transfection with either a control plasmid or VEGF expressing plasmid. As compared to control transfected cells, PEI-PLL mediated VEGF gene delivery to MN9D cells resulted in increased cell viability, increase in the number of Tyrosine hydroxylase (TH) positive cells and decreased apoptosis following 6-OHDA insult. Next, we studied the therapeutic potential of PEI-PLL mediated VEGF gene delivery in SNPc by using unilateral 6-OHDA Medial forebrain bundle (MFB) lesion model of PD in rats. VEGF administration prevented the loss of motor functions induced by 6-OHDA as determined by behavior analysis. Similarly, VEGF inhibited the 6-OHDA mediated loss of DA neurons in Substantia Nigra Pars Compacta (SNPc) as well as DA nerve fibers in striatum as determined by TH immunostaining. In addition, PEI-PLL mediated VEGF gene delivery also prevented apoptosis and microglial activation in PD rat models. Together, these results clearly demonstrated the beneficial effects of PEI-PLL mediated VEGF gene delivery on dopaminergic system in both cell culture and animal models of PD. In this report, we exploited the potential of PEI-PLL to deliver VEGF gene for the potential therapeutic treatment of PD by using both cell culture and animal models of PD. To the best of our knowledge, this is the first report describing the use of novel polymeric gene carriers for the delivery of VEGF gene

  4. Modulation of Corpus Striatal Neurochemistry by Astrocytes and Vasoactive Intestinal Peptide (VIP) in Parkinsonian Rats.

    Science.gov (United States)

    Yelkenli, İbrahim Halil; Ulupinar, Emel; Korkmaz, Orhan Tansel; Şener, Erol; Kuş, Gökhan; Filiz, Zeynep; Tunçel, Neşe

    2016-06-01

    The neurotoxin 6-hydroxydopamine (6-OHDA) is widely used in animal models of Parkinson's disease. In various neurodegenerative diseases, astrocytes play direct, active, and critical roles in mediating neuronal survival and functions. Vasoactive intestinal peptide (VIP) has neurotrophic actions and modulates a number of astrocytic activities. In this study, the effects of VIP on the striatal neurochemistry were investigated in parkinsonian rats. Adult Sprague-Dawley rats were divided into sham-operated, unilaterally 6-OHDA-lesioned, and lesioned + VIP-administered (25 ng/kg i.p.) groups. VIP was first injected 1 h after the intrastriatal 6-OHDA microinjection and then every 2 days throughout 15 days. Extracellular striatal concentration of glutathione (GSH), gamma-aminobutyric acid (GABA), glutamate (GLU), and lactate were measured in microdialysates by high-performance liquid chromatography (HPLC). Quantification of GABA and activity dependent neuroprotective protein (ADNP)-expressing cells were determined by glutamic acid decarboxylase (GAD)/ADNP + glial fibrillary acidic protein (GFAP) double immunohistochemistry. Our results demonstrated that a 6-OHDA lesion significantly increased the density of astrocytes in the striatum and VIP treatment slightly reduced the gliosis. Extracellular concentration of GABA, GLU, and lactate levels did not change, but GSH level significantly increased in the striatum of parkinsonian rats. VIP treatment reduced GSH level comparable to sham-operated groups, but enhanced GABA and GLU levels. Our double labeling results showed that VIP primarily acts on neurons to increase ADNP and GAD expression for protection. These results suggest that, in the 6-OHDA-induced neurodegeneration model, astrocytes were possibly activated for forefront defensiveness by modulating striatal neurochemistry.

  5. Effect of Levodopa on Reward and Impulsivity in a Rat Model of Parkinson’s Disease

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    Miguel M. Carvalho

    2017-08-01

    Full Text Available The use of dopamine replacement therapies (DRT in the treatment of Parkinson’s disease (PD can lead to the development of dopamine dysregulation syndrome (DDS and impulse control disorders (ICD, behavioral disturbances characterized by compulsive DRT self-medication and development of impulsive behaviors. However, the mechanisms behind these disturbances are poorly understood. In animal models of PD, the assessment of the rewarding properties of levodopa (LD, one of the most common drugs used in PD, has produced conflicting results, and its ability to promote increased impulsivity is still understudied. Moreover, it is unclear whether acute and chronic LD therapy differently affects reward and impulsivity. In this study we aimed at assessing, in an animal model of PD with bilateral mesostriatal and mesocorticolimbic degeneration, the behavioral effects of LD therapy regarding reward and impulsivity. Animals with either sham or 6-hydroxydopamine (6-OHDA-induced bilateral lesions in the substantia nigra pars compacta (SNc and ventral tegmental area (VTA were exposed to acute and chronic LD treatment. We used the conditioned place preference (CPP paradigm to evaluate the rewarding effects of LD, whereas impulsive behavior was measured with the variable delay-to-signal (VDS task. Correlation analyses between behavioral measurements of reward or impulsivity and lesion extent in SNc/VTA were performed to pinpoint possible anatomical links of LD-induced behavioral changes. We show that LD, particularly when administered chronically, caused the development of impulsive-like behaviors in 6-OHDA-lesioned animals in the VDS. However, neither acute or chronic LD administration had rewarding effects in 6-OHDA-lesioned animals in the CPP. Our results show that in a bilateral rat model of PD, LD leads to the development of impulsive behaviors, strengthening the association between DRT and DDS/ICD in PD.

  6. Deep brain stimulation exacerbates hypokinetic dysarthria in a rat model of Parkinson's disease.

    Science.gov (United States)

    King, Nathaniel O; Anderson, Collin J; Dorval, Alan D

    2016-02-01

    Motor symptoms of Parkinson's disease (PD) follow the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Deep brain stimulation (DBS) treats some parkinsonian symptoms, such as tremor, rigidity, and bradykinesia, but may worsen certain medial motor symptoms, including hypokinetic dysarthria. The mechanisms by which DBS exacerbates dysarthria while improving other symptoms are unclear and difficult to study in human patients. This study proposes an animal model of DBS-exacerbated dysarthria. We use the unilateral, 6-hydroxydopamine (6-OHDA) rat model of PD to test the hypothesis that DBS exacerbates quantifiable aspects of vocalization. Mating calls were recorded from sexually experienced male rats under healthy and parkinsonian conditions and during DBS of the subthalamic nucleus. Relative to healthy rats, parkinsonian animals made fewer calls with shorter and less complex vocalizations. In the parkinsonian rats, putatively therapeutic DBS further reduced call frequency, duration, and complexity. The individual utterances of parkinsonian rats spanned a greater bandwidth than those of healthy rats, potentially reducing the effectiveness of the vocal signal. This utterance bandwidth was further increased by DBS. We propose that the parkinsonism-associated changes in call frequency, duration, complexity, and dynamic range combine to constitute a rat analog of parkinsonian dysarthria. Because DBS exacerbates the parkinsonism-associated changes in each of these metrics, the subthalamic stimulated 6-OHDA rat is a good model of DBS-induced hypokinetic dysarthria in PD. This model will help researchers examine how DBS alleviates many motor symptoms of PD while exacerbating parkinsonian speech deficits that can greatly diminish patient quality of life.

  7. The Flavonoid Hesperetin Alleviates Behavioral Abnormality in 6-Hydroxydopamine Rat Model of Hemi-Parkinsonism

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    Tourandokht Baluchnejadmojarad

    2010-11-01

    Full Text Available ABSTRACTParkinson’s disease (PD is a neuropathological and debilitating disorder involving the degeneration of mesencephalic dopaminergic neurons. Neuroprotective effect of hesperetin has already been reported, therefore, this study examined whether the administration of this flavonoid would attenuate behavioral abnormalities in an experimental model of PD in rat. For this purpose, unilateral intrastriatal 6-hydroxydopamine (6-OHDA, 12.5 μg/5μl of saline-ascorbate-lesioned rats were pretreated i.p. with hesperetin (10 mg/kg. It was found out that hesperetin administration attenuates the rotational behavior in lesioned rats. In summary, hesperetin administration attenuates behavioral abnormality in hemiparkinsonian rats and this may be of benefit, along with other therapies, in neurodegenerative disorders including PD.

  8. Establishment of a Parkinson's disease model in rats via striatal one-site double injection Feasibility observation

    Institute of Scientific and Technical Information of China (English)

    Bing Liu; Li Ma; Yulong Shi; Boli Zhang

    2008-01-01

    BACKGROUND: To date, many 6-hydroxydopamine (6-OHDA)-lesioned rat models have been established by injecting 6-OHDA into two or more sites in the substantia nigra pars compacta, striatum or median forebrain bundle. The success rate of models established by this method is satisfactory, but it can raise the death rate, and is elaborate and tedious to perform.OBJECTIVE: To observe the difference between injections of 6-OHDA into the striatum from one site and two sites, and to explore the feasibility of establishing Parkinson's disease rat models via striatal one-site double injection.DESIGN, TIME AND SETTING: A randomized, controlled animal experiment based on a modeling comparison was performed at the Pharmacology Laboratory of Traditional Chinese Medicine, Academy of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine between August 2005 and April 2006.MATERIALS: A total of 46 male Wistar rats were purchased from Beijing Weitong Lihua Experimental Animal Technical Co., Ltd., China. 6-OHDA hydrogen bromide was sourced from Sigma Co., Ltd., USA.METHODS: All 46 rats were randomized to three groups: one-site injection (n = 18), two-site injection (n = 18), and control (n = 10). Lesions in rat brains were established by infusing 5 p g 6-OHDA into the striatum at the following coordinates: anteroposterior (AP) 1.0 ram, mediolateral (ML) 2.7 mm,dorsoventral (DV) -5.2 or -6.0 mm for the one-site injection group, and AP 1.0 mm, ML 2.5 ram, DV -4.5 mm/AP -0.4 ram, ML 3.5 mm, DV -4.5 mm for the two-site injection group, respectively. Rats in the control group were injected with the same volume of 0.01% ascorbic acid as above.MAIN OUTCOME MEASURES: Tyrosine hydroxylase-positive neurons were detected by immunohistochemistry. Success rates of PD models established by one-site and two-site injection techniques were examined.RESULTS: One rat died in the one-site injection group and four in the two-site injection group. Thus behavioral testing was

  9. An NR2B-Dependent Decrease in the Expression of trkB Receptors Precedes the Disappearance of Dopaminergic Cells in Substantia Nigra in a Rat Model of Presymptomatic Parkinson's Disease

    Science.gov (United States)

    Riquelme, Eduardo; Abarca, Jorge; Campusano, Jorge M.; Bustos, Gonzalo

    2012-01-01

    Compensatory changes occurring during presymptomatic stages of Parkinson's disease (PD) would explain that the clinical symptoms of the disease appear late, when the degenerative process is quite advanced. Several data support the proposition that brain-derived neurotrophic factor (BDNF) could play a role in these plastic changes. In the present study, we evaluated the expression of the specific BDNF receptor, trkB, in a rat model of presymptomatic PD generated by intrastriatal injection of the neurotoxin 6-OHDA. Immunohistochemical studies revealed a decrease in trkB expression in SN pars compacta (SNc) seven days after 6-OHDA injection. At this time point, no change in the number of tyrosine hydroxylase (TH) immunoreactive (TH-IR) cells is detected, although a decrease is evident 14 days after neurotoxin injection. The decrease in TH-positive cells and trkB expression in SNc was significantly prevented by systemic administration of Ifenprodil, a specific antagonist of NR2B-containing NMDA receptors. Therefore, an NR2B-NMDA receptor-dependent decrease in trkB expression precedes the disappearance of TH-IR cells in SNc in response to 6-OHDA injection. These results support the idea that a functional coupling between NMDA receptors and BDNF/trkB signalling may be important for the maintenance of the dopaminergic phenotype in SNc during presymptomatic stages of PD. PMID:22720191

  10. An NR2B-Dependent Decrease in the Expression of trkB Receptors Precedes the Disappearance of Dopaminergic Cells in Substantia Nigra in a Rat Model of Presymptomatic Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Eduardo Riquelme

    2012-01-01

    Full Text Available Compensatory changes occurring during presymptomatic stages of Parkinson's disease (PD would explain that the clinical symptoms of the disease appear late, when the degenerative process is quite advanced. Several data support the proposition that brain-derived neurotrophic factor (BDNF could play a role in these plastic changes. In the present study, we evaluated the expression of the specific BDNF receptor, trkB, in a rat model of presymptomatic PD generated by intrastriatal injection of the neurotoxin 6-OHDA. Immunohistochemical studies revealed a decrease in trkB expression in SN pars compacta (SNc seven days after 6-OHDA injection. At this time point, no change in the number of tyrosine hydroxylase (TH immunoreactive (TH-IR cells is detected, although a decrease is evident 14 days after neurotoxin injection. The decrease in TH-positive cells and trkB expression in SNc was significantly prevented by systemic administration of Ifenprodil, a specific antagonist of NR2B-containing NMDA receptors. Therefore, an NR2B-NMDA receptor-dependent decrease in trkB expression precedes the disappearance of TH-IR cells in SNc in response to 6-OHDA injection. These results support the idea that a functional coupling between NMDA receptors and BDNF/trkB signalling may be important for the maintenance of the dopaminergic phenotype in SNc during presymptomatic stages of PD.

  11. Regional distributions of manganese, iron, copper, and zinc in the brains of 6-hydroxydopamine-induced parkinsonian rats.

    Science.gov (United States)

    Tarohda, Tohru; Ishida, Yasushi; Kawai, Keiichi; Yamamoto, Masayoshi; Amano, Ryohei

    2005-09-01

    Time courses of changes in manganese, iron, copper, and zinc concentrations were examined in regions of the brain of a 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease using inductively coupled plasma mass spectrometry (ICP-MS). The concentrations were simultaneously determined in brain section at the level of the substantia nigra 1, 3, 7, 10, 14, and 21 days after the 6-OHDA treatment and compared with those of control rats. The distributions of these elements were obtained for 18 regions of the sagittal section (1-mm thick). The ICP-MS results indicated that Mn, Fe, Cu, and Zn levels of the 6-OHDA-induced parkinsonian brain were observed to increase in all regions that lay along the dopaminergic pathway. In the substantia nigra, the increase in Mn level occurred rapidly from 3 to 7 days and preceded those in the other elements, reaching a plateau in the 6-OHDA brain. Iron and Zn levels increased gradually until 7 days and then increased rapidly from 7 to 10 days. The increase in the copper level was slightly delayed. In other regions, such as the globus pallidus, putamen, and amygdala, the levels of Mn, Fe, Cu, and Zn increased with time after 6-OHDA treatment, although the time courses of their changes were region-specific. These findings contribute to our understanding of the roles of Mn and Fe in the induction of neurological symptoms and progressive loss of dopaminergic neurons in the development of Parkinson's disease. Manganese may hold the key to disturbing cellular Fe homeostasis and accelerating Fe levels, which play the most important role in the development of Parkinson's disease.

  12. L-F001, a Multifunction ROCK Inhibitor Prevents 6-OHDA Induced Cell Death Through Activating Akt/GSK-3beta and Nrf2/HO-1 Signaling Pathway in PC12 Cells and Attenuates MPTP-Induced Dopamine Neuron Toxicity in Mice.

    Science.gov (United States)

    Luo, Liting; Chen, Jingkao; Su, Dan; Chen, Meihui; Luo, Bingling; Pi, Rongbiao; Wang, Lan; Shen, Wei; Wang, Rikang

    2017-02-01

    Amounting evidences demonstrated that Rho/Rho-associated kinase (ROCK) might be a novel target for the therapy of Parkinson's disease (PD). Recently, we synthesized L-F001 and revealed it was a potent ROCK inhibitor with multifunctional effects. Here we investigated the effects of L-F001 in PD models. We found that L-F001 potently attenuated 6-OHDA-induced cytotoxicity in PC12 cells and significantly decreased intracellular reactive oxygen species (ROS), prevented the 6-OHDA-induced decline of mitochondrial membrane potential and intracellular GSH levels. In addition, L-F001 increased Akt and GSK-3beta phosphorylation and induced the nuclear Nrf2 and HO-1 expression in a time- and concentration-dependent manner. Moreover, L-F001 restored the levels of p-Akt and p-GSK-3beta (Ser9) as well as HO-1 expression reduced by 6-OHDA. Those effects were blocked by the specific PI3K inhibitor, LY294002, indicating the involvement of Akt/GSK-3beta pathway in the neuroprotective effect of L-F001. In addition, L-F001 significantly attenuated the tyrosinehydroxylase immunoreactive cell loss in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced mice PD model. Together, our findings suggest that L-F001 prevents 6-OHDA-induced cell death through activating Akt/GSK-3beta and Nrf2/HO-1 signaling pathway and attenuates MPTP-induced dopaminergic neuron toxicity in mice. L-F001 might be a promising drug candidate for PD.

  13. Expression of calbindin D28K in substantia nigra of model rats with Parkinson disease

    Institute of Scientific and Technical Information of China (English)

    Dianshuai Gao; Hongmei Liu; Yanxia Ding; Hongjun Wang; Yanqiang Wang

    2006-01-01

    BACKGROUND: Previous researches suggested that expression level of calbindin D28K mRNA decreased in substantia nigra (SN) of model rats with Parkinson disease (PD), and this might be related to the decrease of anti-degeneration potentials of dopaminergic neurons.OBJECTIVE: To observe expression changes of calbindin D28K in SN dopaminergic neurons during their degeneration and death in midbrain of PD model rats.DESIGN: Completely randomized grouping design.SETTING: Department of Neurobiology, Xuzhou Medical College.MATERIALS: A total of 92 healthy male SD rats, with the age of 3 months, weighing 200-250 g, were selected from Experimental Animal Center of Xuzhou Medical College [certification: SCXK (su) 2003-0003].Calbindin D28K(CB), tyroxine hydroxylase (TH), ABC kit, 6-hydroxydopamine (6-OHDA) and Nissl dyes were provided by Sigma Company, and sheep serum was provided by Beijing Zhongshan Company.METHODS: The experiment was carried out in the Neurobiological Center of Xuzhou Medical College from October 2003 to October 2004. ① With lot method, rats were divided into blank control group (n=28), experimental control group (n=28) and experimental group (n=36). Rats in experimental group were injected with 6-OHDA at right corpus striatum for PD modeling; rats in experimental control group were injected with saline at the same site; rats in blank control group did not give any injections. ② On the 7th, 14th, 21st and 28th days, SN segments on right midbrain from every 5 rats in experimental group were fixed, embedded with paraffin and cut into successively coronary pieces. Rats in other two groups were treated with the same methods and then stained with Nissl to show neuronal form. Meanwhile, CB and TH antibodies staining with immunohistochemistry were used to show CB containing dopaminergic neurons and dopaminergic neurons,and cells were calculated and observed under optic microscope. ③ On the 14th and 28th days, every 4 rats in experimental group and every 4

  14. Calcitriol promotes augmented dopamine release in the lesioned striatum of 6-hydroxydopamine treated rats

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    Cass, Wayne A.; Peters, Laura E.; Fletcher, Anita M.; Yurek, David M.

    2014-01-01

    Current therapies for Parkinson's disease (PD) offer symptomatic relief but do not provide a cure or slow the disease process. Treatments that could halt progression of the disease or help restore function to damaged neurons would be of substantial benefit. Calcitriol, the active metabolite of vitamin D, has been shown to have significant effects on the brain. These effects include upregulating trophic factor levels, and reducing the severity of some central nervous system lesions. While previous studies have shown that calcitriol can be neuroprotective in 6-hydroxydopamine (6-OHDA) rodent models of PD, the present experiments were designed to examine the ability of calcitriol to promote restoration of extracellular DA levels and tissue content of DA in animals previously lesioned with 6-OHDA. Male Fischer-344 rats were given a single injection of 12 µg 6-OHDA into the right striatum. Four weeks later the animals were administered vehicle or calcitriol (0.3 or 1.0 µg/kg, s.c.) once a day for eight consecutive days. Three weeks after the calcitriol treatments in vivo microdialysis experiments were conducted to measure potassium and amphetamine evoked overflow of DA from both the left and right striata. In control animals treated with 6-OHDA and vehicle there were significant reductions in both potassium and amphetamine evoked overflow of DA on the lesioned side of the brain compared to the contralateral side. In animals treated with 6-OHDA followed by calcitriol there was significantly greater potassium and amphetamine evoked overflow of DA from the lesioned striatum compared to that from the control animals. The calcitriol treatments also led to increases in postmortem tissue levels of DA in the striatum and substantia nigra. These results suggest that calcitriol may help promote recovery of dopaminergic functioning in injured nigrostriatal neurons. PMID:24858239

  15. Exposure to Early Life Stress Results in Epigenetic Changes in Neurotrophic Factor Gene Expression in a Parkinsonian Rat Model

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    Thabisile Mpofana

    2016-01-01

    Full Text Available Early life adversity increases the risk of mental disorders later in life. Chronic early life stress may alter neurotrophic factor gene expression including those for brain derived neurotrophic factor (BDNF and glial cell derived neurotrophic factor (GDNF that are important in neuronal growth, survival, and maintenance. Maternal separation was used in this study to model early life stress. Following unilateral injection of a mild dose of 6-hydroxydopamine (6-OHDA, we measured corticosterone (CORT in the blood and striatum of stressed and nonstressed rats; we also measured DNA methylation and BDNF and GDNF gene expression in the striatum using real time PCR. In the presence of stress, we found that there was increased corticosterone concentration in both blood and striatal tissue. Further to this, we found higher DNA methylation and decreased neurotrophic factor gene expression. 6-OHDA lesion increased neurotrophic factor gene expression in both stressed and nonstressed rats but this increase was higher in the nonstressed rats. Our results suggest that exposure to early postnatal stress increases corticosterone concentration which leads to increased DNA methylation. This effect results in decreased BDNF and GDNF gene expression in the striatum leading to decreased protection against subsequent insults later in life.

  16. Synergistic Antiparkinsonian Effect of Flunarizine, Glibenclamide and B Vitamins in a Rat 6-Hydroxydopamine Model; The Role of Malondialdehyde

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    Sarookhani

    2016-08-01

    Full Text Available Background The current study evaluated the effects of a combination of flunarizine (flu a calcium channel blocker, glibenclamide (Glib, a KATP channels blocker and B vitamins (B com on the behavioral symptoms of 6-hydroxydopamine (6-OHDA-induced model of Parkinson disease to examine the synergistic antiparkinsonian effects of the drugs and supplements. Also the level of malondialdehyde (MDA was measured in blood and brain suspensions to find probable neuroprotective mechanism of these materials. Methods 6-OHDA was injected into striatum of rats by stereotaxic surgery. Pretreatment with flu, Glib and B com was started before the surgery and continued to three weeks after the surgery. Development and severity of Parkinson disease were evaluated by the conventional behavioral tests. MDA values were measured spectrophotometrically, using thiobarbituric acid test and the MDA standard curve. Results Pretreatment with a combination of flu, Glib and B com ameliorated the behavioral symptoms of Parkinson disease. The effect of the combination was significantly more potent than those of flu, Glib or B com, solely. Pretreatment with the combination or using only Glib or B com separately, reduced the level of MDA in blood and brain, significantly. However, the effect of the combination was significantly more potent than those of Glib or B com, solely. Conclusions Since the severity of the behavioral symptoms in the 6-OHDA-induced model of Parkinson disease reflects the degree of the lesion in substantia nigra (SN dopaminergic neurons, it is suggested that using the combination had neuroprotective effects. The obtained data suggest a synergistic neuroprotective and antiparkinsonian effect for flu, Glib and B com. At least, a part of this effect was mediated through inhibition of oxidative stress.

  17. PI3 kinase/Akt activation mediates estrogen and IGF-1 nigral DA neuronal neuroprotection against a unilateral rat model of Parkinson's disease.

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    Quesada, Arnulfo; Lee, Becky Y; Micevych, Paul E

    2008-04-01

    Recently, using the medial forebrain bundle (MFB) 6-hydroxydopmaine (6-OHDA) lesion rat model of Parkinson's disease (PD), we have demonstrated that blockade of central IGF-1 receptors (IGF-1R) attenuated estrogen neuroprotection of substantia nigra pars compacta (SNpc) DA neurons, but exacerbated 6-OHDA lesions in IGF-1 only treated rats (Quesada and Micevych [2004]: J Neurosci Res 75:107-116). This suggested that the IGF-1 system is a central mechanism through which estrogen acts to protect the nigrostriatal DA system. Moreover, these results also suggest that IGF-1R-induced intracellular signaling pathways are involved in the estrogen mechanism that promotes neuronal survival. In vitro, two convergent intracellular signaling pathways used by estrogen and IGF-1, the mitogen-activated protein kinase (MAPK/ERK), and phosphatidyl-inositol-3-kinase/Akt (PI3K/Akt), have been demonstrated to be neuroprotective. Continuous central infusions of MAPK/ERK and PI3K/Akt inhibitors were used to test the hypothesis that one or both of these signal transduction pathways mediates estrogen and/or IGF-1 neuroprotection of SNpc DA neurons after a unilateral administration of 6-OHDA into the MFB of rats. Motor behavior tests and tyrosine hydroxylase immunoreactivity revealed that the inhibitor of the PI3K/Akt pathway (LY294002) blocked the survival effects of both estrogen and IGF-1, while an inhibitor of the MAPK/ERK signaling (PD98059) was ineffective. Western blot analyses showed that estrogen and IGF-1 treatments increased PI3K/Akt activation in the SN; however, MAPK/ERK activation was decreased in the SN. Indeed, continuous infusions of inhibitors blocked phosphorylation of PI3K/Akt and MAPK/ERK. These findings indicate that estrogen and IGF-1-mediated SNpc DA neuronal protection is dependent on PI3K/Akt signaling, but not on the MAPK/ERK pathway.

  18. EPO-dependent activation of PI3K/Akt/FoxO3a signalling mediates neuroprotection in in vitro and in vivo models of Parkinson's disease.

    Science.gov (United States)

    Jia, Yu; Mo, Shi-Jing; Feng, Qi-Qi; Zhan, Ma-Li; OuYang, Li-Si; Chen, Jia-Chang; Ma, Yu-Xin; Wu, Jia-Jia; Lei, Wan-Long

    2014-05-01

    Erythropoietin (EPO) may become a potential therapeutic candidate for the treatment of the neurodegenerative disorder -- Parkinson's disease (PD), since EPO has been found to prevent neuron apoptosis through the activation of cell survival signalling. However, the underlying mechanisms of how EPO exerts its neuroprotective effect are not fully elucidated. Here we investigated the mechanism by which EPO suppressed 6-hydroxydopamine (6-OHDA)-induced neuron death in in vitro and in vivo models of PD. EPO knockdown conferred 6-OHDA-induced cytotoxicity. This effect was reversed by EPO administration. Treatment of PC12 cells with EPO greatly diminished the toxicity induced by 6-OHDA in a dose- and time-dependent manner. EPO effectively reduced apoptosis of striatal neurons and induced a significant improvement on the neurological function score in the rat models of PD. Furthermore, EPO increased the expression of phosphorylated Akt and phosphorylated FoxO3a, and abrogated the 6-OHDA-induced dysregulation of Bcl-2, Bax and Caspase-3 in PC12 cells and in striatal neurons. Meanwhile, the EPO-dependent neuroprotection was notably reversed by pretreatment with LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K). Our data suggest that PI3K/Akt/FoxO3a signalling pathway may be a possible mechanism involved in the neuroprotective effect of EPO in PD.

  19. Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease

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    Kingsbury Ann E

    2008-05-01

    Full Text Available Abstract Background It has recently become apparent that neuroinflammation may play a significant role in Parkinson's disease (PD. This is also the case in animal paradigms of the disease. The potential neuroprotective action of the glucagon-like peptide 1 receptor (GLP-1R agonist exendin-4 (EX-4, which is protective against cytokine mediated apoptosis and may stimulate neurogenesis, was investigated In paradigms of PD. Methods Two rodent 'models' of PD, 6-hydroxydopamine (6-OHDA and lipopolysaccaride (LPS, were used to test the effects of EX-4. Rats were then investigated in vivo and ex vivo with a wide range of behavioural, neurochemical and histological tests to measure integrity of the nigrostriatal system. Results EX-4 (0.1 and 0.5 μg/kg was given seven days after intracerebral toxin injection. Seven days later circling behaviour was measured following apomorphine challenge. Circling was significantly lower in rats given EX-4 at both doses compared to animals given 6-OHDA/LPS and vehicle. Consistent with these observations, striatal tissue DA concentrations were markedly higher in 6-OHDA/LPS + EX-4 treated rats versus 6-OHDA/LPS + vehicle groups, whilst assay of L-DOPA production by tyrosine hydroxylase was greatly reduced in the striata of 6-OHDA/LPS + vehicle rats, but this was not the case in rats co-administered EX-4. Furthermore nigral TH staining recorded in 6-OHDA/LPS + vehicle treated animals was markedly lower than in sham-operated or EX-4 treated rats. Finally, EX-4 clearly reversed the loss of extracellular DA in the striata of toxin lesioned freely moving rats. Conclusion The apparent ability of EX-4 to arrest progression of, or even reverse nigral lesions once established, suggests that pharmacological manipulation of the GLP-1 receptor system could have substantial therapeutic utility in PD. Critically, in contrast to other peptide agents that have been demonstrated to possess neuroprotective properties in pre-clinical models

  20. Selective destruction of nigrostriatal dopaminergic neurons does not alter [3H]-ryanodine binding in rat striatum

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    Noël F.

    2000-01-01

    Full Text Available Dopamine nigrostriatal neurons are important for motor control and may contain a particularly dense population of ryanodine receptors involved in the control of dopamine release. To test this hypothesis, we used a classical model of unilateral selective lesion of these neurons in rats based on 6-hydroxydopamine (6-OHDA injection into the substantia nigra. Binding of [3H]-GBR 12935, used as a presynaptic marker since it labels specifically the dopamine uptake complex, was dramatically decreased by 83-100% in striatum homogenates after 6-OHDA lesion. On the contrary, no reduction of [3H]-ryanodine binding was observed. The present data indicate that [3H]-ryanodine binding sites present in rat striatum are not preferentially localized in dopaminergic terminals.

  1. Effects of discontinuing a high-fat diet on mitochondrial proteins and 6-hydroxydopamine-induced dopamine depletion in rats.

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    Ma, Delin; Shuler, Jeffrey M; Raider, Kayla D; Rogers, Robert S; Wheatley, Joshua L; Geiger, Paige C; Stanford, John A

    2015-07-10

    Diet-induced obesity can increase the risk for developing age-related neurodegenerative diseases including Parkinson's disease (PD). Increasing evidence suggests that mitochondrial and proteasomal mechanisms are involved in both insulin resistance and PD. The goal of this study was to determine whether diet intervention could influence mitochondrial or proteasomal protein expression and vulnerability to 6-Hydroxydopamine (6-OHDA)-induced nigrostriatal dopamine (DA) depletion in rats' nigrostriatal system. After a 3 month high-fat diet regimen, we switched one group of rats to a low-fat diet for 3 months (HF-LF group), while the other half continued with the high-fat diet (HF group). A chow group was included as a control. Three weeks after unilateral 6-OHDA lesions, HF rats had higher fasting insulin levels and higher Homeostasis model assessment of insulin resistance (HOMA-IR), indicating insulin resistance. HOMA-IR was significantly lower in HF-LF rats than HF rats, indicating that insulin resistance was reversed by switching to a low-fat diet. Compared to the Chow group, the HF group exhibited significantly greater DA depletion in the substantia nigra but not in the striatum. DA depletion did not differ between the HF-LF and HF group. Proteins related to mitochondrial function (such as AMPK, PGC-1α), and to proteasomal function (such as TCF11/Nrf1) were influenced by diet intervention, or by 6-OHDA lesion. Our findings suggest that switching to a low-fat diet reverses the effects of a high-fat diet on systemic insulin resistance, and mitochondrial and proteasomal function in the striatum. Conversely, they suggest that the effects of the high-fat diet on nigrostriatal vulnerability to 6-OHDA-induced DA depletion persist.

  2. Increased efficacy of the 6-hydroxydopamine lesion of the median forebrain bundle in small rats, by modification of the stereotaxic coordinates.

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    Torres, E M; Lane, E L; Heuer, A; Smith, G A; Murphy, E; Dunnett, S B

    2011-08-30

    The 6-hydroxydopamine (6-OHDA) lesion is the most widely used rat model of Parkinson's disease. A single unilateral injection of 6-OHDA into the median forebrain bundle (MFB) selectively destroys dopamine neurons in the ipsilateral substantia nigra pars compacta (SNc) and ventral tegmental area (VTA), removing more than 95% of the dopamine innervation from target areas. The stereotaxic coordinates used to deliver 6-OHDA to the MFB have been used in our laboratory successfully for more than 25 years. However, in recent years we have observed a decline in the success rate of this lesion. Previously regular success rates of >80% of rats lesioned, have become progressively more variable, with rates as low as 20% recorded in some experiments. Having excluded variability of the neurotoxin and operator errors, we hypothesized that the change seen might be due to the use of smaller rats at the time of first surgery. An attempt to proportionally adjust the lesion coordinates base on head size did not increase lesion efficacy. However, in support of the small rat hypothesis it was observed that, using the standard coordinates, rat's heads had a "nose-up" position in the stereotaxic fame. Adjustment of the nose bar to obtain a flat head position during surgery improved lesion success, and subsequent adjustments of the lesion coordinates to account for smaller head size led to a greatly increased lesion efficacy (>90%) as assessed by amphetamine induced rotation.

  3. CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson's disease

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    Hudson Charles E

    2011-01-01

    Full Text Available Abstract Background Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. The cause of the neurodegeneration is unknown. Neuroinflammation has been clearly shown in Parkinson's disease and may be involved in the progressive nature of the disease. Microglia are capable of producing neuronal damage through the production of bioactive molecules such as cytokines, as well as reactive oxygen species (ROS, and nitric oxide (NO. The inflammatory response in the brain is tightly regulated at multiple levels. One form of immune regulation occurs via neurons. Fractalkine (CX3CL1, produced by neurons, suppresses the activation of microglia. CX3CL1 is constitutively expressed. It is not known if addition of exogenous CX3CL1 beyond otherwise physiologically normal levels could decrease microglia activation and thereby minimize the secondary neurodegeration following a neurotoxic insult. Methods The intrastriatal 6-hydroxydopamine (6-OHDA rat model of Parkinson disease, was used to test the hypothesis that exogenous CX3CL1 could be neuroprotective. Treatment with recombinant CX3CL1 was delivered to the striatum by an osmotic minipump for 28 days beginning 7 days after the initial insult. Unbiased stereological methods were used to quantify the lesion size in the striatum, the amount of neuronal loss in the substantia nigra, and the amount of microglia activation. Results As hypothesized, CX3CL1 was able to suppress this microglia activation. The reduced microglia activation was found to be neuroprotective as the CX3CL1 treated rats had a smaller lesion volume in the striatum and importantly significantly fewer neurons were lost in the CX3CL1 treated rats. Conclusion These findings demonstrated that CX3CL1 plays a neuroprotective role in 6-OHDA-induced dopaminergic lesion and it might be an effective therapeutic target for many neurodegenerative diseases, including Parkinson disease and Alzheimer disease

  4. Dopaminergic differentiation of stem cells from human deciduous teeth and their therapeutic benefits for Parkinsonian rats.

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    Fujii, Hiromi; Matsubara, Kohki; Sakai, Kiyoshi; Ito, Mikako; Ohno, Kinji; Ueda, Minoru; Yamamoto, Akihito

    2015-07-10

    Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the loss of nigrostriatal dopaminergic (DAergic) neurons and the depletion of striatal dopamine. Here we show that DAergic-neuron-like cells could be efficiently induced from stem cells derived from human exfoliated deciduous teeth (SHEDs), and that these induced cells had therapeutic benefits in a 6-OHDA-induced Parkinsonian rat model. In our protocol, EGF and bFGF signaling activated the SHED's expression of proneural genes, Ngn2 and Mash1, and subsequent treatment with brain-derived neurotrophic factor (BDNF) promoted their maturation into DAergic neuron-like SHEDs (dSHEDs). A hypoxic DAergic differentiation protocol improved cell viability and enhanced the expression of multiple neurotrophic factors, including BDNF, GDNF, NT-3, and HGF. Engrafted dSHEDs survived in the striatum of Parkinsonian rats, improved the DA level more efficiently than engrafted undifferentiated SHEDs, and promoted the recovery from neurological deficits. Our findings further suggested that paracrine effects of dSHEDs contributed to neuroprotection against 6-OHDA-induced neurodegeneration and to nigrostriatal tract restoration. In addition, we found that the conditioned medium derived from dSHEDs protected primary neurons against 6-OHDA toxicity and accelerated neurite outgrowth in vitro. Thus, our data suggest that stem cells derived from dental pulp may have therapeutic benefits for PD. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Electroacupuncture Alleviates Depressive-Like Symptoms and Modulates BDNF Signaling in 6-Hydroxydopamine Rats

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    Sun, Min; Wang, Ke; Yu, Yan; Su, Wen-Ting; Jiang, Xin-Xin

    2016-01-01

    Previous studies have identified the beneficial effects of electroacupuncture (EA) on motor behaviors in Parkinson's disease (PD). However, the role and potential mechanisms of EA in PD-associated depression remain unclear. In the present study, a rat model of PD with unilateral 6-hydroxydopamine (6-OHDA) lesions in the medial forebrain bundle was treated using EA for 4 weeks. We found that 100 Hz EA improved several motor phenotypes. In addition, tyrosine hydroxylase (TH) immunohistochemical analysis showed that EA had a minimal impact on the TH-positive profiles of the ipsilateral ventral tegmental area. Compared with the 6-OHDA group, long-term EA stimulation significantly increased sucrose solution consumption and decreased immobility time in the forced swim test. EA treatment did not alter dopamine, norepinephrine, and serotonin levels in the striatum and hippocampus. Noticeably, EA treatment reversed the 6-OHDA-induced abnormal expression of brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) in the midbrain and hippocampus. These results demonstrate that EA at 100-Hz possesses the ability to improve depressive-like symptoms in PD rats, which is, at least in part, due to the distinct effect of EA on the mesostriatal and mesocorticolimbic dopaminergic pathways. Moreover, BDNF seems to participate in the effect of EA in PD. PMID:27525025

  6. Effects of Postnatal Enriched Environment in a Model of Parkinson’s Disease in Adult Rats

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    Adel Jungling

    2017-02-01

    Full Text Available Environmental enrichment is a widespread neuroprotective strategy during development and also in the mature nervous system. Several research groups have described that enriched environment in adult rats has an impact on the progression of Parkinson’s disease (PD. The aim of our present study was to examine the effects of early, postnatal environmental enrichment after 6-hydroxydopamine-induced (6-OHDA lesion of the substantia nigra in adulthood. Newborn Wistar rats were divided into control and enriched groups according to their environmental conditions. For environmental enrichment, during the first five postnatal weeks animals were placed in larger cages and exposed to intensive complex stimuli. Dopaminergic cell loss, and hypokinetic and asymmetrical signs were evaluated after inducing PD with unilateral injections of 6-OHDA in three-month-old animals. Treatment with 6-OHDA led to a significant cell loss in the substantia nigra of control animals, however, postnatal enriched circumstances could rescue the dopaminergic cells. Although there was no significant difference in the percentage of surviving cells between 6-OHDA-treated control and enriched groups, the slightly less dopaminergic cell loss in the enriched group compared to control animals resulted in less severe hypokinesia. Our investigation is the first to provide evidence for the neuroprotective effect of postnatal enriched environment in PD later in life.

  7. Effects of Postnatal Enriched Environment in a Model of Parkinson’s Disease in Adult Rats

    Science.gov (United States)

    Jungling, Adel; Reglodi, Dora; Karadi, Zsofia Nozomi; Horvath, Gabor; Farkas, Jozsef; Gaszner, Balazs; Tamas, Andrea

    2017-01-01

    Environmental enrichment is a widespread neuroprotective strategy during development and also in the mature nervous system. Several research groups have described that enriched environment in adult rats has an impact on the progression of Parkinson’s disease (PD). The aim of our present study was to examine the effects of early, postnatal environmental enrichment after 6-hydroxydopamine-induced (6-OHDA) lesion of the substantia nigra in adulthood. Newborn Wistar rats were divided into control and enriched groups according to their environmental conditions. For environmental enrichment, during the first five postnatal weeks animals were placed in larger cages and exposed to intensive complex stimuli. Dopaminergic cell loss, and hypokinetic and asymmetrical signs were evaluated after inducing PD with unilateral injections of 6-OHDA in three-month-old animals. Treatment with 6-OHDA led to a significant cell loss in the substantia nigra of control animals, however, postnatal enriched circumstances could rescue the dopaminergic cells. Although there was no significant difference in the percentage of surviving cells between 6-OHDA-treated control and enriched groups, the slightly less dopaminergic cell loss in the enriched group compared to control animals resulted in less severe hypokinesia. Our investigation is the first to provide evidence for the neuroprotective effect of postnatal enriched environment in PD later in life. PMID:28216584

  8. Effects of Postnatal Enriched Environment in a Model of Parkinson's Disease in Adult Rats.

    Science.gov (United States)

    Jungling, Adel; Reglodi, Dora; Karadi, Zsofia Nozomi; Horvath, Gabor; Farkas, Jozsef; Gaszner, Balazs; Tamas, Andrea

    2017-02-14

    Environmental enrichment is a widespread neuroprotective strategy during development and also in the mature nervous system. Several research groups have described that enriched environment in adult rats has an impact on the progression of Parkinson's disease (PD). The aim of our present study was to examine the effects of early, postnatal environmental enrichment after 6-hydroxydopamine-induced (6-OHDA) lesion of the substantia nigra in adulthood. Newborn Wistar rats were divided into control and enriched groups according to their environmental conditions. For environmental enrichment, during the first five postnatal weeks animals were placed in larger cages and exposed to intensive complex stimuli. Dopaminergic cell loss, and hypokinetic and asymmetrical signs were evaluated after inducing PD with unilateral injections of 6-OHDA in three-month-old animals. Treatment with 6-OHDA led to a significant cell loss in the substantia nigra of control animals, however, postnatal enriched circumstances could rescue the dopaminergic cells. Although there was no significant difference in the percentage of surviving cells between 6-OHDA-treated control and enriched groups, the slightly less dopaminergic cell loss in the enriched group compared to control animals resulted in less severe hypokinesia. Our investigation is the first to provide evidence for the neuroprotective effect of postnatal enriched environment in PD later in life.

  9. The 6-hydroxydopamine-induced nigrostriatal neurodegeneration produces microglia-like NG2 glial cells in the rat substantia nigra.

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    Kitamura, Yoshihisa; Inden, Masatoshi; Minamino, Hideaki; Abe, Mari; Takata, Kazuyuki; Taniguchi, Takashi

    2010-11-01

    Neuron/glial 2 (NG2)-expressing cells are often referred to as oligodendrocyte precursor cells. NG2-expressing cells have also been identified as multipotent progenitor cells. However, microglia-like NG2 glial cells have not been fully examined in neurodegenerative disorders such as Parkinson's disease (PD). In the present study, we chose two rat models of PD, i.e., intranigral or intrastriatal injection of 6-hydroxydopamine (6-OHDA), since the cell bodies of dopamine (DA) neurons, which form a nigrostriatal pathway, are in the substantia nigra pars compacta (SNpc) while their nerve terminals are in the striatum. In the nigral 6-OHDA-injected model, activated NG2-positive cells were detected in the SNpc but not in the striatum. In contrast, in the striatal 6-OHDA-injected model, these cells were detected in both the SNpc and the striatum. In both models, activated NG2-positive cells were located close to surviving tyrosine hydroxylase (TH)-positive neurons in the SNpc. In addition, activated NG2-positive cells in the SNpc coexpressed ionized calcium-binding adaptor molecule 1 (Iba1), a microglia/macrophage marker. Interestingly, these double-positive glial cells coexpressed glial cell line-derived neurotrophic factor (GDNF). These results suggest that microglia-like NG2 glial cells may help protect DA neurons and may lead to new therapeutic targets in PD.

  10. Striatal inhibition of calpains prevents levodopa-induced neurochemical changes and abnormal involuntary movements in the hemiparkinsonian rat model.

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    Chagniel, Laure; Robitaille, Christine; Lebel, Manon; Cyr, Michel

    2012-01-01

    Pharmacological dopamine replacement with l-3,4-dihydroxyphenylalanine (L-DOPA) remains the most effective approach to treat the motor symptoms of Parkinson's disease (PD). However, as the disease progresses, the therapeutic response to L-DOPA gradually becomes erratic and is associated with the emergence of dyskinesia in the majority of patients. The pathogenesis of L-DOPA-induced dyskinesia (LID) is still unknown. In the current study, using the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD, we demonstrated that the calcium-dependent proteins calpains and cdk5 of the striatum play a critical role in the behavioral and molecular changes evoked by L-DOPA therapy. We first confirmed that L-DOPA reversed PD symptoms, assessed by the cylinder, stepping and vibrissae-elicited reaching tests in this animal model, and elicited robust abnormal involuntary movements (AIMs) reminiscent of LID. Interestingly, intrastriatal infusion of the calpains inhibitor MDL28170, and to a lower extent the cdk5 inhibitor roscovitine, reduced the severity and amplitude of AIMs without affecting L-DOPA's antiparkinsonian effects. Notably, the calpains and cdk5 inhibitors totally reversed the striatal molecular changes attributed to L-DOPA therapy, such as ERK1/2 and dynamin phosphorylation. Another fascinating observation was that L-DOPA therapy, in combination with intrastriatal infusion of MDL28170, augmented tyrosine hydroxylase levels in the striatum of lesioned rats without affecting the number of dopaminergic cells in the substantia nigra. These findings disclose a novel mechanism underlying the maladaptive alterations induced by L-DOPA therapy in the 6-OHDA rat model of PD.

  11. Exercise-induced rescue of tongue function without striatal dopamine sparing in a rat neurotoxin model of Parkinson disease.

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    Ciucci, Michelle R; Schaser, Allison J; Russell, John A

    2013-09-01

    Unilateral lesions to the medial forebrain bundle with 6-hydroxydopamine (6-OHDA) lead to force and timing deficits during a complex licking task. We hypothesized that training targeting tongue force generation during licking would improve timing and force measures and also lead to striatal dopamine sparing. Nine month-old male Fisher344/Brown Norway rats were used in this experiment. Sixteen rats were in the control condition and received tongue exercise (n=8) or no exercise (n=8). Fourteen rats were in the 6-OHDA lesion condition and underwent tongue exercise (n=7) and or no exercise (n=7). Following 4 weeks of training and post-training measures, all animals underwent bilateral stimulation of the hypoglossal nerves to measure muscle contractile properties and were then transcardially perfused and brain tissues collected for immunohistochemistry to examine striatal dopamine content. Results demonstrated that exercise animals performed better for maximal force, average force, and press rate than their no-exercise counterparts, and the 6-OHDA animals that underwent exercise performed as well as the Control No Exercise group. Interestingly, there were no group differences for tetanic muscle force, despite behavioral recovery of forces. Additionally, behavioral and neurochemical analyses indicate that there were no differences in striatal dopamine. Thus, targeted exercise can improve tongue force and timing deficits related to 6-OHDA lesions and this exercise likely has a central, versus peripheral (muscle strength) mechanism. However, this mechanism is not related to sparing of striatal dopamine content. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Acupuncture prevents 6-hydroxydopamine-induced neuronal death in the nigrostriatal dopaminergic system in the rat Parkinson's disease model.

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    Park, Hi-Joon; Lim, Sabina; Joo, Wan-Seok; Yin, Chang-Shik; Lee, Hyang-Sook; Lee, Hye-Jung; Seo, Jung Chul; Leem, Kanghyun; Son, Yang-Sun; Kim, Youn-Jung; Kim, Chang-Ju; Kim, Yong-Sik; Chung, Joo-Ho

    2003-03-01

    Parkinson's disease (PD) is a chronic neurodegenerative disorder, and it has been suggested that treatments promoting survival and functional recovery of affected dopaminergic neurons could have a significant and long-term therapeutic value. In the present study, we investigated the neuroprotective effects of acupuncture on the nigrostriatal system in rat unilaterally lesioned with 6-hydroxydopamine (6-OHDA, 4 microg/microl, intrastriatal injection) using tyrosine hydroxylase (TH) and receptor for brain-derived neurotrophic factor, trkB, immunohistochemistries. Two weeks after the lesions were made, rats presented with asymmetry in rotational behavior (118.3 +/- 17.5 turns/h) following injection with apomorphine, a dopamine receptor agonist (0.5 mg/kg, sc). In contrast, acupunctural treatment at acupoints GB34 and LI3 was shown to significantly reduce this motor deficit (14.6 +/- 13.4 turns/h). Analysis via TH immunohistochemistry revealed a substantial loss of cell bodies in the substantia nigra (SN) (45.7% loss) and their terminals in the dorsolateral striatum ipsilateral to the 6-OHDA-induced lesion. However, acupunctural treatment resulted in the enhanced survival of dopaminergic neurons in the SN (21.4% loss) and their terminals in the dorsolateral striatum. Acupuncture also increased the expression of trkB significantly (35.6% increase) in the ipsilateral SN. In conclusion, we observed that only acupuncturing without the use of any drug has the neuroprotective effects against neuronal death in the rat PD model and these protective properties of acupuncture could be mediated by trkB.

  13. PAIN IN A PARKINSON`S DISEASE RODENT ANIMAL MODEL INDUCED WITH 6-HYDROXYDOPAMINE

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    Antioch, I

    2017-06-01

    Full Text Available Pain phenomenon, the unpleasant sensory and emotional event, appears to evidently intrude in Parkinson disease (PD, a disease formally considered to be restricted only to motor deficits. Although over a half of persons with PD suffer from pain manifestations, there are very few reports targeting this issue. Considering the cases when motor symptoms of PD are eclipsed by severe pain disclosure, there is an obvious need of clarifying the intricate implications of pain in PD context. Because there are few studies researching the link between pain and PD in clinical context, but as well in animal models we chose to explore the effects of pain stimuli on a rodent model of PD. Materials and methods: We experimentally induced a PD model in Wistar rats (n=12 by injecting in the substantia nigra, a brain area known to be involved in PD occurrence, one dose of a 6-hydroxidopamine (6-OHDA solution (8µm 6-OHDA base and 4µm physiological saline, utilizing neurosurgery, while their control peers received same dose of saline solution. Two weeks after the intervention the animals were subjected to the hot-plate test, a behavioral task for acquiring pain sensitivity. Results: There was noticed a statistical significant (F(1,10 = 5.67, p=0.038 sensibility of the 6-OHDA rats to thermal pain stimuli (8.2 s ± 0.8 s in 6-OHDA group as compared to their peers (13.8 s ± 1.6 s in controls. Conclusions: The involvement of pain in PD animal models is demonstrated raising questions of how it influences PD evolution. Moreover, this result increases awareness of deficient diagnostic methods of pain in PD and as a consequence, poor treatment of pain manifestations.

  14. Transplantation of human umbilical cord blood-derived mononuclear cells induces recovery of motor dysfunction in a rat model of Parkinson's disease

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    Chen C

    2016-04-01

    Full Text Available Chao Chen,1,* Jing Duan,1,* Aifang Shen,2,* Wei Wang,1 Hao Song,1 Yanming Liu,1 Xianjie Lu,1 Xiaobing Wang,2 Zhiqing You,1 Zhongchao Han,3,4 Fabin Han1 1Center for Stem Cells and Regenerative Medicine, The Liaocheng People's Hospital, Affiliated Liaocheng Hospital, Taishan Medical University, Shandong, People's Republic of China; 2Department of Gynecology and Obstetrics, The Liaocheng People's Hospital, Affiliated Liaocheng Hospital, Taishan Medical University, Shandong, People's Republic of China; 3The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences, Peking Union of Medical College, Tianjin, People's Republic of China; 4National Engineering Research Center of Cell Products, AmCellGene Co. Ltd., TEDA, Tianjin, People's Republic of China*These authors contributed equally to this workAbstract: Human umbilical cord blood-derived mononuclear cells (hUCB-MNCs were reported to have neurorestorative capacity for neurological disorders such as stroke and traumatic brain injury. This study was performed to explore if hUCB-MNC transplantation plays any therapeutic effects for Parkinson's disease (PD in a 6-OHDA-lesioned rat model of PD. hUCB-MNCs were isolated from umbilical cord blood and administered to the striatum of the 6-OHDA-lesioned rats. The apomorphine-induced locomotive turning-overs were measured to evaluate the improvement of motor dysfunctions of the rats after administration of hUCB-MNCs. We observed that transplanted hUCB-MNCs significantly improve the motor deficits of the PD rats and that grafted hUCB-MNCs integrated to the host brains and differentiated to neurons and dopamine neurons in vivo after 16 weeks of transplantation. Our study provided evidence that transplanted hUCB-MNCs play therapeutic effects in a rat PD model by differentiating to neurons and dopamine neurons. Keywords: hUCB-MNCs, Parkinson's disease, transplantation

  15. Neuroprotective and behavioral efficacy of intravenous transplanted adipose stem cells in experimental Parkinsonian rat models

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    Malihe Nakhaeifard

    2016-02-01

    Full Text Available Background: Parkinson's disease is a deficiency of dopamine in the striatum, characterized by bradykinesis, rigidity and resting tremor. Adipose tissue-Derived Stem Cells (ADSCs have many advantages for cell therapy because of the easy availability and pluripotency without ethical problems. In this research, the effects of ADSCs transplantation on motor impairment of rat Parkinsonian models were evaluated. Materials and Methods: Parkinson model was constructed by the unilateral lesion of striatum of male Wistar rats using 20µg of 6-hydroxydopamine (6-OHDA as lesion group. Cell and α-MEM (α-minimal essential medium groups were lesioned animals that received intravenous injection of 3×106 cells suspended in medium and medium repectively. All rats were evaluated behaviorally with rotarod and apomorphine-induced rotation tests, at 4 and 8 weeks after cell transplantation. Results: Lesion and α-MEM groups showed increased contralateral turns while cell group significantly ameliorated both in rotarod and apomorphine-induced rotation tests. There was a significant difference of contralateral turns between cell and lesioned groups at 8 weeks after transplantation. Lesioned rats showed significant decrease of staying on the rod as compared to control, but in cell group there was a significant increase in comparision with the lesioned animals. Conclusion: ADSCs injected intravenously promote functional recovery in Parkinsonian rats.

  16. Magnetic resonance imaging as a tool to image neuroinflammation in a rat model of Parkinson's disease--phagocyte influx to the brain is promoted by bilberry-enriched diet.

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    Virel, Ana; Rehnmark, Anna; Orädd, Greger; Olmedo-Díaz, Sonia; Faergemann, Erik; Strömberg, Ingrid

    2015-11-01

    Neuroinflammation is a chronic event in neurodegenerative disorders. In the rat model of Parkinson's disease, including a striatal injection of the neurotoxin 6-hydroxydopamine (6-OHDA), antioxidant treatment affects the inflammatory process. Despite a heavy accumulation of microglia early after the injury, dopamine nerve fibre regeneration occurs. It remains unclear why this heavy accumulation of microglia is found early after the lesion in antioxidant-treated animals, or even more, what is the origin of these microglia. In this study magnetic resonance imaging (MRI) was used to elucidate whether the inflammatory response was generated from the blood or from activated brain microglia. Superparamagnetic iron oxide (SPIO) nanoparticles were injected intravenously prior to a striatal 6-OHDA injection to tag phagocytes in the blood. Rats were fed either with bilberry-enriched or control diet. T2*-weighted MRI scans were performed 1 week after the lesion, and hypointense areas were calculated from T2*-weighted images, to monitor the presence of SPIO particles. The results revealed that feeding the animals with bilberries significantly promoted accumulation of blood-derived immune cells. Gadolinium-enhanced MRI demonstrated no difference in leakage of the blood-brain barrier independent of diets. To conclude, bilberry-enriched diet promotes an influx of periphery-derived immune cells to the brain early after injury.

  17. Neuroprotective activity of peripherally administered liver growth factor in a rat model of Parkinson's disease.

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    Rafael Gonzalo-Gobernado

    Full Text Available Liver growth factor (LGF is a hepatic mitogen purified some years ago that promotes proliferation of different cell types and the regeneration of damaged tissues, including brain tissue. Considering the possibility that LGF could be used as a therapeutic agent in Parkinson's disease, we analyzed its potential neuroregenerative and/or neuroprotective activity when peripherally administered to unilaterally 6-hydroxydopamine (6-OHDA-lesioned rats. For these studies, rats subjected to nigrostriatal lesions were treated intraperitoneally twice a week with LGF (5 microg/rat for 3 weeks. Animals were sacrificed 4 weeks after the last LGF treatment. The results show that LGF stimulates sprouting of tyrosine hydroxylase-positive terminals and increases tyrosine hydroxylase and dopamine transporter expression, as well as dopamine levels in the denervated striatum of 6-OHDA-lesioned rats. In this structure, LGF activates microglia and raises tumor necrosis factor-alpha protein levels, which have been reported to have a role in neuroregeneration and neuroprotection. Besides, LGF stimulates the phosphorylation of MAPK/ERK1/2 and CREB, and regulates the expression of proteins which are critical for cell survival such as Bcl2 and Akt. Because LGF partially protects dopamine neurons from 6-OHDA neurotoxicity in the substantia nigra, and reduces motor deficits in these animals, we propose LGF as a novel factor that may be useful in the treatment of Parkinson's disease.

  18. Novel Food Supplement "CP1" Improves Motor Deficit, Cognitive Function, and Neurodegeneration in Animal Model of Parkinson's Disease.

    Science.gov (United States)

    Wattanathorn, Jintanaporn; Sutalangka, Chatchada

    2016-08-01

    Based on pivotal roles of oxidative stress, dopaminergic and cholinergic systems on the pathophysiology of Parkinson's disease (PD), the searching for functional food for patients attacked with PD from Cyperus rotundus and Zingiber officinale, the substances possessing antioxidant activity, and the suppression effects on monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE) have been considered. In this study, we aimed to determine the effect of the combined extract of C. rotundus and Z. officinale (CP1) to improve motor and memory deficits, neurodegeneration, oxidative stress, and functions of both cholinergic and dopaminergic systems in the animal model of PD induced by 6-hydroxydopamine hydrochloride (6-OHDA). Male Wistar rats, weighing 180-220 g, were induced unilateral lesion at right substantia nigra by 6-OHDA and were orally given CP1 at doses of 100, 200, and 300 mg/kg body weight for 14 days after 6-OHDA injection. The results showed that the 6-OHDA rats treated with CP1 increased spatial memory, but decreased neurodegeneration, malondialdehyde level, and AChE activity in hippocampus. The decreased motor disorder and neurodegeneration in substantia nigra together with the enhanced catalase activity, but decreased MAO-B activity in striatum, were also observed. The memory enhancing effect of CP1 might occur through the improved oxidative stress and the enhanced cholinergic function, whereas the effect to improve motor disorder of CP1 might occur through the enhanced dopaminergic function in striatum by decreasing the degeneration of dopaminergic neurons and the suppression of MAO-B. Therefore, CP1 is the potential functional food against PD. However, further researches in clinical trial and drug interactions are essential.

  19. Nonuniform cardiac denervation observed by 11C-meta-hydroxyephedrine PET in 6-OHDA-treated monkeys.

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    Valerie Joers

    Full Text Available Parkinson's disease presents nonmotor complications such as autonomic dysfunction that do not respond to traditional anti-parkinsonian therapies. The lack of established preclinical monkey models of Parkinson's disease with cardiac dysfunction hampers development and testing of new treatments to alleviate or prevent this feature. This study aimed to assess the feasibility of developing a model of cardiac dysautonomia in nonhuman primates and preclinical evaluations tools. Five rhesus monkeys received intravenous injections of 6-hydroxydopamine (total dose: 50 mg/kg. The animals were evaluated before and after with a battery of tests, including positron emission tomography with the norepinephrine analog (11C-meta-hydroxyephedrine. Imaging 1 week after neurotoxin treatment revealed nearly complete loss of specific radioligand uptake. Partial progressive recovery of cardiac uptake found between 1 and 10 weeks remained stable between 10 and 14 weeks. In all five animals, examination of the pattern of uptake (using Logan plot analysis to create distribution volume maps revealed a persistent region-specific significant loss in the inferior wall of the left ventricle at 10 (P<0.001 and 14 weeks (P<0.01 relative to the anterior wall. Blood levels of dopamine, norepinephrine (P<0.05, epinephrine, and 3,4-dihydroxyphenylacetic acid (P<0.01 were notably decreased after 6-hydroxydopamine at all time points. These results demonstrate that systemic injection of 6-hydroxydopamine in nonhuman primates creates a nonuniform but reproducible pattern of cardiac denervation as well as a persistent loss of circulating catecholamines, supporting the use of this method to further develop a monkey model of cardiac dysautonomia.

  20. Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: Focusing on neuroprotective effects of stromal cell-derived factor-1α

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    Tayra Judith

    2010-04-01

    Full Text Available Abstract Background Mesenchymal stem cells (MSCs are pluripotent stem cells derived from bone marrow with secretory functions of various neurotrophic factors. Stromal cell-derived factor-1α (SDF-1α is also reported as one of chemokines released from MSCs. In this research, the therapeutic effects of MSCs through SDF-1α were explored. 6-hydroxydopamine (6-OHDA, 20 μg was injected into the right striatum of female SD rats with subsequent administration of GFP-labeled MSCs, fibroblasts, (i.v., 1 × 107 cells, respectively or PBS at 2 hours after 6-OHDA injection. All rats were evaluated behaviorally with cylinder test and amphetamine-induced rotation test for 1 month with consequent euthanasia for immunohistochemical evaluations. Additionally, to explore the underlying mechanisms, neuroprotective effects of SDF-1α were explored using 6-OHDA-exposed PC12 cells by using dopamine (DA assay and TdT-mediated dUTP-biotin nick-end labeling (TUNEL staining. Results Rats receiving MSC transplantation significantly ameliorated behaviorally both in cylinder test and amphetamine-induced rotation test compared with the control groups. Correspondingly, rats with MSCs displayed significant preservation in the density of tyrosine hydroxylase (TH-positive fibers in the striatum and the number of TH-positive neurons in the substantia nigra pars compacta (SNc compared to that of control rats. In the in vitro study, SDF-1α treatment increased DA release and suppressed cell death induced by 6-OHDA administration compared with the control groups. Conclusions Consequently, MSC transplantation might exert neuroprotection on 6-OHDA-exposed dopaminergic neurons at least partly through anti-apoptotic effects of SDF-1α. The results demonstrate the potentials of intravenous MSC administration for clinical applications, although further explorations are required.

  1. 脑内移植间充质干细胞治疗大鼠帕金森病模型的研究%Intracerebral Transplantation of Rat Bone Marrow-derived Mesenchymal Stem Cells for Treatment of 6-OHDA Model of Parkinson's Disease

    Institute of Scientific and Technical Information of China (English)

    付文玉; 邢海霞; 王晓萃; 吕娥; 王玉良; 郑志娟; 庄文欣

    2009-01-01

    目的 研究大鼠骨髓间充质干细胞(MSCs)脑内移植治疗帕金森病(PD)大鼠的可行性.方法 贴壁培养法分离、培养大鼠骨髓MSCs.将BrdU标记的第3代MSCs移植PD大鼠纹状体内,移植后1、2和4周检测PD大鼠的行为学变化,应用BrdU免疫荧光观察移植细胞在脑内的存活情况,应用免疫组化法检测酪氨酸羟化酶(TH)在移植细胞及黑质的表达.结果 移植细胞后1周、2周和4周PD大鼠与移植前相比行为学有改善,旋转圈数明显减少(P<0.05);PD大鼠损毁侧和健侧黑质内TH阳性细胞数之比随移植时间的延长而增加,但未发现移植细胞呈现TH阳性表达.细胞移植后1周、2周和4周检测均可见纹状体内BrdU阳性细胞散在分布.结论 植入脑内的MSCs能够生存和迁移,MSCs脑内移植对PD大鼠有一定的治疗作用.

  2. The Vermicelli Handling Test: A Simple Quantitative Measure of Dexterous Forepaw Function in Rats

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    Allred, Rachel P.; Adkins, DeAnna L.; Woodlee, Martin T.; Husbands, Lincoln C.; Maldonado, Mónica A.; Kane, Jacqueline R.; Schallert, Timothy; Jones, Theresa A.

    2008-01-01

    Loss of function in the hands occurs with many brain disorders, but there are few measures of skillful forepaw use in rats available to model these impairments that are both sensitive and simple to administer. Whishaw and Coles (1996) previously described the dexterous manner in which rats manipulate food items with their paws, including thin pieces of pasta. We set out to develop a measure of this food handling behavior that would be quantitative, easy to administer, sensitive to the effects of damage to sensory and motor systems of the CNS and useful for identifying the side of lateralized impairments. When rats handle 7 cm lengths of vermicelli, they manipulate the pasta by repeatedly adjusting the forepaw hold on the pasta piece. As operationally defined, these adjustments can be easily identified and counted by an experimenter without specialized equipment. After unilateral sensorimotor cortex (SMC) lesions, transient middle cerebral artery occlusion (MCAO) and striatal dopamine depleting (6-hydroxydopamine, 6-OHDA) lesions in adult rats, there were enduring reductions in adjustments made with the contralateral forepaw. Additional pasta handling characteristics distinguished between the lesion types. MCAO and 6-OHDA lesions increased the frequency of several identified atypical handling patterns. Severe dopamine depletion increased eating time and adjustments made with the ipsilateral forepaw. However, contralateral forepaw adjustment number most sensitively detected enduring impairments across lesion types. Because of its ease of administration and sensitivity to lateralized impairments in skilled forepaw use, this measure may be useful in rat models of upper extremity impairment. PMID:18325597

  3. Neuroprotective Properties of Mildronate, a Small Molecule, in a Rat Model of Parkinson’s Disease

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    Harry V. Vinters

    2010-11-01

    Full Text Available Previously, we have found that mildronate [3-(2,2,2-trimethylhydrazinium propionate dihydrate], a small molecule with charged nitrogen and oxygen atoms, protects mitochondrial metabolism that is altered by inhibitors of complex I and has neuroprotective effects in an azidothymidine-neurotoxicity mouse model. In the present study, we investigated the effects of mildronate in a rat model of Parkinson’s disease (PD that was generated via a unilateral intrastriatal injection of the neurotoxin 6-hydroxydopamine (6‑OHDA. We assessed the expression of cell biomarkers that are involved in signaling cascades and provide neural and glial integration: the neuronal marker TH (tyrosine hydroxylase; ubiquitin (a regulatory peptide involved in the ubiquitin-proteasome degradation system; Notch-3 (a marker of progenitor cells; IBA-1 (a marker of microglial cells; glial fibrillary acidic protein, GFAP (a marker of astrocytes; and inducible nitric oxide synthase, iNOS (a marker of inflammation. The data show that in the 6-OHDA-lesioned striatum, mildronate completely prevented the loss of TH, stimulated Notch-3 expression and decreased the expression of ubiquitin, GFAP and iNOS. These results provide evidence for the ability of mildronate to control the expression of an array of cellular proteins and, thus, impart multi-faceted homeostatic mechanisms in neurons and glial cells in a rat model of PD. We suggest that the use of mildronate provides a protective effect during the early stages of PD that can delay or halt the progression of this neurodegenerative disease.

  4. Autoradiographic study of dopamine transporter in rat Model of Parkinson' s disease with 125I-β-CIT

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    Liu Zhenguo; Chen Shengdi; Shum Wenshan

    2000-01-01

    Objective To evaluate the value of iaaging for dopamine transpter(DAT) wi th 125I- β-CIT. Methods The partial and complete lesioned rat models of hemiparkinsonism were rendered with 6- hydroxy-dopamine (6-OHDA). Each rat was injected intravenously with 1251-β-CIT containing 40 μ Ci. Coronal t issue sections were imaged by autoradiography. The levets of dopamine (DA)and its metabolites were measured by high performance 1iquid choromatography and electro-chemical detection (HPLC-ECD). The t yros i nc hydroxylase(Tll)-positive cells and fibres in substantia nigra and striatum of the rats were observed by immunohistochemieal staining. Results The radioactivities in the lesioned striatum of both partial and complete lesioned hemiparkinsonian rats were 2.67±0.25 and O. 98±0.29 respectively , and were singificantly decreased by.18% and 72% respectively, as compared with those of unlesioned side. The levels of DA in the lesioned striatum of partial and complete lesioned models were decreased by 39% and 98% respectively. The loss of TH-positive eells and fibres in the substantia nigra and striatum was found in the lesioned striatum of both partial and complete-lesioned models. Conclusion The imaging study of DAT may be helpful for the early diagnosis of Parkinson's disease and for the monitor of the progression of this discaose;.

  5. Striatal adenosine A{sub 2A} receptor-mediated positron emission tomographic imaging in 6-hydroxydopamine-lesioned rats using [{sup 18}F]-MRS5425

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    Bhattacharjee, Abesh Kumar; Lang Lixin; Jacobson, Orit [Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892 (United States); Shinkre, Bidhan [Chemical Biology Unit, Laboratory of Cell Biochemistry and Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 (United States); Ma Ying [Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892 (United States); Niu Gang [Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892 (United States); Department of Radiology and Imaging Sciences, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892 (United States); Trenkle, William C. [Chemical Biology Unit, Laboratory of Cell Biochemistry and Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 (United States); Jacobson, Kenneth A. [Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 (United States); Chen Xiaoyuan [Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892 (United States); Kiesewetter, Dale O., E-mail: dk7k@nih.gov [Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892 (United States)

    2011-08-15

    Introduction: A{sub 2A} receptors are expressed in the basal ganglia, specifically in striatopallidal GABAergic neurons in the striatum (caudate-putamen). This brain region undergoes degeneration of presynaptic dopamine projections and depletion of dopamine in Parkinson's disease. We developed an {sup 18}F-labeled A{sub 2A} analog radiotracer ([{sup 18}F]-MRS5425) for A{sub 2A} receptor imaging using positron emission tomography (PET). We hypothesized that this tracer could image A{sub 2A} receptor changes in the rat model for Parkinson's disease, which is created following unilateral injection of the monoaminergic toxin 6-hydroxydopamine (6-OHDA) into the substantia nigra. Methods: [{sup 18}F]-MRS5425 was injected intravenously in anesthetized rats, and PET imaging data were collected. Image-derived percentage injected doses per gram (%ID/g) in regions of interest was measured in the striatum of normal rats and in rats unilaterally lesioned with 6-OHDA after intravenous administration of saline (baseline), D{sub 2} agonist quinpirole (1.0 mg/kg) or D{sub 2} antagonist raclopride (6.0 mg/kg). Results: Baseline %ID/g reached a maximum at 90 s and maintained plateau for 3.5 min, and then declined slowly thereafter. In 6-OHDA-lesioned rats, %ID/g was significantly higher in the lesioned side compared to the intact side, and the baseline total %ID/g (data from both hemispheres were combined) was significantly higher compared to quinpirole stimulation starting from 4.5 min until the end of acquisition at 30 min. Raclopride did not produce any change in uptake compared to baseline or between the hemispheres. Conclusion: Thus, increase of A{sub 2A} receptor-mediated uptake of radioactive MRS5425 could be a superior molecular target for Parkinson's imaging.

  6. 帕金森病大鼠模型的行为学及神经元形态学评价%Evaluation on behaviours and neuron morphology of Parkinson's disease rat model

    Institute of Scientific and Technical Information of China (English)

    陆建明; 周厚广

    2004-01-01

    背景:由于黑质致密部体积狭小,应用6-羟基多巴胺(6-Hydroxydopamine,6-OHDA)损毁黑质多巴胺神经元(Nigral dopaminergic neuron,NDN)制作帕金森病大鼠模型的成功率较低,一般仅为30%~40%左右.目的:探讨帕金森病大鼠模型建立后的行为学及神经元形态学改变.设计:完全随机的实验研究.地点和材料:安徽省药物研究所,SD大鼠,6-OHDA,阿朴吗啡,兔抗TH血清,SR-6N大鼠脑立体定向仪等.干预:将6-OHDA立体定向注射于90只SD大鼠的左侧黑质区及黑质纹状体通路,观察大鼠行为及多巴胺神经元形态学变化.主要观察指标:旋转行为,震颤及其他异常行为,免疫组织化学观察,电镜观察.结果:经阿朴吗啡诱导共筛选出64只成功大鼠模型(占71%);免疫组化观察发现注射侧黑质区NDN较对侧明显减少,电镜观察发现其普遍存在凋亡及坏死样改变.结论:本方法是建立帕金森病大鼠模型的有效方法,在行为学和神经元形态学等方面同帕金森病人有许多相似之处.%BACKGROUND: The successful rate in the establishment of Parkinson' s disease(PD) model in rat is comparatively low through destroying Nigral dopaminergic neuron (NDN) by 6-hydroxydopamine (6-OJDA) because of the small volume of pars compacta of substantia nigra(SNC), which is only about 30% to 40%.OBJECTIVE: To discuss the changes on behaviour and neuron morphology after the establishment of PD rat model.DESIGN: A complete random control study.SETTING and MATERIALS: Study was completed in the Pharmaceutical Institute of Anhui Province. Materials included SD rats, 6-OHDA, apomorphine,rabbit-anti-TH serum, SR-6N rat cerebral solid orientation apparatus, etc.INTERVENTIONS: 6-OHDA was solidly and directionally injected into left SN area and corpus striatum pathway in SN in 90 SD rats to observe the changes in the behaviours and dopaminergic neuron morphology.MAIN OUTCOME MEASURES: Rotation behaviour, tremor and other abnormal

  7. 5-Hydroxy-tryptophan for the treatment of L-DOPA-induced dyskinesia in the rat Parkinson's disease model.

    Science.gov (United States)

    Tronci, Elisabetta; Lisci, Carlo; Stancampiano, Roberto; Fidalgo, Camino; Collu, Maria; Devoto, Paola; Carta, Manolo

    2013-12-01

    The serotonin system has recently emerged as an important player in the appearance of L-DOPA-induced dyskinesia (LID) in experimental models of Parkinson's disease, as it provides an unregulated source of L-DOPA-derived dopamine release in the dopamine-depleted striatum. Accordingly, toxin lesion or pharmacological silencing of serotonin neurons suppressed LID in the rat and monkey models of Parkinson's disease. However, 5-HT1 receptor agonists were also found to partially reduce the therapeutic effect of L-DOPA. In this study, we evaluated whether enhancement of the serotonin tone induced by the administration of the serotonin precursor 5-hydroxy-tryptophan (5-HTP) could affect induction and expression of LID, as well as the therapeutic effect of L-DOPA, in 6-OHDA-lesioned rats. Drug naïve and L-DOPA-primed 6-OHDA-lesioned rats were chronically treated with a daily injection of L-DOPA (6 mg/kg plus benserazide, s.c.) alone, or in combination with 5-HTP (24-48 mg/kg, i.p.). The abnormal involuntary movements (AIMs) test, as well as the stepping and the motor activity tests, were performed during the chronic treatments. Results showed that 5-HTP reduced the appearance of LID of about 50% at both tested doses. A partial reduction of the therapeutic effect of L-DOPA was seen with the higher but not with the lower dose of 5-HTP. 5-HTP 24 mg/kg was also able to reduce the expression of dyskinesia in L-DOPA-primed dyskinetic rats, to a similar extent than in L-DOPA-primed rats. Importantly, the antidyskinetic effect of 5-HTP 24 mg/kg does not appear to be due to a competition with L-DOPA for crossing the blood-brain barrier; in fact, similar L-DOPA striatal levels were found in L-DOPA only and L-DOPA plus 5-HTP 24 mg/kg treated animals. These data further confirm the involvement of the serotonin system in the appearance of LID, and suggest that 5-HTP may be useful to counteract the appearance of dyskinesia in Parkinson's disease patients.

  8. Long-term protective effects of AAV9-mesencephalic astrocyte-derived neurotrophic factor gene transfer in parkinsonian rats.

    Science.gov (United States)

    Hao, Fei; Yang, Chun; Chen, Sha-Sha; Wang, Yan-Yan; Zhou, Wei; Hao, Qiang; Lu, Tao; Hoffer, Barry; Zhao, Li-Ru; Duan, Wei-Ming; Xu, Qun-Yuan

    2017-05-01

    Intrastriatal injection of mesencephalic astrocyte-derived neurotrophic factor (MANF) protein has been shown to provide neuroprotective and neurorestorative effects in a 6-hydroxydopamine (6-OHDA) - lesioned rat model of Parkinson's disease. Here, we used an adeno-associated virus serotype 9 (AAV9) vector to deliver the human MANF (hMANF) gene into the rat striatum 10days after a 6-OHDA lesion to examine long-term effects of hMANF on nigral dopaminergic neurons and mechanisms underlying MANF neuroprotection. Intrastriatal injection of AAV9-hMANF vectors led to a robust and widespread expression of the hMANF gene in the injected striatum up to 24weeks. Increased levels of hMANF protein were also detected in the ipsilateral substantia nigra. The hMANF gene transfer promoted the survival of nigral dopaminergic neurons, regeneration of striatal dopaminergic fibers and an upregulation of striatal dopamine levels, resulting in a long-term improvement of rotational behavior up to 16weeks after viral injections. By using SH-SY5Y cells, we found that intra- and extracellular application of MANF protected cells against 6-OHDA-induced toxicity via inhibiting the endoplasmic reticulum stress and activating the PI3K/Akt/mTOR pathway. Our results suggest that AAV9-mediated hMANF gene delivery into the striatum exerts long-term neuroprotective and neuroregenerative effects on the nigrostriatal dopaminergic system in parkinsonian rats, and provide insights into mechanisms responsible for MANF neuroprotection. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Anodal transcranial direct current stimulation relieves the unilateral bias of a rat model of Parkinson's disease.

    Science.gov (United States)

    Li, Yiyan; Tian, Xulong; Qian, Long; Yu, Xuehong; Jiang, Weiwei

    2011-01-01

    The unilaterally lesioned rat model of Parkinson's disease which fails to orient to the food stimuli presented on the contralateral side of its preferential side of body could be induced by the injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB). We employed transcranial direct current stimulation (tDCS, current intensity: 80 μA, and 40 μA; anodal electrode area: 3.14 mm(2); stimulation time: 30 minutes) over the M1 area to relieve the ipsilateral bias in the rat model. A corridor test was set to count the ipsilateral bias of the rats. In this experiment, 30 Sprague-Dawley rats (80 μA: n = 8, 40 μA: n = 8, sham: n = 7, healthy control: n = 7) were chosen for the corridor test and the tDCS session. The lesioned rats exhibited increased ipsilateral bias 4 weeks after the lesion surgery (P < 0.01), and the anodal tDCS with the active electrode on the lesioned side relieved the ipsilateral bias significantly (P < 0.01) immediately after the surgery and the improvement lasted for nearly 1 day. The rats in the group of 80 μA exhibited more significant changes than the 40 μA group after one day. After all the experiments, the histological process showed no neurotrauma led by the tDCS. In conclusion, the modulatory function of the cortical excitability of the tDCS may awaken the compensatory mechanisms and the response mechanisms which modulate the loss of the brain function. Further studies should be done to provide more evidence about the assumption.

  10. estudo do efeito neuroprotetor da berberina sobre o dano neuronal, comportamento motor e memÃria de ratos com degeneraÃÃo nigro-estrialtal por 6-ohda

    OpenAIRE

    Ana Carla Lima Nunes

    2015-01-01

    RESUMO A doenÃa de Parkinson à a segunda condiÃÃo neurodegenerativa mais prevalente no mundo. Para aumentar o conhecimento sobre a etiopatogenia de doenÃas neurodegenerativas e avaliar a eficÃcia dos potenciais tratamentos, uma sÃrie de modelos animais està sendo usada atualmente. A 6-hidroxidopamina (6-OHDA) à uma das neurotoxinas mais comumente usadas experimentalmente no modelo de degeneraÃÃo nigro-estriatal. A berberina à o alcalÃide mais abundante isolado da Berberis sp, com aÃÃes ant...

  11. Influência da adrenalectomia bilateral nos eventos neurodegenerativos no modelo do parkinsonismo experimental pela 6-OHDA nigral. Enfoque aos mecanismos parácrinos gliais envolvidos na neuroproteção e cicatrização

    OpenAIRE

    Camila Silva Siqueira

    2009-01-01

    Este trabalho tem o objetivo avaliar o efeito da adrenalectomia bilateral no processo neurodegenerativo e cicatricial na via nigro estriatal dopaminérgica lesada pela 6- hidroxidopamina (6-OHDA) em ratos, e deste modo contribuir para a interpretação dos efeitos dos hormônios adreno esteróides nos processos neurodegenerativos e neurotróficos nas lesões do sistema nervoso central. Ratos Wistar adultos jovens foram submetidos à cirurgia de retirada bilateral das glândulas adrenais ou cirurgia si...

  12. Pramipexole- and methamphetamine-induced reward-mediated behavior in a rodent model of Parkinson's disease and controls.

    Science.gov (United States)

    Riddle, J L; Rokosik, S L; Napier, T C

    2012-07-15

    Pramipexole (PPX) is a dopamine agonist that is FDA-approved for treatment of motor dysfunction in Parkinson's disease and restless leg syndrome. In a subpopulation of treated patients, PPX can lead to impulsive-compulsive disorders including behavioral addictions and dopamine dysregulation syndrome, a phenomenon that mirrors drug addiction. Regardless of this clinical picture, the capacity of PPX to regulate reward-mediated behaviors remains unclear and has not been evaluated in an animal model of Parkinson's disease. To fill this gap, we examined the rewarding potential of PPX in parkinsonian-like rats using conditioned place preference (CPP) and also evaluated associated motor behaviors. Methamphetamine (meth) and saline served as positive and negative controls, respectively. To model Parkinson's disease, the neurotoxin 6-OHDA was injected bilaterally into the dorsolateral striatum. The resulting lesions were verified functionally using a forelimb adjusting step and post mortem immunohistochemical staining of striatal tyrosine hydroxylase. Three pairings of meth (1mg/kg, ip), paired with a unique context, induced CPP in both 6-OHDA-treated and sham-operated rats; saline pairings had no effect. Three pairings of (±)PPX at 2mg/kg ip (equal to 1mg/kg of the active racimer) induced CPP in 6-OHDA-treated rats, but a higher dose (4 mg/kg, ip (±)PPX) was needed to induce CPP in sham rats. In all rats, acute administration of 2mg/kg (±)PPX decreased locomotor activity; the behavior was normalized by the third (±)PPX administration. In summary, these findings reveal that (±)PPX has motor and rewarding effects and suggest the parkinsonian brain state may be more sensitive to the rewarding, but not motoric effects.

  13. [High-frequency electro-acupuncture stimulation modulates intracerebral γ-aminobutyric acid content in rat model of Parkinson's disease].

    Science.gov (United States)

    Du, Jing; Sun, Zuo-Li; Jia, Jun; Wang, Xuan; Wang, Xiao-Min

    2011-08-25

    The purpose of the present study is to observe the effect of electro-acupuncture (EA) stimulation on intracerebral neurotransmitters in a rat model of Parkinson's disease (PD), and explore the possible mechanism. We used 6-hydroxydopamine (6-OHDA) injection in medial forebrain bundle (MFB) in the right brain of Sprague Dawley (SD) rat to establish the parkinsonian rat model, and randomly divided the PD rats into model and 100 Hz EA stimulation groups (n =10 in each group). EA stimulation group received 4 courses of EA stimulation on Baihui (GV-20) and Dazhui (GV-14) acupuncture points. Moreover, ten rats were randomly selected as sham operation group, only receiving normal saline (NS) injection in MFB. Then apomorphine (APO)-induced rotational behavior in different groups was recorded, and the contents of γ-aminobutyric acid (GABA) in the brain were analyzed with high pressure/performance liquid chromatography-electrochemical detection (HPLC-ECD). The results showed that model group exhibited abnormal rotational behavior with APO treatment, suggesting the successful establishment of PD model. Compared with sham operation group, model group showed increased GABA contents in cortex and striatum, as well as decreased GABA content in ventral midbrain, on the lesioned side. EA stimulation could effectively ameliorate the abnormal rotational behavior of PD rat. Compared with the model group, EA stimulation decreased the ratio of GABA content on the lesioned side to that on unlesioned side in the cortex, while increased the ratios in the striatum and cerebellum. However, there was no difference of the ratio in the ventral midbrain among three groups. These results suggest high-frequency EA stimulation significantly improves the abnormal behavior of PD rats, which may exert through enhancing the inhibitory effect of cerebellum-basal ganglia-cortical loop on motor center.

  14. The C-terminal domain of the heavy chain of tetanus toxin given by intramuscular injection causes neuroprotection and improves the motor behavior in rats treated with 6-hydroxydopamine.

    Science.gov (United States)

    Mendieta, Liliana; Bautista, Elizabeth; Sánchez, Alejandra; Guevara, Jorge; Herrando-Grabulosa, Mireia; Moran, José; Martínez, Rebeca; Aguilera, José; Limón, Ilhuicamina Daniel

    2012-10-01

    We have previously shown that the intrastriatal injection of the C-terminal domain of tetanus toxin (Hc-TeTx) protects the nigrostriatal-dopaminergic pathways and improves motor behavior in hemiparkinsonism-rat models caused by MPP(+) (1-methyl-4-phenylpyridinium). Here we have investigated the protective effects of the intramuscular application of the Hc-TeTx on motor asymmetry and neurodegeneration in the striatum of 6-hydroxydopamine (6-OHDA)-treated rats. Adult male rats were intramuscularly injected with the recombinant Hc-TeTx protein (0.1-20μg/kg, daily) 3days before the stereotaxic injection of 6-OHDA into the left striatum. Our results showed that the motor-improvement functions were extended for 4weeks in all Hc-TeTx-treated groups, obtaining the maximum performance with the highest dose of Hc-TeTx (20μg/kg). The improvements found were 97%, 87%, and 70% in the turning behavior, stepping test, and cylinder test, respectively. The striatal levels of dopamine and its metabolites did not vary compared to the control group. Moreover, the peripheral treatment with Hc-TeTx in rats prevents, for 30days, the neurodegeneration in the striatum caused by the toxicity of the 6-OHDA. Our results lead us to believe that the Hc-TeTx could be a potential therapeutic agent in pathologies caused by impairment of dopaminergic innervations such as Parkinson's disease. Copyright © 2012 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

  15. Modulation of connexin 36 expression in basal ganglia and motor cortex in rat model of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    CHEN Xian-wen

    2013-08-01

    Full Text Available Objective To observe the expression of connexin 36 (Cx36 in the striatum and motor cortex of rat model of Parkinson's disease (PD in order to explore whether gap junction is involved in the pathogenesis of the cortex-basal ganglia circuit disturbances in PD. Methods Hemi-parkinsonian rat model was produced by stereotaxically injecting 6-hydroxydopamine (6-OHDA to right medial forebrain bundle (MFB. Immunohistochemical staining and Western blotting analysis were used to observe the expression changes of Cx36 in the striatum and motor cortex. Double immunofluorescence labeling was used to analyze the expression of Cx36 in enkephalin (ENK positive medium spiny neurons and Parvalbumin (PV positive interneurons in the striatum. Results Immunohistochemical staining showed Cx36 expression was elevated in the right striatum as well as right motor cortex of PD group compared with normal control group (t = 2.474, P = 0.048; t = 2.614, P = 0.040. Double immunofluorescence labeling staining revealed that ENK-positive striatum neurons were elevated (t = 3.987, P = 0.007 and Cx36 expression was increased in ENK-positive striatum neurons (t = 3.271, P = 0.017 in PD group compared with normal control group. While PV-positive interneurons decreased (t = 2.777, P = 0.032 and Cx36 expression was down-regulated in PV-positive interneurons (t = 2.624, P = 0.039 compared with the normal control group. Western blotting indicated that the 6-OHDA lesion induced a significant upregulation of Cx36 to (119.31 ± 8.92% in comparison with the normal group [(104.05 ± 3.82%] in right striatum (t = 3.516, P = 0.024. In right motor cortex Cx36 increased to (138.20 ± 17.88% , induced a significant upregulation of Cx36 in the right motor cortex in comparison with the normal control group [(105.27 ± 2.82%; t = 4.068, P = 0.015]. Conclusion The Cx36 expression was generally increased in the striatum and motor cortex of PD rat model, with upregulation in ENK-positive striatum

  16. Experimental Study on Heterograft of Glomus Ccl ls of Carotid Body for Hemioarkinsonian Rats

    Institute of Scientific and Technical Information of China (English)

    曹学兵; 孙圣刚; 童萼塘

    2002-01-01

    Summary: To observe the effects of heterograft of glomus cells of carotid body on hemiparkinsonian rat models, rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the right dopamin ergic neurons of substantia nigra received intrastriatal glomus cells heterograft. Apomorphine-induced rotation was monitored for 30 rmin at various time points after grafting. The striata were cut and ex-amined for dopamine content by HPLC and for immunohistochemical staining of tyrosine hydroxylase positive neurons (TH+ ) at the end of the experiments. The results showed that apomorphine-induced rotational behavior was significantly reduced for 12 weeks and the dopamine contents were signifi cantly elevated after grafting (P<0.01), and TH+ cells survived better. The present study demon strates that intrastriatal heterograft of glomus cells within carotid body in rats with 6-OHDA-elicited lesions could reduce apomorphine-induced rotational behavior and elevate the dopamine contents and numbers of TH+ cell surviving within striatum, and can serve as a new and effective alternative for Parkinson disease.

  17. Decreased response of interneurons in the medial prefrontal cortex to 5-HT₁A receptor activation in the rat 6-hydroxydopamine Parkinson model.

    Science.gov (United States)

    Zhang, Qiaojun; Wang, Shuang; Zhang, Lina; Zhang, Huan; Qiao, Hongfei; Niu, Xiaolin; Liu, Jian

    2014-08-01

    This study examined the response of interneurons in the medial prefrontal cortex (mPFC) to 5-HT1A receptor agonist 8-OH-DPAT and change in expression of 5-HT1A receptor on glutamate decarboxylase 67 (GAD67)-positive neurons in rats with 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc). Systemic administration of 5-HT1A receptor agonist 8-OH-DPAT dose-dependently inhibited the firing rate of the interneurons at all doses tested in sham-operated rats. In 6-OHDA-lesioned rats, 8-OH-DPAT, at the same doses, also inhibited the firing rate of the interneurons, whereas the inhibition was significant only at a high cumulative dose. Furthermore, injection of 8-OH-DPAT into the mPFC inhibited the interneurons in sham-operated rats, while having no effect on firing rate of the interneurons in 6-OHDA-lesioned rats. In contrast to sham-operated rats, SNc lesion reduced the expression of 5-HT1A receptor on GAD67-positive neurons in the prelimbic cortex, a sub-region of the mPFC. Our results indicate that degeneration of the nigrostriatal pathway leads to decreased response of mPFC interneurons to 5-HT1A receptor activation, which attributes to the down-regulation of 5-HT1A receptor expression in these interneurons.

  18. CART modulates the effects of levodopa in rat model of Parkinson's disease.

    Science.gov (United States)

    Upadhya, Manoj A; Shelkar, Gajanan P; Subhedar, Nishikant K; Kokare, Dadasaheb M

    2016-03-15

    Parkinson's disease (PD) is an age-related disorder characterized by a progressive degeneration of dopaminergic neurons of substantia nigra (SN). The neuropeptide cocaine- and amphetamine-regulated transcript (CART) is known to closely interact with the dopamine system and regulate psychomotor activity. We screened the effectiveness of CART in reversing the symptoms of PD in a rat model. PD like condition was induced by administering 6-hydroxydopamine (6-OHDA) directly in the SN of the right side. Fifteen days later, intraperitoneal (IP) treatment with apomorphine hydrochloride to these rats, resulted in contralateral rotations in the rotation test chamber suggesting induction of PD-like symptoms. This action of apomorphine was significantly attenuated by intracerebroventricular (ICV) treatment with CART and potentiated by CART antibody. IP treatment with levodopa also produced contralateral rotation in PD induced rats, and showed anti-Parkinson-like action. Prior treatment with CART via ICV route potentiated the anti-Parkinsonian effects of levodopa, while CART antibody produced opposite effects. CART treatment per se, to PD induced rats produced ipsilateral rotations, suggesting that the peptide may promote the endogenous release of dopamine from intact neurons. While CART-immunoreactivity in arcuate nucleus, paraventricular nucleus, striatum, substantia nigra, ventral tegmental area and locus coeruleus was reduced in the PD induced rats, levodopa treatment restored the expression of CART-immunoreactivity in these nuclei. These results suggest that endogenous CART might closely interact with the dopamine containing SN-striatal pathway which is known to profoundly influence the motor system. The study underscores the importance of CART as a potential therapeutic agent in the treatment of PD.

  19. Assessment of the Protection of Dopaminergic Neurons by an α7 Nicotinic Receptor Agonist, PHA 543613 Using [18F]LBT-999 in a Parkinson’s Disease Rat Model

    Science.gov (United States)

    Sérrière, Sophie; Doméné, Aurélie; Vercouillie, Johnny; Mothes, Céline; Bodard, Sylvie; Rodrigues, Nuno; Guilloteau, Denis; Routier, Sylvain; Page, Guylène; Chalon, Sylvie

    2015-01-01

    The inverse association between nicotine intake and Parkinson’s disease (PD) is well established and suggests that this molecule could be neuroprotective through anti-inflammatory action mediated by nicotinic receptors, including the α7-subtype (α7R). The objective of this study was to evaluate the effects of an agonist of α7R, PHA 543613, on striatal dopaminergic neurodegeneration and neuroinflammation in a rat model of PD induced by 6-hydroxydopamine (6-OHDA) lesion. Adult male Wistar rats were lesioned in the right striatum and assigned to either the PHA group (n = 7) or the Sham group (n = 5). PHA 543613 hydrochloride at the concentration of 6 mg/kg (PHA group) or vehicle (Sham group) was intra-peritoneally injected 2 h before 6-OHDA lesioning and then at days 2, 4, and 6 post-lesion. Positron emission tomography (PET) imaging was performed at 7 days post-lesion using [18F]LBT-999 to quantify the striatal dopamine transporter (DAT). After PET imaging, neuroinflammation was evaluated in same animals in vitro through the measurement of the microglial activation marker 18 kDa translocator protein (TSPO) by quantitative autoradiography with [3H]PK-11195. The DAT density reflecting the integrity of dopaminergic neurons was significantly decreased while the intensity of neuroinflammation measured by TSPO density was significantly increased in the lesioned compared to intact striatum in both groups. However, these both modifications were partially reversed in the PHA group compared to Sham. In addition, a significant positive correlation between the degree of lesion and the intensity of neuroinflammation was evidenced. These findings indicate that PHA 543613 exerts neuroprotective effects on the striatal dopaminergic neurons associated with a reduction in microglial activation in this model of PD. This reinforces the hypothesis that an α7R agonist could provide beneficial effects for the treatment of PD. PMID:26389120

  20. In vivo studies of the SERT-selective [{sup 18}F]FPBM and VMAT2-selective [{sup 18}F]AV-133 radiotracers in a rat model of Parkinson's disease

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Julie L. [Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 (United States); Oya, Shunichi; Parhi, Ajit K.; Lieberman, Brian P.; Ploessl, Karl; Hou, Catherine [Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 (United States); Kung, Hank F. [Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 (United States); Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 (United States)], E-mail: kunghf@sunmac.spect.upenn.edu

    2010-05-15

    Introduction: The utility of [{sup 18}F]FPBM [2-(2'-((dimethylamino)methyl)-4'-(3-[{sup 18}F] -fluoropropoxy)phenylthio)benzenamine], a selective serotonin transporter (SERT) tracer, and [{sup 18}F]AV-133 [(+)-2-Hydroxy-3-isobutyl-9-(3-fluoropropoxy)-10-methoxy-1,2,3,4,6, 7-hexahydro-11bH-benzo[a]quinolizine], a selective vesicular monoamine transporter 2 (VMAT2) tracer, were tested in the 6-hydroxydopamine (6-OHDA) unilateral lesioned rat model. Methods: Positron emission tomography (PET) imaging of three 6-OHDA unilateral lesioned male Sprague Dawley rats (Rats 1-3) were performed with [{sup 18}F]FPBM and [{sup 18}F]AV-133 to examine whether changes in SERT and VMAT2 binding, respectively, could be detected in the brain. The brains of the three rats were then removed and examined by in vitro autoradiography with [{sup 18}F]FPBM and the dopamine transporter ligand, [{sup 125}I]IPT [N-(3'-[{sup 125}I]-iodopropen-2'-yl)-2-beta-carbomethoxy-3-beta-(4-chloro phenyl) tropane, for confirmation. Biodistribution of [{sup 18}F]FPBM in a separate group of p-chloroamphetamine (PCA) treated rats were also performed. Results: PET image analysis showed varying levels of SERT binding reduction (Rat 1=-11%, Rat 2=-4%, Rat 3=-43%; n=2) and a clear and definitive loss of VMAT2 binding (Rat 1=-87%, Rat 2=-72%, and Rat 3=-91%; n=1) in the left striatum when compared to the right (non-lesioned side) striatum. The results from PET imaging were corroborated with quantitative in vitro autoradiography. Rats treated with a selective serotonin toxin (p-chloroamphetamine) showed a significant reduction of [{sup 18}F]FPBM uptake in the cortex and hypothalamus regions of the brain. Conclusion: The preliminary data suggest that [{sup 18}F]FPBM and [{sup 18}F]AV-133 may be useful for the examination of serotonergic and dopaminergic neuron integrity, respectively, in the living brain.

  1. Preparation of 6—[18F]fluoro—L—DOPA and its biodistribution in normal and unilateral PD model rats

    Institute of Scientific and Technical Information of China (English)

    ZHANGLan; TANGGang-Hua; 等

    2002-01-01

    No-carrier-added 6-[18F] fluoro-L-DOPA(6-FDOPA) was synthesized via a multistep procedure from a commercial available precursor,6-nitroveratraldehyde,The total synthesis time was 75min,with a radiochemical yield of (10±3)%,high radiochemical purity(>99%) and high enantiomeric purity(>95%).The biodistributions of 6-FDOPA in normal and unilateral PD model rats were measured.The results from normal rats showed the expected high concentration of radioactivity in striatum and low distrbutions in cerebrum,cortex and cerebellum.The ration of the radioactivity in striatum to cerebellum reached a peak value(5.9) at 60 min.In unilateral PD model rate.whose substania nigra of the right side had been damaged by pre-treated with 6-OHDA,the radioactive concentration in striatum of the damaged side was significantly lower than that of the undamaged side or that of both sides in striatum of control groups.

  2. Feasibility of establishing model of Parkinson disease by injecting 6-hydroxydopamine at different parts of the nigrostriatal pathway in the brain of rats

    Institute of Scientific and Technical Information of China (English)

    Yuefei Shen; Xuean Mo; Guifang Long

    2006-01-01

    BACKGROUND: Previous researches found that animal models with Parkinson disease (PD) could be established by injecting 6-hydroxydopamine (6-OHDA) into medial forebrain bundle (MFB), substantia nigra compacta (SNC) and caudate-putamen complex (CPU) of the nigrostriatal pathway.OBJECTIVE: To compare behavioral, biochemical and histological properties of these rats undergoing the 6-OHDA injections in the areas of MFB, SNC and CPU respectively.DESIGN: Controlled observational study.SETTING: Department of Neurology, First Affiliated Hospital of Guangxi Medical University.MATERIALS: A total of 64 adult female SD rats weighing 180-230 g were provided by the Animal Experimental Center of Guangxi Medical University. 6-OHDA (Sigma Company, USA); Brain solid positioner (Standard model 51600, Stoelting Co., IL, USA); rotational monitoring of little animal (type QL-1, USA);high liquid chromatography (HLC, Waters Company).METHODS: The experiment was carried out in the Medical Experimental Center of Guangxi Medical University from February to December 2005. ① According to digital table, 64 SD rats were divided into MFB group, SNC group, CPU group and control group with 16 in each group. On the basis of the brain atlas of Paxinos, rats in the first three groups were injected with 5 μL 6-OHDA into right MFB (0 mm of line of incisor tooth, A/P 4.4 mm, L/R 1.2 mm, O/V -7.8 mm), SNC (line of incisor tooth just equal to horizon,A/P -4.8 mm, L/R 1.6 mm, O/V -7.8 mm) and CPU (0 mm of line of incisor tooth, A/P 1.2 mm, L/R 2.7 mm,O/V -5.4 mm), respectively. The rats in control group were injected with 5 μL ascorbic acid solution (2 g/L). One week after operation, 0.1 g/L apomorphine (Apo, 0.05 mg/kg) was subcutaneously injected into neck and then rotational behavior induced by Apo was recorded once a week for 8 weeks. The PD models were considered successful only when rotational times more than or equal to 7 times per minute.② Eight weeks after operation, micro-perfusion was used to

  3. Neuron-derived IgG protects dopaminergic neurons from insult by 6-OHDA and activates microglia through the FcγR I and TLR4 pathways.

    Science.gov (United States)

    Zhang, Jie; Niu, Na; Wang, Mingyu; McNutt, Michael A; Zhang, Donghong; Zhang, Baogang; Lu, Shijun; Liu, Yuqing; Liu, Zhihui

    2013-08-01

    Oxidative and immune attacks from the environment or microglia have been implicated in the loss of dopaminergic neurons of Parkinson's disease. The role of IgG which is an important immunologic molecule in the process of Parkinson's disease has been unclear. Evidence suggests that IgG can be produced by neurons in addition to its traditionally recognized source B lymphocytes, but its function in neurons is poorly understood. In this study, extensive expression of neuron-derived IgG was demonstrated in dopaminergic neurons of human and rat mesencephalon. With an in vitro Parkinson's disease model, we found that neuron-derived IgG can improve the survival and reduce apoptosis of dopaminergic neurons induced by 6-hydroxydopamine toxicity, and also depress the release of NO from microglia triggered by 6-hydroxydopamine. Expression of TNF-α and IL-10 in microglia was elevated to protective levels by neuron-derived IgG at a physiologic level via the FcγR I and TLR4 pathways and microglial activation could be attenuated by IgG blocking. All these data suggested that neuron-derived IgG may exert a self-protective function by activating microglia properly, and IgG may be involved in maintaining immunity homeostasis in the central nervous system and serve as an active factor under pathological conditions such as Parkinson's disease.

  4. MANF alleviates the neural lesion in rat model of Parkinson's disease%MANF减轻帕金森病大鼠模型的神经损伤

    Institute of Scientific and Technical Information of China (English)

    汪运红; 沈玉君; 冯利杰; 王海萍; 方圣云; 沈玉先

    2012-01-01

    Objective To observe whether MANF ( mesencephalic astrocyte -derived neurotrophic factor ) is effective in restoration of 6-OHDA lesioned dopaminergic neurons. Methods Human recombinant MANF was expressed and purified; The model of Parkinson' s disease was prepared by injecting 6-OHDA into the striatums of the rats with a stereotaxic frame; The purified protein of MANF, with three doses of 5, 10 and 20 μg, or PBS ( as a nega- tive control ) was injected into the same site of striatums of rats; Selegiline was intraperitoneally injected as a positive control; The behavioral performance was tested by counting the times of apomorphine-induced rotational activity from lesion side to the intact side; The numbers of tyrosine hydroxylase ( TH ) positive neurons and fibers in substantial nigra ( SN ) and striatum ( STR ) in each group of rats were observed by immunohistochemistry. Results 10 μg of MANF was effective to reduced the behavioral performance of the PD rats compared with PBS group. Selegiline showed the similar effect on PD rats. Meanwhile, compared with PBS treatment, the numbers of the TH positive neurons in the parts of SN and the neuronal fibers in the parts of STR was significantly increased in the PD rats which treated with MANF and selegiline. Conclusion MANF restores the impairment of dopaminergic neurons induced by 6-OHDA.%目的 观察中脑星形胶质细胞源性神经营养因子(MANF)对6-OHDA引起的多巴胺能神经元损伤的影响.方法 表达纯化人重组MANF蛋白;将6-OHDA立体定位注射至大鼠纹状体区,制备大鼠帕金森模型;将3个剂量(5、10、20 μg)纯化的MANF注射至模型大鼠纹状体区,腹腔注射司来吉兰作为阳性对照,纹状体直接注射PBS作为阴性对照;计数大鼠给药前后由阿扑吗啡诱导的由损伤侧向健侧不对称的旋转次数;免疫组化方法检测各大鼠黑质、纹状体部位酪氨酸羟化酶(TH)阳性神经元和神经纤维.结果 10 μg MANF组大鼠的旋

  5. Pramipexole-induced increased probabilistic discounting: comparison between a rodent model of Parkinson's disease and controls

    National Research Council Canada - National Science Library

    Rokosik, Sandra L; Napier, T Celeste

    2012-01-01

    .... We included assessments of a rodent model of PD, wherein 6-OHDA was injected into the dorsolateral striatum of both hemispheres, which produced persistent PD-like deficits in posture adjustment...

  6. Cardiac Dysregulation and Myocardial Injury in a 6-Hydroxydopamine-Induced Rat Model of Sympathetic Denervation.

    Directory of Open Access Journals (Sweden)

    Yue-Hua Jiang

    Full Text Available Cardiac sympathetic denervation is found in various cardiac pathologies; however, its relationship with myocardial injury has not been thoroughly investigated.Twenty-four rats were assigned to the normal control group (NC, sympathectomy control group (SC, and a sympathectomy plus mecobalamin group (SM. Sympathectomy was induced by injection of 6-OHDA, after which, the destruction and distribution of sympathetic and vagal nerve in the left ventricle (LV myocardial tissue were determined by immunofluorescence and ELISA. Heart rate variability (HRV, ECG and echocardiography, and assays for myocardial enzymes in serum before and after sympathectomy were examined. Morphologic changes in the LV by HE staining and transmission electron microscope were used to estimate levels of myocardial injury and concentrations of inflammatory cytokines were used to reflect the inflammatory reaction.Injection of 6-OHDA decreased NE (933.1 ± 179 ng/L for SC vs. 3418.1± 443.6 ng/L for NC, P < 0.01 and increased NGF (479.4± 56.5 ng/mL for SC vs. 315.85 ± 28.6 ng/mL for NC, P < 0.01 concentrations. TH expression was reduced, while ChAT expression showed no change. Sympathectomy caused decreased HRV and abnormal ECG and echocardiography results, and histopathologic examinations showed myocardial injury and increased collagen deposition as well as inflammatory cell infiltration in the cardiac tissue of rats in the SC and SM groups. However, all pathologic changes in the SM group were less severe compared to those in the SC group.Chemical sympathectomy with administration of 6-OHDA caused dysregulation of the cardiac autonomic nervous system and myocardial injuries. Mecobalamin alleviated inflammatory and myocardial damage by protecting myocardial sympathetic nerves.

  7. Anti-Inflammatory Modulation of Microglia via CD163-Targeted Glucocorticoids Protects Dopaminergic Neurons in the 6-OHDA Parkinson's Disease Model

    DEFF Research Database (Denmark)

    Tentillier, Noemie; Etzerodt, Anders; Olesen, Mads N;

    2016-01-01

    intravenous CD163-targeted liposomes with Dexa for 3 weeks exhibited better motor performance than the control groups and had minimal glucocorticoid-driven side effects. Furthermore, these animals showed better survival of dopaminergic neurons in substantia nigra and an increased number of microglia......UNLABELLED: Increasing evidence supports a decisive role for inflammation in the neurodegenerative process of Parkinson's disease (PD). The immune response in PD seems to involve, not only microglia, but also other immune cells infiltrated into the brain. Indeed, we observed here the infiltration...... for the modulation of brain neurodegeneration and specifically highlight the potential of CD163-targeted liposomes as a therapeutic tool in PD. SIGNIFICANCE STATEMENT: The immune response now evident in the progression of Parkinson's disease comprises both local microglia and other immune cells. We provide evidence...

  8. Serotonin 2A receptor mRNA levels in the neonatal dopamine-depleted rat striatum remain upregulated following suppression of serotonin hyperinnervation.

    Science.gov (United States)

    Basura, G J; Walker, P D

    1999-08-05

    Sixty days after bilateral dopamine (DA) depletion (>98%) with 6-hydroxydopamine (6-OHDA) in neonatal rats, serotonin (5-HT) content doubled and 5-HT(2A) receptor mRNA expression rose 54% within the rostral striatum. To determine if striatal 5-HT(2A) receptor mRNA upregulation is dependent on increased 5-HT levels following DA depletion, neonatal rats received dual injections of 6-OHDA and 5,7-dihydroxytryptamine (5,7-DHT) which suppressed 5-HT content by approximately 90%. In these 6-OHDA/5,7-DHT-treated rats, striatal 5-HT(2A) receptor mRNA expression was still elevated (87% above vehicle controls). Comparative analysis of 5-HT(2C) receptor mRNA expression yielded no significant changes in any experimental group. These results demonstrate that upregulated 5-HT(2A) receptor biosynthesis in the DA-depleted rat is not dependent on subsequent 5-HT hyperinnervation.

  9. Effects of age, gender, and gonadectomy on neurochemistry and behavior in animal models of Parkinson's disease.

    Science.gov (United States)

    Tamás, Andrea; Lubics, Andrea; Lengvári, István; Reglodi, Dóra

    2006-04-01

    The effects of aging and gender on the neurochemistry of the dopaminergic system have been studied extensively; however, data on comparative behavioral consequences of lesions of the dopaminergic system in aging and in female animals are limited. This study presents experimental results on the behavioral and morphological outcome in young, aging, and gonadectomized male and female rats in the 6-OHDA model of Parkinson's disease. Both young and aging male animals were more susceptible to 6-OHDA than females: female rats had significantly less dopaminergic cell loss and showed a higher degree of behavioral recovery. Although the dopaminergic cell loss was only slightly more in the aging rats of the same sex, they showed more severe behavioral deficits in both gender groups. Ovariectomy did not significantly influence the dopaminergic cell loss, but behavioral recovery was worse when compared to non-ovariectomized females. In contrast, castrated males had significantly less dopaminergic cell loss than non-castrated males, but the behavioral recovery was not significantly better. The obtained results are discussed in light of the available literature on the age and gender differences in animals models of Parkinson's disease.

  10. Protective Effect of Tetrahydroxystilbene Glucoside on 6-OHDA-Induced Apoptosis in PC12 Cells through the ROS-NO Pathway

    OpenAIRE

    Tao, Lizhen; Li, Xiaofeng; Zhang, Lingling; Tian, Jiyu; Li, Xiaobing; Sun, Xin; Li, Xuefen; Jiang, Lin; Zhang, Xiaojun; Chen, Jianzong

    2011-01-01

    Oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease. The molecule, 2,3,5,4′-tetrahydr- oxystilbene-2-O-β-D-glucoside (TSG), is a potent antioxidant derived from the Chinese herb, Polygonum multiflorum Thunb. In this study, we investigated the protective effect of TSG against 6-hydroxydopamine-induced apoptosis in rat adrenal pheochromocytoma PC12 cells and the possible mechanisms. Our data demonstrated that TSG significantly ...

  11. Dietary and Intraperitoneal Administration of Selenium Provide Comparable Protection in the 6-Hydroxydopamine Lesion Rat Model of Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Cecilia M. Fox

    2007-01-01

    Full Text Available Significant research implicates the involvement of free radicals in the manifestation of Parkinson's disease. The antioxidant, selenium is a vital dietary component for mammals. It is present in the active center of glutathione peroxidase, an antioxidant enzyme that scavenges peroxides and protects membrane lipids and macromolecules from oxidative insult. The purpose of this research was to determine an effective means of delivering selenium as well as an appropriate time frame for antioxidant administration that would elicit a protective response in rats challenged with an intranigral 6-hydroxydopamine (6-OHDA lesion. In the first part of this study, Fischer 344 rats were placed into one of four groups: selenium enhanced diet, control diet, intraperitoneal injection of selenium as Na2SeO3 or intraperitoneal injection of distilled water. All treatments were delivered prior to an intranigral 6-OHDA lesion. Animals were euthanized two weeks post lesion and their brains processed for tyrosine hydroxylase (TH immunocytochemistry. Average dopamine neuron survival in the substantia nigra of control animals was less than 22%; whereas nigral dopamine neuron survival in the selenium fed group was 49.7% and 56.0% in the selenium injected group. Based on these results, a subsequent study was designed utilizing the selenium enhanced diet method of antioxidant administration. To examine the neuroprotective effect of long-term selenium treatment, pregnant Fischer 344 rats were exposed to either selenium enhanced or control rat chow. Their pups were treated with the same diet as their mothers and lesioned with 6-OHDA at two months of age. Animals were euthanized and their brains were processed for TH immunocytochemistry. Nigral dopamine neuron survival for the selenium treated animals was significantly protective (59% when compared to the control chow fed animals (29.6%. However, when compared to the short-term exposure of selenium rat chow in the previous

  12. A Nurr1 agonist causes neuroprotection in a Parkinson's disease lesion model primed with the toll-like receptor 3 dsRNA inflammatory stimulant poly(I:C.

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    Gaynor A Smith

    Full Text Available Dopaminergic neurons in the substantia nigra pars compacta (SNpc are characterized by the expression of genes required for dopamine synthesis, handling and reuptake and the expression of these genes is largely controlled by nuclear receptor related 1 (Nurr1. Nurr1 is also expressed in astrocytes and microglia where it functions to mitigate the release of proinflammatory cytokines and neurotoxic factors. Given that Parkinson's disease (PD pathogenesis has been linked to both loss of Nurr1 expression in the SNpc and inflammation, increasing levels of Nurr1 maybe a promising therapeutic strategy. In this study a novel Nurr1 agonist, SA00025, was tested for both its efficiency to induce the transcription of dopaminergic target genes in vivo and prevent dopaminergic neuron degeneration in an inflammation exacerbated 6-OHDA-lesion model of PD. SA00025 (30mg/kg p.o. entered the brain and modulated the expression of the dopaminergic phenotype genes TH, VMAT, DAT, AADC and the GDNF receptor gene c-Ret in the SN of naive rats. Daily gavage treatment with SA00025 (30mg/kg for 32 days also induced partial neuroprotection of dopaminergic neurons and fibers in rats administered a priming injection of polyinosinic-polycytidylic acid (poly(I:C and subsequent injection of 6-OHDA. The neuroprotective effects of SA00025 in this dopamine neuron degeneration model were associated with changes in microglial morphology indicative of a resting state and a decrease in microglial specific IBA-1 staining intensity in the SNpc. Astrocyte specific GFAP staining intensity and IL-6 levels were also reduced. We conclude that Nurr1 agonist treatment causes neuroprotective and anti-inflammatory effects in an inflammation exacerbated 6-OHDA lesion model of PD.

  13. Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease.

    Science.gov (United States)

    Danielyan, Lusine; Schäfer, Richard; von Ameln-Mayerhofer, Andreas; Bernhard, Felix; Verleysdonk, Stephan; Buadze, Marine; Lourhmati, Ali; Klopfer, Tim; Schaumann, Felix; Schmid, Barbara; Koehle, Christoph; Proksch, Barbara; Weissert, Robert; Reichardt, Holger M; van den Brandt, Jens; Buniatian, Gayane H; Schwab, Matthias; Gleiter, Christoph H; Frey, William H

    2011-02-01

    Safe and effective cell delivery remains one of the main challenges in cell-based therapy of neurodegenerative disorders. Graft survival, sufficient enrichment of therapeutic cells in the brain, and avoidance of their distribution throughout the peripheral organs are greatly influenced by the method of delivery. Here we demonstrate for the first time noninvasive intranasal (IN) delivery of mesenchymal stem cells (MSCs) to the brains of unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. IN application (INA) of MSCs resulted in the appearance of cells in the olfactory bulb, cortex, hippocampus, striatum, cerebellum, brainstem, and spinal cord. Out of 1 × 10⁶ MSCs applied intranasally, 24% survived for at least 4.5 months in the brains of 6-OHDA rats as assessed by quantification of enhanced green fluorescent protein (EGFP) DNA. Quantification of proliferating cell nuclear antigen-positive EGFP-MSCs showed that 3% of applied MSCs were proliferative 4.5 months after application. INA of MSCs increased the tyrosine hydroxylase level in the lesioned ipsilateral striatum and substantia nigra, and completely eliminated the 6-OHDA-induced increase in terminal deoxynucleotidyl transferase (TdT)-mediated 2'-deoxyuridine, 5'-triphosphate (dUTP)-biotin nick end labeling (TUNEL) staining of these areas. INA of EGFP-labeled MSCs prevented any decrease in the dopamine level in the lesioned hemisphere, whereas the lesioned side of the control animals revealed significantly lower levels of dopamine 4.5 months after 6-OHDA treatment. Behavioral analyses revealed significant and substantial improvement of motor function of the Parkinsonian forepaw to up to 68% of the normal value 40-110 days after INA of 1 × 10⁶ cells. MSC-INA decreased the concentrations of inflammatory cytokines-interleukin-1β (IL-1β), IL-2, -6, -12, tumor necrosis factor (TNF), interferon-γ (IFN-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF)-in the lesioned side to their

  14. Lentivirus-mediated delivery of sonic hedgehog into the striatum stimulates neuroregeneration in a rat model of Parkinson disease.

    Science.gov (United States)

    Zhang, Yi; Dong, Weiren; Guo, Suiqun; Zhao, Shu; He, Suifen; Zhang, Lihua; Tang, Yinjuan; Wang, Haihong

    2014-12-01

    Parkinson disease (PD) is a progressive neurodegenerative disorder in which the nigrostriatal pathway, consisting of dopaminergic neuronal projections from the substantia nigra to the striatum, degenerates. Viral transduction is currently the most promising in vivo strategy for delivery of therapeutic proteins into the brain for treatment of PD. Sonic hedgehog (Shh) is necessary for cell proliferation, differentiation and neuroprotection in the central nervous system. In this study, we investigated the effects of overexpressed N-terminal product of SHH (SHH-N) in a PD model rat. A lentiviral vector containing SHH-N was stereotactically injected into the striatum 24 h after a striatal 6-OHDA lesion. We found that overexpressed SHH-N attenuated behavioral deficits and reduced the loss of dopamine neurons in the substantia nigra and the loss of dopamine fibers in the striatum. In addition, fluoro-ruby-labeled nigrostriatal projections were also repaired. Together, our results demonstrate the feasibility and efficacy of using the strategy of lentivirus-mediated Shh-N delivery to delay nigrostriatal pathway degeneration. This strategy holds the potential for therapeutic application in the treatment of PD.

  15. Differential dopamine receptor occupancy underlies L-DOPA-induced dyskinesia in a rat model of Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Gurdal Sahin

    Full Text Available Dyskinesia is a major side effect of an otherwise effective L-DOPA treatment in Parkinson's patients. The prevailing view for the underlying presynaptic mechanism of L-DOPA-induced dyskinesia (LID suggests that surges in dopamine (DA via uncontrolled release from serotonergic terminals results in abnormally high level of extracellular striatal dopamine. Here we used high-sensitivity online microdialysis and PET imaging techniques to directly investigate DA release properties from serotonergic terminals both in the parkinsonian striatum and after neuronal transplantation in 6-OHDA lesioned rats. Although L-DOPA administration resulted in a drift in extracellular DA levels, we found no evidence for abnormally high striatal DA release from serotonin neurons. The extracellular concentration of DA remained at or below levels detected in the intact striatum. Instead, our results showed that an inefficient release pool of DA associated with low D2 receptor binding remained unchanged. Taken together, these findings suggest that differential DA receptor activation rather than excessive release could be the underlying mechanism explaining LID seen in this model. Our data have important implications for development of drugs targeting the serotonergic system to reduce DA release to manage dyskinesia in patients with Parkinson's disease.

  16. Protective effect of tetrahydroxystilbene glucoside on 6-OHDA-induced apoptosis in PC12 cells through the ROS-NO pathway.

    Directory of Open Access Journals (Sweden)

    Lizhen Tao

    Full Text Available Oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease. The molecule, 2,3,5,4'-tetrahydr- oxystilbene-2-O-β-D-glucoside (TSG, is a potent antioxidant derived from the Chinese herb, Polygonum multiflorum Thunb. In this study, we investigated the protective effect of TSG against 6-hydroxydopamine-induced apoptosis in rat adrenal pheochromocytoma PC12 cells and the possible mechanisms. Our data demonstrated that TSG significantly reversed the 6-hydroxydopamine-induced decrease in cell viability, prevented 6-hydroxydopamine-induced changes in condensed nuclei and decreased the percentage of apoptotic cells in a dose-dependent manner. In addition, TSG slowed the accumulation of intracellular reactive oxygen species and nitric oxide, counteracted the overexpression of inducible nitric oxide syntheses as well as neuronal nitric oxide syntheses, and also reduced the level of protein-bound 3-nitrotyrosine. These results demonstrate that the protective effects of TSG on rat adrenal pheochromocytoma PC12 cells are mediated, at least in part, by the ROS-NO pathway. Our results indicate that TSG may be effective in providing protection against neurodegenerative diseases associated with oxidative stress.

  17. Protective effect of tetrahydroxystilbene glucoside on 6-OHDA-induced apoptosis in PC12 cells through the ROS-NO pathway.

    Science.gov (United States)

    Tao, Lizhen; Li, Xiaofeng; Zhang, Lingling; Tian, Jiyu; Li, Xiaobing; Sun, Xin; Li, Xuefen; Jiang, Lin; Zhang, Xiaojun; Chen, Jianzong

    2011-01-01

    Oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease. The molecule, 2,3,5,4'-tetrahydr- oxystilbene-2-O-β-D-glucoside (TSG), is a potent antioxidant derived from the Chinese herb, Polygonum multiflorum Thunb. In this study, we investigated the protective effect of TSG against 6-hydroxydopamine-induced apoptosis in rat adrenal pheochromocytoma PC12 cells and the possible mechanisms. Our data demonstrated that TSG significantly reversed the 6-hydroxydopamine-induced decrease in cell viability, prevented 6-hydroxydopamine-induced changes in condensed nuclei and decreased the percentage of apoptotic cells in a dose-dependent manner. In addition, TSG slowed the accumulation of intracellular reactive oxygen species and nitric oxide, counteracted the overexpression of inducible nitric oxide syntheses as well as neuronal nitric oxide syntheses, and also reduced the level of protein-bound 3-nitrotyrosine. These results demonstrate that the protective effects of TSG on rat adrenal pheochromocytoma PC12 cells are mediated, at least in part, by the ROS-NO pathway. Our results indicate that TSG may be effective in providing protection against neurodegenerative diseases associated with oxidative stress.

  18. Dopaminergic regeneration by neurturin-overexpressing c17.2 neural stem cells in a rat model of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Wang Gang

    2007-10-01

    Full Text Available Abstract Background Genetically engineered neural stem cell (NSC lines are promising vectors for the treatment of neurodegenerative diseases, particularly Parkinson's disease (PD. Neurturin (NTN, a member of the glial cell line-derived neurotrophic factor (GDNF family, has been demonstrated to act specifically on mesencephalic dopaminergic neurons, suggesting its therapeutic potential for PD. In our previous work, we demonstrated that NTN-overexpressing c17.2 NSCs exerted dopaminergic neuroprotection in a rat model of PD. In this study, we transplanted NTN-c17.2 into the striatum of the 6-hydroxydopamine (6-OHDA PD model to further determine the regenerative effect of NTN-c17.2 on the rat models of PD. Results After intrastriatal grafting, NTN-c17.2 cells differentiated and gradually downregulated nestin expression, while the grafts stably overexpressed NTN. Further, an observation of rotational behavior and the contents of neurotransmitters tested by high-performance liquid chromatography showed that the regenerative effect of the NTN-c17.2 group was significantly better than that of the Mock-c17.2 group, and the regenerative effect of the Mock-c17.2 group was better than that of the PBS group. Further research through reverse-transcriptase polymerase chain reaction assays and in vivo histology revealed that the regenerative effect of Mock-c17.2 and NTN-c17.2 cell grafts may be attributed to the ability of NSCs to produce neurotrophic factors and differentiate into tyrosine hydroxylase-positive cells. Conclusion The transplantation of NTN-c17.2 can exert neuroregenerative effects in the rat model of PD, and the delivery of NTN by NSCs may constitute a very useful strategy in the treatment of PD.

  19. Intracarotid Infusion of Mesenchymal Stem Cells in an Animal Model of Parkinson's Disease, Focusing on Cell Distribution and Neuroprotective and Behavioral Effects.

    Science.gov (United States)

    Cerri, Silvia; Greco, Rosaria; Levandis, Giovanna; Ghezzi, Cristina; Mangione, Antonina Stefania; Fuzzati-Armentero, Marie-Therese; Bonizzi, Arianna; Avanzini, Maria Antonietta; Maccario, Rita; Blandini, Fabio

    2015-09-01

    Mesenchymal stem cells (MSCs) have been proposed as a potential therapeutic tool for Parkinson's disease (PD) and systemic administration of these cells has been tested in preclinical and clinical studies. However, no information on survival and actual capacity of MSCs to reach the brain has been provided. In this study, we evaluated homing of intraarterially infused rat MSCs (rMSCs) in the brain of rats bearing a 6-hydroxydopamine (6-OHDA)-induced lesion of the nigrostriatal tract, to establish whether the toxin-induced damage is sufficient to grant MSC passage across the blood-brain barrier (BBB) or if a transient BBB disruption is necessary. The rMSC distribution in peripheral organs and the effects of cell infusion on neurodegenerative process and motor deficits were also investigated. rMSCs were infused 14 days after 6-OHDA injection. A hyperosmolar solution of mannitol was used to transiently permeabilize the BBB. Behavioral impairment was assessed by adjusting step test and response to apomorphine. Animals were sacrificed 7 and 28 days after cell infusion. Our work shows that appreciable delivery of rMSCs to the brain of 6-OHDA-lesioned animals can be obtained only after mannitol pretreatment. A notable percentage of infused cells accumulated in peripheral organs. Infusion of rMSCs did not modify the progression of 6-OHDA-induced damage or the motor impairment at the stepping test, but induced progressive normalization of the pathological response (contralateral turning) to apomorphine administration. These findings suggest that many aspects should be further investigated before considering any translation of MSC systemic administration into the clinical setting for PD treatment. This study demonstrates that mesenchymal stem cells infused through the carotid artery do not efficiently cross the blood-brain barrier in rats with a Parkinson's disease-like degeneration of nigrostriatal neurons, unless a permeabilizing agent (e.g., mannitol) is used. The infusion

  20. Exercise partly reverses the effect of maternal separation on hippocampal proteins in 6-hydroxydopamine-lesioned rat brain.

    Science.gov (United States)

    Dimatelis, J J; Hendricks, S; Hsieh, J; Vlok, N M; Bugarith, K; Daniels, W M U; Russell, V A

    2013-01-01

    Animals subjected to maternal separation stress during the early stages of development display behavioural, endocrine and growth factor abnormalities that mirror the clinical findings in anxiety/depression. In addition, maternal separation has been shown to exacerbate the behavioural deficits induced by 6-hydroxydopamine (6-OHDA) in a rat model of Parkinson's disease. In contrast, voluntary exercise reduced the detrimental effects of 6-OHDA in the rat model. The beneficial effects of exercise appeared to be largely due to compensation in the non-lesioned hemisphere. The aim of the present study was to investigate whether voluntary exercise for 3 weeks could reverse the effects of maternal separation in rats challenged with the neurotoxin 6-OHDA infused into the medial forebrain bundle after 1 week of exercise, at postnatal day 60. The rats were killed 2 weeks later, at postnatal day 74. Their brains were dissected and the hippocampus rapidly removed for proteomic analysis by isobaric tagging (iTRAQ) and quantification of peptides by matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS). Maternal separation upregulated hippocampal proteins functionally involved in energy metabolism (nucleoside diphosphate kinase B, enolase and triosephosphate isomerase) and synaptic plasticity (α-synuclein, tenascin-R, Ba1-667, brevican and neurocan core protein) in the non-lesioned hemisphere. Exercise reversed many of these changes by downregulating the levels of hippocampal proteins functionally associated with energy metabolism (nucleoside diphosphate kinase B, enolase and triosephosphate isomerase) and synaptic plasticity (α-synuclein, tenascin-R, Ba1-667, brevican and neurocan core protein) in the non-lesioned hemisphere of rats subjected to maternal separation. Exercise and maternal separation therefore appeared to have opposing effects on the hippocampus in the non-lesioned hemisphere of the rat brain. Exercise seemed partly to reverse the

  1. Loss of parvalbumin-positive neurons from the globus pallidus in animal models of Parkinson disease.

    Science.gov (United States)

    Fernández-Suárez, Diana; Celorrio, Marta; Lanciego, Jose L; Franco, Rafael; Aymerich, María S

    2012-11-01

    The external segment of the globus pallidus (GPe) in humans and the equivalent structure in rodents, the globus pallidus (GP), influence signal processing in the basal ganglia under normal and pathological conditions. Parvalbumin (PV) immunoreactivity defines 2 main neuronal subpopulations in the GP/GPe: PV-immunopositive cells that project mainly to the subthalamic nucleus and the internal segment of the GP and PV-negative cells that mainly project to the striatum. We evaluated the number of neurons in the GP/GPe in animal models of Parkinson disease. In rats, dopaminergic denervation with 6-hydroxydopamine (6-OHDA) provoked a significant decrease in the number of GP neurons (12% ± 4%, p loss in the basal ganglia of 6-OHDA-lesioned rats and suggest that a similar loss may occur in the MPTP monkey. These data suggest that in patients with Parkinson disease, the loss of GABAergic neurons projecting to the subthalamic nucleus may contribute to the hyperactivity of this nucleus despite the absence of gross alterations in GAD mRNA expression.

  2. Laser Acupuncture at HT7 Acupoint Improves Cognitive Deficit, Neuronal Loss, Oxidative Stress, and Functions of Cholinergic and Dopaminergic Systems in Animal Model of Parkinson's Disease.

    Science.gov (United States)

    Wattanathorn, Jintanaporn; Sutalangka, Chatchada

    2014-01-01

    To date, the therapeutic strategy against cognitive impairment in Parkinson's disease (PD) is still not in satisfaction level and requires novel effective intervention. Based the oxidative stress reduction and cognitive enhancement induced by laser acupuncture at HT7, the beneficial effect of laser acupuncture at HT7 against cognitive impairment in PD has been focused. In this study, we aimed to determine the effect of laser acupuncture at HT7 on memory impairment, oxidative stress status, and the functions of both cholinergic and dopaminergic systems in hippocampus of animal model of PD. Male Wistar rats, weighing 180-220 g, were induced unilateral lesion at right substantianigra by 6-OHDA and were treated with laser acupuncture continuously at a period of 14 days. The results showed that laser acupuncture at HT7 enhanced memory and neuron density in CA3 and dentate gyrus. The decreased AChE, MAO-B, and MDA together with increased GSH-Px in hippocampus of a 6-OHDA lesion rats were also observed. In conclusion, laser acupuncture at HT7 can improve neuron degeneration and memory impairment in animal model of PD partly via the decreased oxidative stress and the improved cholinergic and dopaminergic functions. More researches concerning effect of treatment duration are still required.

  3. Drinking hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamine-induced Parkinson’s disease in rats

    Directory of Open Access Journals (Sweden)

    Ito Mikako

    2012-05-01

    Full Text Available Abstract Background Lactulose is a synthetic disaccharide that can be catalyzed only by intestinal bacteria in humans and rodents, and a large amount of hydrogen is produced by bacterial catalysis of lactulose. We previously reported marked effects of ad libitum administration of hydrogen water on prevention of a rat model of Parkinson’s disease (PD. Methods End-alveolar breath hydrogen concentrations were measured in 28 healthy subjects and 37 PD patients, as well as in 9 rats after taking hydrogen water or lactulose. Six-hydroxydopamine (6-OHDA-induced hemi-PD model was stereotactically generated in rats. We compared effects of hydrogen water and lactulose on prevention of PD. We also analyzed effects of continuous and intermittent administration of 2% hydrogen gas. Results Hydrogen water increased breath hydrogen concentrations from 8.6 ± 2.1 to 32.6 ± 3.3 ppm (mean and SEM, n = 8 in 10 min in healthy subjects. Lactulose increased breath hydrogen concentrations in 86% of healthy subjects and 59% of PD patients. Compared to monophasic hydrogen increases in 71% of healthy subjects, 32% and 41% of PD patients showed biphasic and no increases, respectively. Lactulose also increased breath hydrogen levels monophasically in 9 rats. Lactulose, however, marginally ameliorated 6-OHDA-induced PD in rats. Continuous administration of 2% hydrogen gas similarly had marginal effects. On the other hand, intermittent administration of 2% hydrogen gas prevented PD in 4 of 6 rats. Conclusions Lack of dose responses of hydrogen and the presence of favorable effects with hydrogen water and intermittent hydrogen gas suggest that signal modulating activities of hydrogen are likely to be instrumental in exerting a protective effect against PD.

  4. Pramipexole reverses Parkinson's disease-related motivational deficits in rats.

    Science.gov (United States)

    Favier, Mathieu; Duran, Theo; Carcenac, Carole; Drui, Guillaume; Savasta, Marc; Carnicella, Sebastien

    2014-06-01

    Recent evidence suggests that Parkinson's disease affects not only movement, but also cognitive and psychiatric functions. Among these nonmotor complications, apathy, which is defined as a lack of motivation and operationalized as a quantitative reduction in goal-directed behavior, may even precede motor impairments, disappearing with the introduction of dopaminergic (DA) therapies and possibly reappearing with its discontinuation, suggesting a causal role of DA. We recently developed a lesion-based model, with stereotaxic infusion of 6-hydroxydopamine (6-OHDA) into precise areas of the rat SNc or ventral tegmental area and showed, in several operant tasks, that a partial denervation of the nigrostriatal, but not of the mesocorticolimbic, DA system induced profound motivational deficits during instrumental action. We investigated the time course of the effects of nigrostriatal DA denervation on motivation in rats, by assessing the negative effect of SNc bilateral 6-OHDA infusion on preacquired operant behavior, and determining whether the induced deficits were sensitive to the introduction and withdrawal of a clinically relevant PD treatment, the DA D2/D3 receptor agonist, pramipexole (PRA). Partial nigrostriatal DA denervation was accompanied by a significant reduction in operant behavior. This deficit, indicative of a decrease in motivation, was fully reversed by PRA and reappeared after treatment withdrawal. This longitudinal preclinical study provides evidence for the implication of the DA nigrostriatal system in PD-associated apathy. Moreover, by showing a good isomorphy and predictive value, our model highlights the relevance of D2/D3 receptors as potential targets for alleviating apathy in PD.

  5. Alterations of BDNF and trkB mRNA expression in the 6-hydroxydopamine-induced model of preclinical stages of Parkinson's disease: an influence of chronic pramipexole in rats.

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    Klemencja Berghauzen-Maciejewska

    Full Text Available Our recent study has indicated that a moderate lesion of the mesostriatal and mesolimbic pathways in rats, modelling preclinical stages of Parkinson's disease, induces a depressive-like behaviour which is reversed by chronic treatment with pramipexole. The purpose of the present study was to examine the role of brain derived neurotrophic factor (BDNF signalling in the aforementioned model of depression. Therefore, we investigated the influence of 6-hydoxydopamine (6-OHDA administration into the ventral region of the caudate-putamen on mRNA levels of BDNF and tropomyosin-related kinase B (trkB receptor. The BDNF and trkB mRNA levels were determined in the nigrostriatal and limbic structures by in situ hybridization 2 weeks after the operation. Pramipexole (1 mg/kg sc twice a day and imipramine (10 mg/kg ip once a day were injected for 2 weeks. The lesion lowered the BDNF and trkB mRNA levels in the hippocampus [CA1, CA3 and dentate gyrus (DG] and amygdala (basolateral/lateral as well as the BDNF mRNA content in the habenula (medial/lateral. The lesion did not influence BDNF and trkB expression in the caudate-putamen, substantia nigra, nucleus accumbens (shell and core and ventral tegmental area (VTA. Chronic imipramine reversed the lesion-induced decreases in BDNF mRNA in the DG. Chronic pramipexole increased BDNF mRNA, but decreased trkB mRNA in the VTA in lesioned rats. Furthermore, it reduced BDNF and trkB mRNA expression in the shell and core of the nucleus accumbens, BDNF mRNA in the amygdala and trkB mRNA in the caudate-putamen in these animals. The present study indicates that both the 6-OHDA-induced dopaminergic lesion and chronic pramipexole influence BDNF signalling in limbic structures, which may be related to their pro-depressive and antidepressant activity in rats, respectively.

  6. Alterations of BDNF and trkB mRNA expression in the 6-hydroxydopamine-induced model of preclinical stages of Parkinson's disease: an influence of chronic pramipexole in rats.

    Science.gov (United States)

    Berghauzen-Maciejewska, Klemencja; Wardas, Jadwiga; Kosmowska, Barbara; Głowacka, Urszula; Kuter, Katarzyna; Ossowska, Krystyna

    2015-01-01

    Our recent study has indicated that a moderate lesion of the mesostriatal and mesolimbic pathways in rats, modelling preclinical stages of Parkinson's disease, induces a depressive-like behaviour which is reversed by chronic treatment with pramipexole. The purpose of the present study was to examine the role of brain derived neurotrophic factor (BDNF) signalling in the aforementioned model of depression. Therefore, we investigated the influence of 6-hydoxydopamine (6-OHDA) administration into the ventral region of the caudate-putamen on mRNA levels of BDNF and tropomyosin-related kinase B (trkB) receptor. The BDNF and trkB mRNA levels were determined in the nigrostriatal and limbic structures by in situ hybridization 2 weeks after the operation. Pramipexole (1 mg/kg sc twice a day) and imipramine (10 mg/kg ip once a day) were injected for 2 weeks. The lesion lowered the BDNF and trkB mRNA levels in the hippocampus [CA1, CA3 and dentate gyrus (DG)] and amygdala (basolateral/lateral) as well as the BDNF mRNA content in the habenula (medial/lateral). The lesion did not influence BDNF and trkB expression in the caudate-putamen, substantia nigra, nucleus accumbens (shell and core) and ventral tegmental area (VTA). Chronic imipramine reversed the lesion-induced decreases in BDNF mRNA in the DG. Chronic pramipexole increased BDNF mRNA, but decreased trkB mRNA in the VTA in lesioned rats. Furthermore, it reduced BDNF and trkB mRNA expression in the shell and core of the nucleus accumbens, BDNF mRNA in the amygdala and trkB mRNA in the caudate-putamen in these animals. The present study indicates that both the 6-OHDA-induced dopaminergic lesion and chronic pramipexole influence BDNF signalling in limbic structures, which may be related to their pro-depressive and antidepressant activity in rats, respectively.

  7. 5-HT1A Receptor Activation Improves Anti-Cataleptic Effects of Levodopa in 6-Hydroxydopamine-Lesioned Rats

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    S. Reyhani-Rad

    2011-12-01

    Full Text Available Background and the purpose of the study: In Parkinsons disease (PD prolong use of L-DOPA causes some motor disorders such as wearing-off and L-DOPA induced dyskinesia (LID. In this investigation the effect of 8-OHDAPT, as a 5-HT1A agonist on anti-cataleptic effect of L-DOPA in 6-hydroxydopamine (6-OHDA lesioned male Wistar rats was investigated. Methods: Catalepsy was induced by unilateral injection of 6-OHDA (8 μg/2μl/rat into the central region of the SNc. After 3 weeks as a recovery period, animals received intraperitoneally (i.p. L-DOPA (15 mg/kg twice daily for 20 days, and anti-cataleptic effect of L-DOPA was assessed by bar-test at days of 5, 10, 15 and 20. Results and major conclusion: The results showed that L-DOPA had anti-cataleptic effect only until the day of 15, and its effect was decreased on the day of 20. On the day of 21, rats were co-injected with three different doses of 8-OHDAPT (0.1, 0.5 and 2.5 mg/kg, i.p. and L-DOPA (15 mg/kg, ip. 8-Hydroxy-2-(di-n-propylamino tetralin (8-OHDAPT improved anti-cataleptic effect of L-DOPA at the dose of 0.5 mg/kg. Moreover the effect of 8-OHDAPT on anti-cataleptic effect of L-DOPA (15 mg/kg, ip was abolished by 1-(2-methyoxyphenyl-4-[4-(2-phthalamido butyl] piperazine hydrobromide (NAN-190; 0.5 mg/kg, i.p. as a 5-HT1A receptor antagonist. According to the obtained results, it may be concluded that activation of 5-HT1A receptors by 8-OHDAPT may improve anti-cataleptic effect of L-DOPA in a 6-OHDA- induced rat model of PD. Further studies are required to clarify the exact mechanism of interaction between 5-HT1A and dopaminergic neurons.

  8. Iptakalim hydrochloride protects cells against neurotoxin-induced glutamate transporter dysfunction in in vitro and in vivo models.

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    Yang, Yan-Ling; Meng, Chang-Hong; Ding, Jian-Hua; He, Hai-Rong; Ellsworth, Kevin; Wu, Jie; Hu, Gang

    2005-07-01

    Iptakalim hydrochloride (Ipt), a novel antihypertensive drug, exhibits K(ATP) channel activation. Here, we report that Ipt remarkably protects cells against neurotoxin-induced glutamate transporter dysfunction in in vitro and in vivo models. Chronic exposure of cultured PC12 cells to neurotoxins, such as 6-OHDA, MPP+, or rotenone, decreased overall [3H]-glutamate uptake in a concentration-dependent manner. Pre-treatment using 10 microM Ipt significantly protected cells against neurotoxin-induced glutamate uptake diminishment, and this protection was abolished by the K(ATP) channel blocker glibenclamide (20 microM), suggesting that the protective mechanisms may involve the opening of K(ATP) channels. In 6-OHDA-treated rats (as an in vivo Parkinson's disease model), [3H]-glutamate uptake was significantly lower in synaptosomes isolated from the striatum and cerebral cortex, but not the hippocampus. Pre-conditioning using 10, 50, and 100 microM Ipt significantly restored glutamate uptake impairment and these protections were abolished by blockade of K(ATP) channels. It is concluded that Ipt exhibits substantial protection of cells against neurotoxicity in in vitro and in vivo models. The cellular mechanisms of this protective effect may involve the opening of K(ATP) channels. Collectively, Ipt may serve as a novel and effective drug for PD therapy.

  9. An in vivo microdialysis study of FLZ penetration through the blood-brain barrier in normal and 6-hydroxydopamine induced Parkinson's disease model rats.

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    Hou, Jinfeng; Liu, Qian; Li, Yingfei; Sun, Hua; Zhang, Jinlan

    2014-01-01

    FLZ (N-[2-(4-hydroxy-phenyl)-ethyl]-2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide) is a novel synthetic squamosamide derivative and a potential anti-Parkinson's disease (PD) agent. The objective of the present study was to investigate the penetration of free FLZ across the BBB and the effects of P-gp inhibition on FLZ transport in normal and 6-hydroxydopamine (6-OHDA) induced PD model rats. In vivo microdialysis was used to collect FLZ containing brain and blood dialysates following intravenous (i.v.) drug administration either with or without pretreatment with the specific P-gp inhibitor, zosuquidar trihydrochloride (zosuquidar·3HCl). A sensitive, rapid, and reliable ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique was developed and validated to quantitate free FLZ levels in the dialysates. No significant differences were observed in the brain/blood FLZ area under the concentration-time curve (AUC) ratio between normal and PD model rats. However, pretreatment with zosuquidar·3HCl markedly increased the AUC ratio in both rat models. In addition, FLZ penetration was similar in zosuquidar·3HCl-pretreated normal and PD rats. These results suggest that P-gp inhibition increases BBB permeability to FLZ, thereby supporting the hypothesis that P-gp normally restricts FLZ transfer to the brain. These findings could provide reference data for future clinical trials and may aid investigation of the BBB permeability of other CNS-active substances.

  10. Vocal training, levodopa, and environment effects on ultrasonic vocalizations in a rat neurotoxin model of Parkinson disease

    Science.gov (United States)

    Kelm-Nelson, Cynthia A.; Brauer, Alexander F.L.; Ciucci, Michelle R.

    2016-01-01

    Levodopa does not improve dysarthria in patients with Parkinson Disease (PD), although vocal exercise therapy, such as “LSVT/LOUD®”, does improve vocal communication. Most patients receive vocal exercise therapy while concurrently being treated with levodopa, although the interaction between levodopa and vocal exercise therapy on communication in PD is relatively unknown. Further, carryover of vocal exercise therapy to novel situations is critical for successful outcomes, but the influence of novel situations on rehabilitated vocal communication is not well understood. To address the influence of exercise, medications, and environment on vocal communication with precise experimental control, we employed the widely used 6-OHDA rat neurotoxin model of PD (infusion to the medial forebrain bundle), and assessed ultrasonic vocalizations after: vocal exercise, vocal exercise with levodopa, levodopa alone, and control conditions. We tested USVs in the familiar training environment of the home cage and a novel cage. We hypothesized that parkinsonian rats that undergo vocal exercise would demonstrate significant improvement of ultrasonic vocalization (USV) acoustic parameters as compared to the control exercise and levodopa-only treatment groups. We further hypothesized that vocal exercise in combination with levodopa administration, similar to what is common in humans, would lead to improvement in USV outcomes, particularly when tested in a familiar versus a novel environment. We found that the combination of exercise and levodopa lead to some improvement in USV acoustic parameters and these effects were stronger in a familiar vs. a novel environment. Our results suggest that although treatment can improve aspects of communication, environment can influence the benefits of these effects. PMID:27025445

  11. Effects of Hypericum perforatum on turning behavior in an animal model of Parkinson's disease

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    Débora Dalla Vecchia

    2015-03-01

    Full Text Available Parkinson's disease (PD is an age-related neurodegenerative disorder characterized by the slow and progressive death of dopaminergic neurons in the (substantia nigra pars compact. Hypericum perforatum (H. perforatum is a plant widely used as an antidepressant, that also presents antioxidant and anti-inflammatory properties. We evaluated the effects of H. perforatum on the turning behavior of rats submitted to a unilateral administration of 6-hydroxydopamine (6-OHDA into the medial forebrain bundle as an animal model of PD. The animals were treated with H. perforatum (100, 200, or 400 mg/kg, v.o. for 35 consecutive days (from the 28th day before surgery to the 7th day after. The turning behavior was evaluated at 7, 14 and 21 days after the surgery, and the turnings were counted as contralateral or ipsilateral to the lesion side. All tested doses significantly reduced the number of contralateral turns in all days of evaluation, suggesting a neuroprotective effect. However, they were not able to prevent the 6-OHDA-induced decrease of tyrosine hydroxylase expression in the lesioned striatum. We propose that H. perforatum may counteract the overexpression of dopamine receptors on the lesioned striatum as a possible mechanism for this effect. The present findings provide new evidence that H. perforatum may represent a promising therapeutic tool for PD.

  12. Regional brain catecholamine levels and the development of hypertension in the spontaneously hypertensive rat: the effect of 6-hydroxydopamine

    NARCIS (Netherlands)

    Jong, Wybren de; Buuse, M. van den; Kloet, E.R. de; Versteeg, D.H.G.

    1984-01-01

    To investigate the role of central catecholaminergic pathways in the development of hypertension in the spontaneously hypertensive rat (SHR) the effects of intracerebroventricular (i.c.v.) injections of 6-hydroxydopamine (6-OHDA) were compared with those of local injections near the main ascending n

  13. The Effect of Ethanolic The effect of ethanolic extract of Saffron (Crocus sativus L. on improving the spatial memory parameters in the experimental models of Parkinson disease in male rats

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    Homeyra Hatami

    2016-03-01

    Full Text Available Background & Objective: The axial role of the oxidative stress in the pathophysiology of Parkinson disease has been identified. On the other hand, the learning and memory impairment in Parkinson disease has a distinguished outlook. Since Saffron has antioxidative stress effects, the aim of the present study is to investigate the improving effects of Saffron extract on the spatial memory parameters in the experimental models of Parkinson disease in male rats. Methods & Materials: In this experimental study, 35 male rats weighing approximately 250±50 gram were randomly divided in five equal groups: control, sham (saline + ascorbat, Parkinson's model (injection of 6-OHDA, 2/5 μg/ μl and 2 groups of Parkinson's model + saffron extract pretreatment (5 and 10 μg/rat for 5 days. The Parkinson’s induction model was made by intracerebral injection of 6 – hydroxy dopamine. The Morris Water maze was used for studying the spatial learning and memory.  The data analysis was performed by using One-Way ANOVA. Results: Intracerebral injection of 6- hydroxy dopamine increased the time latency required for finding the hidden platform and damaged the spatial memory (P<0.05. The pretreatment of Saffron extract (5 and 10 μg/rat, 5 days improved the reduced spatial memory in Parkinson's rats (P < 0.05. Conclusion: The Saffron extract is able to restore the spatial memory parameters such as the time latency and the distance travelled for finding the hidden platform in Parkinson's rats as compared to the level of the control group.

  14. Oxidative Stress Effect of Electro-Acupuncture for "Baihui" "Fengfu" and "Yanglingquan" on PD Model Rat%电针 "百会"、"风府"和"阳陵泉"对帕金森病模型大鼠氧化应激反应的影响

    Institute of Scientific and Technical Information of China (English)

    郭春霞; 张晓雷; 邵水金; 郝莉; 朱晶

    2012-01-01

    目的:探讨电针 "百会"、"风府"和"阳陵泉"对帕金森病模型大鼠的治疗作用及作用机理.方法:采用 6-羟基多巴胺(6-OHDA)注射于脑右侧黑质建立偏侧 PD 模型,造模成功后随机分为电针组、美多芭组、电针结合美多芭组与模型对照组,另设正常对照组;各组分别给予相应处理,实验结束后,应用化学比色法测定大鼠中脑黑质纹状体部位谷胱甘肽(GSH)、丙二醛(MDA)的含量,超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)的活性.结果:电针组、美多芭组、电针结合美多芭组均可增加SOD、GSH-PX 活性,GSH含量,降低MDA 含量.结论:电针可明显提高PD 模型大鼠的抗氧化能力,降低自由基对脑的损伤.%Objective: To research the effect of electro -acupuncture for "Baihui" "Fengfu" and "Yanglingquan" in the treatment of the PD model rat and reveal the oxidative stress mechanism of the acupuncture preventing and curing Parkinson ' s Disease ( PD ) . Methods : The PD model rats were induced by injecting 6 - OHDA into the right striatum, The valid PD rats were randomly divided into four groups: electro - acupuncture group, Madopa group, Madopa/ electro - acupuncture group and model control group, normal control group were also established. All groups were given corresponding treatments. At last, the contents of malondialdehyde (MDA) , glutathione (GSH) , GSH -peroxidase ( GSH -Px) , and superoxidedismutase (SOD) in nigrostriatal area were measured with chemical chromatometry. Results: Electro -acupuncture group, Madopa group, Madopa/electro -acupuncture group can increase significantly the average activity of SOD, GSH - PX, GSH, and decrease obvi-ousely the average level of MDA. Conclusion; Electro - acupuncture can enhance the antioxidant capacity of the nerve cells of the substantia nigra in PD model rat, reducing the damage of free radicals on the brain.

  15. Therapeutic effects of repetitive transcranial magnetic stimulation in an animal model of Parkinson's disease.

    Science.gov (United States)

    Lee, Ji Yong; Kim, Sung Hoon; Ko, Ah-Ra; Lee, Jin Suk; Yu, Ji Hea; Seo, Jung Hwa; Cho, Byung Pil; Cho, Sung-Rae

    2013-11-06

    Repetitive transcranial magnetic stimulation (rTMS) is used to treat neurological diseases such as stroke and Parkinson's disease (PD). Although rTMS has been used clinically, its underlying therapeutic mechanism remains unclear. The objective of the present study was to clarify the neuroprotective effect and therapeutic mechanism of rTMS in an animal model of PD. Adult Sprague-Dawley rats were unilaterally injected with 6-hydroxydopamine (6-OHDA) into the right striatum. Rats with PD were then treated with rTMS (circular coil, 10 Hz, 20 min/day) daily for 4 weeks. Behavioral assessments such as amphetamine-induced rotational test and treadmill locomotion test were performed, and the dopaminergic (DA) neurons of substantia nigra pas compacta (SNc) and striatum were histologically examined. Expression of neurotrophic/growth factors was also investigated by multiplex ELISA, western blotting analysis and immunohistochemistry 4 weeks after rTMS application. Among the results, the number of amphetamine-induced rotations was significantly lower in the rTMS group than in the control group at 4 weeks post-treatment. Treadmill locomotion was also significantly improved in the rTMS-treated rats. Tyrosine hydroxylase-positive DA neurons and DA fibers in rTMS group rats were greater than those in untreated group in both ipsilateral SNc and striatum, respectively. The expression levels of brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, platelet-derived growth factor, and vascular endothelial growth factor were elevated in both the 6-OHDA-injected hemisphere and the SNc of the rTMS-treated rats. In conclusion, rTMS treatment improved motor functions and survival of DA neurons, suggesting that the neuroprotective effect of rTMS treatment might be induced by upregulation of neurotrophic/growth factors in the PD animal model.

  16. Major Alterations of Phosphatidylcholine and Lysophosphotidylcholine Lipids in the Substantia Nigra Using an Early Stage Model of Parkinson’s Disease

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    Kyle Farmer

    2015-08-01

    Full Text Available Parkinson’s disease (PD is a progressive neurodegenerative disease affecting the nigrostriatal pathway, where patients do not manifest motor symptoms until >50% of neurons are lost. Thus, it is of great importance to determine early neuronal changes that may contribute to disease progression. Recent attention has focused on lipids and their role in pro- and anti-apoptotic processes. However, information regarding the lipid alterations in animal models of PD is lacking. In this study, we utilized high performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS and novel HPLC solvent methodology to profile phosphatidylcholines and sphingolipids within the substantia nigra. The ipsilateral substantia nigra pars compacta was collected from rats 21 days after an infusion of 6-hydroxydopamine (6-OHDA, or vehicle into the anterior dorsal striatum. We identified 115 lipid species from their mass/charge ratio using the LMAPS Lipid MS Predict Database. Of these, 19 lipid species (from phosphatidylcholine and lysophosphotidylcholine lipid classes were significantly altered by 6-OHDA, with most being down-regulated. The two lipid species that were up-regulated were LPC (16:0 and LPC (18:1, which are important for neuroinflammatory signalling. These findings provide a first step in the characterization of lipid changes in early stages of PD-like pathology and could provide novel targets for early interventions in PD.

  17. Co-transplantation of GDNF-overexpressing neural stem cells and fetal dopaminergic neurons mitigates motor symptoms in a rat model of Parkinson's disease.

    Science.gov (United States)

    Deng, Xingli; Liang, Yuanxin; Lu, Hua; Yang, Zhiyong; Liu, Ru'en; Wang, Jinkun; Song, Xiaobin; Long, Jiang; Li, Yu; Lei, Deqiang; Feng, Zhongtang

    2013-01-01

    Striatal transplantation of dopaminergic (DA) neurons or neural stem cells (NSCs) has been reported to improve the symptoms of Parkinson's disease (PD), but the low rate of cell survival, differentiation, and integration in the host brain limits the therapeutic efficacy. We investigated the therapeutic effects of intracranial co-transplantation of mesencephalic NSCs stably overexpressing human glial-derived neurotrophic factor (GDNF-mNSCs) together with fetal DA neurons in the 6-OHDA rat model of PD. Striatal injection of mNSCs labeled by the contrast enhancer superparamagnetic iron oxide (SPIO) resulted in a hypointense signal in the striatum on T2-weighted magnetic resonance images that lasted for at least 8 weeks post-injection, confirming the long-term survival of injected stem cells in vivo. Co-transplantation of GDNF-mNSCs with fetal DA neurons significantly reduced apomorphine-induced rotation, a behavioral endophenotype of PD, compared to sham-treated controls, rats injected with mNSCs expressing empty vector (control mNSCs) plus fetal DA neurons, or rats injected separately with either control mNSCs, GDNF-mNSCs, or fetal DA neurons. In addition, survival and differentiation of mNSCs into DA neurons was significantly greater following co-transplantation of GDNF-mNSCs plus fetal DA neurons compared to the other treatment groups as indicated by the greater number of cell expressing both the mNSCs lineage tracer enhanced green fluorescent protein (eGFP) and the DA neuron marker tyrosine hydroxylase. The success of cell-based therapies for PD may be greatly improved by co-transplantation of fetal DA neurons with mNSCs genetically modified to overexpress trophic factors such as GDNF that support differentiation into DA cells and their survival in vivo.

  18. Co-transplantation of GDNF-overexpressing neural stem cells and fetal dopaminergic neurons mitigates motor symptoms in a rat model of Parkinson's disease.

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    Xingli Deng

    Full Text Available Striatal transplantation of dopaminergic (DA neurons or neural stem cells (NSCs has been reported to improve the symptoms of Parkinson's disease (PD, but the low rate of cell survival, differentiation, and integration in the host brain limits the therapeutic efficacy. We investigated the therapeutic effects of intracranial co-transplantation of mesencephalic NSCs stably overexpressing human glial-derived neurotrophic factor (GDNF-mNSCs together with fetal DA neurons in the 6-OHDA rat model of PD. Striatal injection of mNSCs labeled by the contrast enhancer superparamagnetic iron oxide (SPIO resulted in a hypointense signal in the striatum on T2-weighted magnetic resonance images that lasted for at least 8 weeks post-injection, confirming the long-term survival of injected stem cells in vivo. Co-transplantation of GDNF-mNSCs with fetal DA neurons significantly reduced apomorphine-induced rotation, a behavioral endophenotype of PD, compared to sham-treated controls, rats injected with mNSCs expressing empty vector (control mNSCs plus fetal DA neurons, or rats injected separately with either control mNSCs, GDNF-mNSCs, or fetal DA neurons. In addition, survival and differentiation of mNSCs into DA neurons was significantly greater following co-transplantation of GDNF-mNSCs plus fetal DA neurons compared to the other treatment groups as indicated by the greater number of cell expressing both the mNSCs lineage tracer enhanced green fluorescent protein (eGFP and the DA neuron marker tyrosine hydroxylase. The success of cell-based therapies for PD may be greatly improved by co-transplantation of fetal DA neurons with mNSCs genetically modified to overexpress trophic factors such as GDNF that support differentiation into DA cells and their survival in vivo.

  19. Co-Transplantation of GDNF-Overexpressing Neural Stem Cells and Fetal Dopaminergic Neurons Mitigates Motor Symptoms in a Rat Model of Parkinson’s Disease

    Science.gov (United States)

    Lu, Hua; Yang, Zhiyong; Liu, Ru’en; Wang, Jinkun; Song, Xiaobin; Long, Jiang; Li, Yu; Lei, Deqiang; Feng, Zhongtang

    2013-01-01

    Striatal transplantation of dopaminergic (DA) neurons or neural stem cells (NSCs) has been reported to improve the symptoms of Parkinson’s disease (PD), but the low rate of cell survival, differentiation, and integration in the host brain limits the therapeutic efficacy. We investigated the therapeutic effects of intracranial co-transplantation of mesencephalic NSCs stably overexpressing human glial-derived neurotrophic factor (GDNF-mNSCs) together with fetal DA neurons in the 6-OHDA rat model of PD. Striatal injection of mNSCs labeled by the contrast enhancer superparamagnetic iron oxide (SPIO) resulted in a hypointense signal in the striatum on T2-weighted magnetic resonance images that lasted for at least 8 weeks post-injection, confirming the long-term survival of injected stem cells in vivo. Co-transplantation of GDNF-mNSCs with fetal DA neurons significantly reduced apomorphine-induced rotation, a behavioral endophenotype of PD, compared to sham-treated controls, rats injected with mNSCs expressing empty vector (control mNSCs) plus fetal DA neurons, or rats injected separately with either control mNSCs, GDNF-mNSCs, or fetal DA neurons. In addition, survival and differentiation of mNSCs into DA neurons was significantly greater following co-transplantation of GDNF-mNSCs plus fetal DA neurons compared to the other treatment groups as indicated by the greater number of cell expressing both the mNSCs lineage tracer enhanced green fluorescent protein (eGFP) and the DA neuron marker tyrosine hydroxylase. The success of cell-based therapies for PD may be greatly improved by co-transplantation of fetal DA neurons with mNSCs genetically modified to overexpress trophic factors such as GDNF that support differentiation into DA cells and their survival in vivo. PMID:24312503

  20. Hypericum Perforatum Hydroalcoholic Extract Mitigates Motor Dysfunction and is Neuroprotective in Intrastriatal 6-Hydroxydopamine Rat Model of Parkinson's Disease.

    Science.gov (United States)

    Kiasalari, Zahra; Baluchnejadmojarad, Tourandokht; Roghani, Mehrdad

    2016-05-01

    Parkinson's disease is the second most common neurodegenerative disorder with selective and progressive decline of nigral dopaminergic neurons. Hypericum perforatum L. (H. perforatum, St. John's wort) has been traditionally used for management of different disorders, especially mild-to-moderate depression. This study was conducted to evaluate the effect of H. perforatum extract against unilateral striatal 6-hydroxydopamine (6-OHDA) toxicity and to unmask some involved mechanisms. Intrastriatal 6-OHDA-lesioned rats were treated with H. perforatum hydroalcoholic extract at a dose of 200 mg/kg/day started 1 week pre-surgery for 1 week post-surgery. The extract attenuated apomorphine-induced rotational behavior, decreased the latency to initiate and the total time on the narrow beam task, lowered striatal level of malondialdehyde and enhanced striatal catalase activity and reduced glutathione content, normalized striatal expression of glial fibrillary acidic protein, tumor necrosis factor α with no significant effect on mitogen-activated protein kinase, lowered nigral DNA fragmentation, and prevented damage of nigral dopaminergic neurons with a higher striatal tyrosine hydroxylase immunoreactivity. These findings reveal the beneficial effect of H. perforatum via attenuation of DNA fragmentation, astrogliosis, inflammation, and oxidative stress.

  1. Phytic Acid Protects against 6-Hydroxydopamine-Induced Dopaminergic Neuron Apoptosis in Normal and Iron Excess Conditions in a Cell Culture Model

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    Qi Xu

    2011-01-01

    Full Text Available Iron may play an important role in Parkinson's disease (PD since it can induce oxidative stress-dependent neurodegeneration. The objective of this study was to determine whether the iron chelator, phytic acid (IP6 can protect against 6-hydroxydopamine- (6-OHDA- induced apoptosis in immortalized rat mesencephalic dopaminergic cells under normal and iron-excess conditions. Caspase-3 activity was increased about 6-fold after 6-OHDA treatment (compared to control; <.001 and 30 μmol/L IP6 pretreatment decreased it by 38% (<.05. Similarly, a 63% protection (<.001 against 6-OHDA induced DNA fragmentation was observed with IP6 pretreatment. Under iron-excess condition, a 6-fold increase in caspase-3 activity (<.001 and a 42% increase in DNA fragmentation (<.05 with 6-OHDA treatment were decreased by 41% (<.01 and 27% (<.05, respectively, with 30 μmol/L IP6. Together, our data suggest that IP6 protects against 6-OHDA-induced cell apoptosis in both normal and iron-excess conditions, and IP6 may offer neuroprotection in PD.

  2. Effect of Passive Smoking on the Rotational Behavior and Striatal Dopamine Content of 6-hydroxydopamine-induced Rat Model of Parkinson Disease%被动吸烟对帕金森病大鼠旋转行为和纹状体多巴胺含量的影响

    Institute of Scientific and Technical Information of China (English)

    董宁; 孙圣刚; 陈吉相; 王涛

    2001-01-01

    目的 观察被动吸烟对帕金森病(PD)大鼠的影响,以验证流行病学研究的结论,为PD研究提供一条新的线索。方法 用6-羟基多巴胺(6-OHDA)立体定向注入大鼠一侧黑质致密部和中脑被盖腹侧区建立偏侧PD模型,观察术前4周开始给予的被动吸烟(持续6周)和术后2周对成功模型给予的被动吸烟(持续2周)对阿朴吗啡诱发的旋转行为及纹状体DA含量的影响。结果 术前4周开始被动吸烟的大鼠旋转行为有减少趋势,受损侧纹状体DA含量较对照组升高。术后2周,成功模型给予的被动吸烟对PD大鼠的旋转行为及纹状体DA含量均无影响。结论 被动吸烟可减轻6-OHDA对黑质DA能神经元的损伤。%Objective To observe the effect of passive smoking on therotational behavior and striatal dopamine content of the rat Parkinson disease (PD) model. Methods Creating the PD rat model by unilaterally injecting 6-hydroxydopamine(6-OHDA) into the substantia nigra pars compacta(SNpc) and the ventral tegmental area(VTA), the effects of passive smoking on the apomorphine-induced rotation behavior and the dopamine content of striatum beginning four weeks before the operation(lasting six weeks) or two weeks after the operation(lasting two weeks) in the successful models were observed. Results Rats received passive smoking beginning four weeks before the operation had a tendency to decrease the apomorphine-induced rotation behavior. The dopamine content of the striatum was elevated as compared to the control group. Passive smoking beginning two weeks after the operation in the successful models did not alter either the rotation behavior or the DA content of striatum. Conclusions Passive smoking can partially protect DA neurons of substantia nigra from the damage of 6-OHDA.

  3. MK-801 (Dizocilpine) Regulates Multiple Steps of Adult Hippocampal Neurogenesis and Alters Psychological Symptoms via Wnt/β-Catenin Signaling in Parkinsonian Rats.

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    Singh, Sonu; Mishra, Akanksha; Srivastava, Neha; Shukla, Shubha

    2017-03-15

    Adult hippocampal neurogenesis is directly involved in regulation of stress, anxiety, and depression that are commonly observed nonmotor symptoms in Parkinson's disease (PD). These symptoms do not respond to pharmacological dopamine replacement therapy. Excitotoxic damage to neuronal cells by N-methyl-d-aspartate (NMDA) receptor activation is also a major contributing factor in PD development, but whether it regulates hippocampal neurogenesis and nonmotor symptoms in PD is yet unexplored. Herein, for the first time, we studied the effect of MK-801, an NMDA receptor antagonist, on adult hippocampal neurogenesis and behavioral functions in 6-OHDA (6-hydroxydopamine) induced rat model of PD. MK-801 treatment (0.2 mg/kg, ip) increased neural stem cell (NSC) proliferation, self-renewal capacity, long-term survival, and neuronal differentiation in the hippocampus of rat model of PD. MK-801 potentially enhanced long-term survival, improved dendritic arborization of immature neurons, and reduced 6-OHDA induced neurodegeneration via maintaining the NSC pool in hippocampus, leading to decreased anxiety and depression-like phenotypes in the PD model. MK-801 inhibited glycogen synthase kinase-3β (GSK-3β) through up-regulation of Wnt-3a, which resulted in the activation of Wnt/β-catenin signaling leading to enhanced hippocampal neurogenesis in PD model. Additionally, MK-801 treatment protected the dopaminergic (DAergic) neurons in the nigrostriatal pathway and improved motor functions by increasing the expression of Nurr-1 and Pitx-3 in the PD model. Therefore, MK-801 treatment serves as a valuable tool to enhance hippocampal neurogenesis in PD, but further studies are needed to revisit the role of MK-801 in the neurodegenerative disorder before proposing a potential therapeutic candidate.

  4. Anterior ventral tegmental area dopaminergic neurons are not involved in the motivational effects of bromocriptine, pramipexole and cocaine in drug-free rats.

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    Ouachikh, Omar; Dieb, Wisam; Durif, Franck; Hafidi, Aziz

    2014-04-01

    Dopamine dysregulation syndrome in Parkinson's disease has been attributed to dopamine replacement therapies and/or a lesion of the dopaminergic system. Dopaminergic neuronal loss targets the substantia nigra and the ventral tegmental area (VTA). We hypothesize that dopamine replacement therapy is responsible for the potential reinforcement effect in Parkinson's disease, by acting on the neuronal reward circuitry. We previously demonstrated that the posterior (p) VTA, which projects to the nucleus accumbens (NAc), is implicated in the motivational effect of dopamine receptor agonists in 6-OHDA bilateral pVTA-lesioned drug-free animals. In the present study we investigated the implication of the anterior (a) VTA in the potential reinforcement effect of dopamine receptor agonists. Using the conditioned place preference (CPP) behavioral paradigm, we investigated the motivational effects of dopamine receptor agonists (bromocriptine and pramipexole), and cocaine in rats with a 6-OHDA bilateral lesion of the aVTA. Bromocriptine and pramipexole did not induce a significant CPP at 1mg/kg in both sham and bilateral 6-OHDA-lesioned rats. However bromocriptine induced CPP only at a dose of 3mg/kg in both animal groups. Moreover cocaine, which is known to increase dopamine release, induced reinforcing effects in both 6-OHDA-lesioned and sham rats. Our data show a lack of involvement of aVTA dopamine neurons in the motivational effects of bromocriptine, pramipexole and cocaine.

  5. The effects of prenatal methylmercury exposure on trace element and antioxidant levels in rats following 6-hydroxydopamine-induced neuronal insult.

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    Mohamed Moosa, Zulfiah; Daniels, Willie M U; Mabandla, Musa V

    2014-06-01

    Methylmercury (MeHg) is a metal toxin found commonly in the environment. Studies have shown severe neurotoxic effects of MeHg poisoning especially during pregnancy where it crosses the foetoplacental and the blood brain barrier of the foetus leading to neurodevelopmental deficits in the offspring. These deficits may predispose offspring to neurodegenerative diseases later in life. In this study we investigated the effects of prenatal methylmercury exposure (2.5 mg/L in drinking water from GND 1-GND 21) on the trace element status in the brain of adolescent offspring (PND 28). Total antioxidant capacity (TAC) was measured in their blood plasma. In a separate group of animals that was also exposed prenatally to MeHg, 6-hydroydopamine (6-OHDA) was administered at PND 60 as a model of neuronal insult. Trace element and TAC levels were compared before and after 6-OHDA exposure. Prenatal MeHg treatment alone resulted in significantly higher concentrations of zinc, copper, manganese and selenium in the brain of offspring at PND 28 (p levels in MeHg-exposed adolescent offspring were significantly lower than their controls (p levels of iron, zinc, copper and manganese were increased compared to sham-lesioned offspring (p levels thereby promoting toxicity (p levels were higher in adult male rats than in female rats during adolescence however male rats that had been exposed to MeHg in utero failed to show this increase at PND 74. Prenatal MeHg exposure results in trace element dyshomeostasis in the brain of offspring and reduces total antioxidant capacity. This may reflect a mechanism by which methylmercury exerts its neurotoxicity and/or predispose offspring to further neurological insults during adulthood.

  6. Phytic Acid Protects against 6-Hydroxydopamine-Induced Dopaminergic Neuron Apoptosis in Normal and Iron Excess Conditions in a Cell Culture Model.

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    Xu, Qi; Kanthasamy, Anumantha G; Reddy, Manju B

    2011-02-07

    Iron may play an important role in Parkinson's disease (PD) since it can induce oxidative stress-dependent neurodegeneration. The objective of this study was to determine whether the iron chelator, phytic acid (IP6) can protect against 6-hydroxydopamine- (6-OHDA-) induced apoptosis in immortalized rat mesencephalic dopaminergic cells under normal and iron-excess conditions. Caspase-3 activity was increased about 6-fold after 6-OHDA treatment (compared to control; P IP6 pretreatment decreased it by 38% (P IP6 pretreatment. Under iron-excess condition, a 6-fold increase in caspase-3 activity (P IP6. Together, our data suggest that IP6 protects against 6-OHDA-induced cell apoptosis in both normal and iron-excess conditions, and IP6 may offer neuroprotection in PD.

  7. Bee Venom Alleviates Motor Deficits and Modulates the Transfer of Cortical Information through the Basal Ganglia in Rat Models of Parkinson’s Disease

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    Maurice, Nicolas; Deltheil, Thierry; Melon, Christophe; Degos, Bertrand; Mourre, Christiane

    2015-01-01

    Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson’s disease (PD). Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure) in pharmacological (neuroleptic treatment) and lesional (unilateral intranigral 6-hydroxydopamine injection) PD models. In the hemi-parkinsonian 6-hydroxydopamine lesion model, subchronic bee venom treatment significantly alleviates contralateral forelimb akinesia and apomorphine-induced rotations. Moreover, a single injection of bee venom reverses haloperidol-induced catalepsy, a pharmacological model reminiscent of parkinsonian akinetic deficit. This effect is mimicked by apamin, a blocker of small conductance Ca2+-activated K+ (SK) channels, and blocked by CyPPA, a positive modulator of these channels, suggesting the involvement of SK channels in the bee venom antiparkinsonian action. In vivo electrophysiological recordings in the substantia nigra pars reticulata (basal ganglia output structure) showed no significant effect of BV on the mean neuronal discharge frequency or pathological bursting activity. In contrast, analyses of the neuronal responses evoked by motor cortex stimulation show that bee venom reverses the 6-OHDA- and neuroleptic-induced biases in the influence exerted by the direct inhibitory and indirect excitatory striatonigral circuits. These data provide the first evidence for a beneficial action of bee venom on the pathological functioning of the cortico-basal ganglia circuits underlying motor PD symptoms with potential relevance to the symptomatic treatment of this disease. PMID:26571268

  8. Reynosin protects against neuronal toxicity in dopamine-induced SH-SY5Y cells and 6-hydroxydopamine-lesioned rats as models of Parkinson's disease: Reciprocal up-regulation of E6-AP and down-regulation of α-synuclein.

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    Ham, Ahrom; Kim, Dong-Woo; Kim, Kyeong Ho; Lee, Sung-Jin; Oh, Ki-Bong; Shin, Jongheon; Mar, Woongchon

    2013-08-01

    Aggregation of α-synuclein (ASYN) is considered a major determinant of neuronal loss in Parkinson's disease (PD). E6-associated protein (E6-AP), an E3 ubiquitin protein ligase, has been known to promote the degradation of α-synuclein. The aim of this study was to assess the effects of the sesquiterpene lactone reynosin on dopamine (DA)-induced neuronal toxicity and regulation of E6-associated protein and α-synuclein proteins in both in vitro and in vivo models of Parkinson's disease. Usi"ng flow cytometry and western blot analysis, we determined that reynosin significantly protected both against cell death from dopamine-induced toxicity in human neuroblastoma SH-SY5Y cells and against the loss of tyrosine hydroxylase (TH)-positive cells in 6-hydroxydopamine (6-OHDA)-lesioned rats (a rodent Parkinson's disease model system). In addition, reynosin made up-regulation of E6-associated protein expression and down-regulation of the over-expression of α-synuclein protein in both dopamine-treated SH-SY5Y cells and 6-hydroxydopamine-lesioned rats. These results suggest that the protective effect of reynosin against dopamine-induced neuronal cell death may be due to the reciprocal up-regulation of E6-associated protein and down-regulation of α-synuclein protein expression.

  9. Cyclosporin promotes neurorestoration and cell replacement therapy in pre-clinical models of Parkinson's disease.

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    Tamburrino, Anna; Churchill, Madeline J; Wan, Oi W; Colino-Sanguino, Yolanda; Ippolito, Rossana; Bergstrand, Sofie; Wolf, Daniel A; Herz, Niculin J; Sconce, Michelle D; Björklund, Anders; Meshul, Charles K; Decressac, Mickael

    2015-12-14

    The early clinical trials using fetal ventral mesencephalic (VM) allografts in Parkinson's disease (PD) patients have shown efficacy (albeit not in all cases) and have paved the way for further development of cell replacement therapy strategies in PD. The preclinical work that led to these clinical trials used allografts of fetal VM tissue placed into 6-OHDA lesioned rats, while the patients received similar allografts under cover of immunosuppression in an α-synuclein disease state. Thus developing models that more faithfully replicate the clinical scenario would be a useful tool for the translation of such cell-based therapies to the clinic. Here, we show that while providing functional recovery, transplantation of fetal dopamine neurons into the AAV-α-synuclein rat model of PD resulted in smaller-sized grafts as compared to similar grafts placed into the 6-OHDA-lesioned striatum. Additionally, we found that cyclosporin treatment was able to promote the survival of the transplanted cells in this allografted state and surprisingly also provided therapeutic benefit in sham-operated animals. We demonstrated that delayed cyclosporin treatment afforded neurorestoration in three complementary models of PD including the Thy1-α-synuclein transgenic mouse, a novel AAV-α-synuclein mouse model, and the MPTP mouse model. We then explored the mechanisms for this benefit of cyclosporin and found it was mediated by both cell-autonomous mechanisms and non-cell autonomous mechanisms. This study provides compelling evidence in favor for the use of immunosuppression in all grafted PD patients receiving cell replacement therapy, regardless of the immunological mismatch between donor and host cells, and also suggests that cyclosporine treatment itself may act as a disease-modifying therapy in all PD patients.

  10. Expression of the fibroblast growth factor-2 isoforms and the FGF receptor 1-4 transcripts in the rat model system of Parkinson's disease.

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    Claus, Peter; Werner, Stefan; Timmer, Marco; Grothe, Claudia

    2004-04-29

    Basic fibroblast growth factor (FGF)-2 occurs in different isoforms representing different translation products of a single mRNA. We have previously shown that the high molecular weight FGF-2 isoforms (21, 23 kD) stimulated survival- and neurite-promoting activities and protective effects on cultured embryonic dopaminergic (DA) neurons of the substantia nigra (Neuroscience 100 (2000) 73). In this study the expression of FGF-2 isoforms in the striatum and substantia nigra was analyzed by Western blot in adult intact rats and following complete unilateral 6-hydroxydopamine (6-OHDA) lesion. In intact rats, all three FGF-2 isoforms (18, 21, 23 kD) are expressed. Neurotoxin-mediated lesion of nigral DA neurons revealed no change of the FGF-2 isoform expression pattern in the nigrostriatal system. Additionally, the FGF receptors 1, 2 and 3 are expressed in these tissues and displayed no alterations after 6-OHDA injection as demonstrated by RT-PCR. The presence of all three FGF-2 isoforms and the FGFR 1-3, together with the previous demonstrated neurotrophic effects of FGF-2 on dopaminergic neurons, suggest a physiological function of the FGF-2 isoforms in the nigrostriatal system.

  11. Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson's disease.

    Science.gov (United States)

    Yue, X; Hariri, D J; Caballero, B; Zhang, S; Bartlett, M J; Kaut, O; Mount, D W; Wüllner, U; Sherman, S J; Falk, T

    2014-01-31

    Vascular endothelial growth factor B (VEGF-B) has recently been shown to be a promising novel neuroprotective agent for several neurodegenerative conditions. In the current study we extended previous work on neuroprotective potential for Parkinson's disease (PD) by testing an expanded dose range of VEGF-B (1 and 10 μg) and directly comparing both neuroprotective and neurorestorative effects of VEGF-B in progressive unilateral 6-hydroxydopamine (6-OHDA) PD models to a single dose of glial cell line-derived neurotrophic factor (GDNF, 10 μg), that has been established by several groups as a standard in both preclinical PD models. In the amphetamine-induced rotational tests the treatment with 1 and 10 μg VEGF-B resulted in significantly improved motor function of 6-OHDA-lesioned rats compared to vehicle-treated 6-OHDA-lesioned rats in the neuroprotection paradigm. Both doses of VEGF-B caused an increase in tyrosine hydroxylase (TH)-positive cell and fiber count in the substantia nigra (SN) and striatum in the neuroprotective experiment. The effect size was comparable to the effects seen with GDNF. In the neurorestoration paradigm, VEGF-B injection had no significant effect in either the behavioral or the immunohistochemical analyses, whereas GDNF injection significantly improved the amphetamine-induced rotational behavior and reduced TH-positive neuronal cell loss in the SN. We also present a strong positive correlation (p=1.9e-50) of the expression of VEGF-B with nuclear-encoded mitochondrial genes involved in fatty acid metabolism in rat midbrain, pointing to the mitochondria as a site of action of VEGF-B. GDNF showed a positive correlation with nuclear-encoded mitochondrial genes that was not nearly as strong (p=0.018). VEGF-B counteracted rotenone-induced reduction of (a) fatty acid transport protein 1 and 4 levels and (b) both Akt protein and phosphorylation levels in SH-SY5Y cells. We further verified VEGF-B expression in the human SN pars compacta of healthy

  12. Animal models to guide clinical drug development in ADHD: lost in translation?

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    Wickens, Jeffery R; Hyland, Brian I; Tripp, Gail

    2011-10-01

    We review strategies for developing animal models for examining and selecting compounds with potential therapeutic benefit in attention-deficit hyperactivity disorder (ADHD). ADHD is a behavioural disorder of unknown aetiology and pathophysiology. Current understanding suggests that genetic factors play an important role in the aetiology of ADHD. The involvement of dopaminergic and noradrenergic systems in the pathophysiology of ADHD is probable. We review the clinical features of ADHD including inattention, hyperactivity and impulsivity and how these are operationalized for laboratory study. Measures of temporal discounting (but not premature responding) appear to predict known drug effects well (treatment validity). Open-field measures of overactivity commonly used do not have treatment validity in human populations. A number of animal models have been proposed that simulate the symptoms of ADHD. The most commonly used are the spontaneously hypertensive rat (SHR) and the 6-hydroxydopamine-lesioned (6-OHDA) animals. To date, however, the SHR lacks treatment validity, and the effects of drugs on symptoms of impulsivity and inattention have not been studied extensively in 6-OHDA-lesioned animals. At the present stage of development, there are no in vivo models of proven effectiveness for examining and selecting compounds with potential therapeutic benefit in ADHD. However, temporal discounting is an emerging theme in theories of ADHD, and there is good evidence of increased value of delayed reward following treatment with stimulant drugs. Therefore, operant behaviour paradigms that measure the effects of drugs in situations of delayed reinforcement, whether in normal rats or selected models, show promise for the future.

  13. Autoradiography of dopamine receptors and dopamine uptake sites in the spontaneously hypertensive rat

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    Kujirai, K.; Przedborski, S.; Kostic, V.; Jackson-Lewis, V.; Fahn, S.; Cadet, J.L. (Columbia Univ., New York, NY (USA))

    1990-11-01

    We examined the status of dopamine (DA) D1 and D2 receptors by using (3H)SCH 23390 and (3H)spiperone binding, respectively, and DA uptake sites by using (3H)mazindol binding in spontaneously hypertensive rats (SHR) and Sprague-Dawley (SD) rats. SHR showed significantly higher (3H)SCH 23390 and (3H)spiperone binding in the caudate-putamen (CPu), the nucleus accumbens (NAc) and the olfactory tubercle (OT) in comparison to the SD rats. There were no significant differences in (3H)mazindol-labeled DA uptake sites between the two strains. Unilateral 6-hydroxydopamine (6-OHDA) injection into the striatum resulted in more than 90% depletion of DA uptake sites in the CPu in both strains. 6-OHDA-induced DA depletion was associated with significant increases in striatal (3H)spiperone binding which were of similar magnitude in the SD rats (+64.1%) and SHR (+51.3%). There were only small decreases (-5.4%) in D1 receptor binding in the dorsolateral aspect of the CPu in the SHR, whereas there were no changes in striatal D1 receptors in the SD rats. These results indicate that, although the SHR have higher concentrations of both D1 and D2 receptors in the basal ganglia, these receptors are regulated in a fashion similar to DA receptors in SD rats after 6-OHDA-induced striatal DA depletion.

  14. Effect of acupuncture on 6-hydroxydopamine-induced nigrostratal dopaminergic neuronal cell death in rats.

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    Kim, Yeung-Kee; Lim, Hyung-Ho; Song, Yun-Kyung; Lee, Hee-Hyuk; Lim, Sabina; Han, Seung-Moo; Kim, Chang-Ju

    In this study, we investigated the effect of acupuncture at the Zusanli acupoint (ST36) on the nigrostriatal dopaminergic neuronal cell death in the rats with Parkinson's disease. Two weeks after unilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum, an apomorphine-induced rotational behavior test showed significant rotational asymmetry in the rats with Parkinson's disease. Immunostaining for tyrosine hydroxylase demonstrated a dopaminergic neuronal loss in the substantia nigra and dopaminergic fiber loss in the striatum. Acupuncture at the ST36 for 14 days significantly inhibited rotational asymmetry in the rats with Parkinson's disease, and also protected against 6-OHDA-induced nigrostriatal dopaminergic neuronal loss. These effects of acupuncture were not observed for the non-acupoint (hip) acupuncture. The present study shows that acupuncture at the ST36 acupoint can be used as a useful strategy for the treatment of Parkinson's disease.

  15. Human albumin prevents 6-hydroxydopamine-induced loss of tyrosine hydroxylase in in vitro and in vivo.

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    Li-Juan Zhang

    Full Text Available Human albumin has recently been demonstrated to protect brain neurons from injury in rat ischemic brain. However, there is no information available about whether human albumin can prevent loss of tyrosine hydroxylase (TH expression of dopaminergic (DA neurons induced by 6-hydroxydopamine (6-OHDA toxicity that is most commonly used to create a rat model of Parkinson's disease (PD. In the present study, two microliters of 1.25% human albumin were stereotaxically injected into the right striatum of rats one day before or 7 days after the 6-OHDA lesion in the same side. D-Amphetamine-induced rotational asymmetry was measured 7 days, 3 and 10 weeks after 6-OHDA lesion. We observed that intrastriatal administration of human albumin significantly reduced the degree of rotational asymmetry. The number of TH-immunoreactive neurons present in the substantia nigra was greater in 6-OHDA lesioned rats following human albumin-treatment than non-human albumin treatment. TH-immunoreactivity in the 6-OHDA-lesioned striatum was also significantly increased in the human albumin-treated rats. To examine the mechanisms underlying the effects of human albumin, we challenged PC12 cells with 6-OHDA as an in vitro model of PD. Incubation with human albumin prevented 6-OHDA-induced reduction of cell viability in PC12 cell cultures, as measured by MTT assay. Furthermore, human albumin reduced 6-OHDA-induced formation of reactive oxygen species (ROS and apoptosis in cultured PC12 cells, as assessed by flow cytometry. Western blot analysis showed that human albumin inhibited 6-OHDA-induced activation of JNK, c-Jun, ERK, and p38 mitogen-activated protein kinases (MAPK signaling in PC12 cultures challenged with 6-OHDA. Human albumin may protect against 6-OHDA toxicity by influencing MAPK pathway followed by anti-ROS formation and anti-apoptosis.

  16. Striatal trophic activity is reduced in the aged rat brain.

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    Ling, Z D; Collier, T J; Sortwell, C E; Lipton, J W; Vu, T Q; Robie, H C; Carvey, P M

    2000-02-21

    Our previous studies demonstrated that the survival of a mesencephalic graft was reduced in aged animals suggesting an age-related decline in target-derived neurotrophic activity. We tested this hypothesis by examining dopamine (DA) and trophic activities from the striatum of intact or unilateral 6-hydroxydopamine (6-OHDA) lesioned rats of increasing age. Fisher 344 rats were 4, 12, 18, and 23 months old (m.o.) at sacrifice. Half the animals had received unilateral 6-OHDA lesions of the mesostriatal DA pathway 8 weeks earlier. Striatal tissue punches were analyzed for DA, homovanillic acid (HVA), and DA activity (HVA/DA) using HPLC. The remainder of the striatal tissue was homogenized to generate tissue extracts which were added to E14.5 ventral mesencephalic cultures to test trophic activity. In the non-lesioned animals, striatal DA was reduced and striatal DA activity was increased in the 18 and 23 m.o. animals relative to the 4 and 12 m.o. animals. Striatal trophic activity was inversely related to age. In the lesioned animals, striatal DA ipsilateral to 6-OHDA infusion was below detection limits while the contralateral striatum exhibited age-related changes in DA similar to those seen in the non-lesioned animals. In 4 m.o. lesioned rats, striatal trophic activity ipsilateral to 6-OHDA infusion was elevated by 26% relative to the contralateral side. The ipsi/contra-lateral differences in striatal trophic activity were reduced in 12 m.o. animals and absent in the 18 and 23 m.o. groups. These data suggest that advancing age is associated with a reduction in striatal DA as well as trophic activity. Moreover, the aged striatum loses its ability to biochemically and trophically compensate for DA reduction and therefore may represent a more challenging environment for the survival, growth, and function of a fetal graft.

  17. Influence of chronic L-DOPA treatment on immune response following allogeneic and xenogeneic graft in a rat model of Parkinson's disease.

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    Breger, Ludivine S; Kienle, Korbinian; Smith, Gaynor A; Dunnett, Stephen B; Lane, Emma L

    2017-03-01

    Although intrastriatal transplantation of fetal cells for the treatment of Parkinson's disease had shown encouraging results in initial open-label clinical trials, subsequent double-blind studies reported more debatable outcomes. These studies highlighted the need for greater preclinical analysis of the parameters that may influence the success of cell therapy. While much of this has focused on the cells and location of the transplants, few have attempted to replicate potentially critical patient centered factors. Of particular relevance is that patients will be under continued L-DOPA treatment prior to and following transplantation, and that typically the grafts will not be immunologically compatible with the host. The aim of this study was therefore to determine the effect of chronic L-DOPA administered during different phases of the transplantation process on the survival and function of grafts with differing degrees of immunological compatibility. To that end, unilaterally 6-OHDA lesioned rats received sham surgery, allogeneic or xenogeneic transplants, while being treated with L-DOPA before and/or after transplantation. Irrespective of the L-DOPA treatment, dopaminergic grafts improved function and reduced the onset of L-DOPA induced dyskinesia. Importantly, although L-DOPA administered post transplantation was found to have no detrimental effect on graft survival, it did significantly promote the immune response around xenogeneic transplants, despite the administration of immunosuppressive treatment (cyclosporine). This study is the first to systematically examine the effect of L-DOPA on graft tolerance, which is dependent on the donor-host compatibility. These findings emphasize the importance of using animal models that adequately represent the patient paradigm.

  18. A mouse model of non-motor symptoms in Parkinson’s disease: focus on pharmacological interventions targeting affective dysfunctions

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    Alessandra eBonito Oliva

    2014-08-01

    Full Text Available Non-motor symptoms, including psychiatric disorders, are increasingly recognized as a major challenge in the treatment of Parkinson’s disease (PD. These ailments, which often appear in the early stage of the disease, affect a large number of patients and are only partly resolved by conventional antiparkinsonian medications, such as L-DOPA. Here, we investigated non-motor symptoms of PD in a mouse model based on bilateral injection of the toxin 6-hydroxydopamine (6-OHDA in the dorsal striatum. This model presented only subtle gait modifications, which did not affect horizontal motor activity in the open-field test. Bilateral 6-OHDA lesion also impaired olfactory discrimination, in line with the anosmia typically observed in early stage parkinsonism. The effect of 6-OHDA was then examined for mood-related dysfunctions. Lesioned mice showed increased immobility in the forced swim test and tail suspension test, two behavioral paradigms of depression. Moreover, the lesion exerted anxiogenic effects, as shown by reduced time spent in the open arms, in the elevated plus maze test, and by increased thigmotaxis in the open-field test. L-DOPA did not modify depressive- and anxiety-like behaviors, which were instead counteracted by the dopamine D2/D3 receptor agonist, pramipexole. Reboxetine, a noradrenaline reuptake inhibitor, was also able to prevent the depressive and anxiogenic effects produced by the lesion with 6-OHDA. Interestingly, pre-treatment with desipramine prior to injection of 6-OHDA, which is commonly used to preserve noradrenaline neurons, did not modify the effect of the lesion on depressive- and anxiety-like behaviors. Thus, in the present model, mood-related conditions are independent of the reduction of noradrenaline caused by 6-OHDA. Based on these findings we propose that the anti-depressive and anxiolytic action of reboxetine is mediated by promoting dopamine transmission through blockade of dopamine uptake from residual

  19. Therapeutic effect of human amniotic epithelial cell transplantation into the lateral ventricle of hemiparkinsonian rats

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    YANG Xin-xin; XUE Shou-ru; DONG Wan-li; Kong Yan

    2009-01-01

    Background Human amniotic epithelial cells (HAECs) are able to secrete biologically active neurotrophins such as brain-derived neurotrophic factor and neurotrophin-3, both of which exhibit trophic activities on dopamine neurons.Previous study showed that when human amniotic epithelial cells were transplanted into the striatum of 6-hydroxydopamine (6-OHDA)-induced Parkinson disease rats, the cells could survive and exert functional effects. The purpose of this study was to investigate the survival and the differentiation of human amniotic epithelial cells after being transplanted into the lateral ventricle of Parkinson's disease (PD) rats, and to investigate the effects of grafts on healing PD in models.Methods The Parkinson's model was made with stereotactic microinjection of 6-hydroxydopamine (6-OHDA) into the striatum of a rat. The PD models were divided into two groups: the HAECs group and the normal saline (NS) group.Some untreated rats were taken as the control. The rotational asymmetry induced by apomorphine of the HAECs group and the NS group were measured post cell transplantation. The expression of nestin and vimentin in grafts were determined by immunohistology. Ten weeks after transplantation the density of tyrosine hydroxylase positive cells in the substantia nigra of the HAECs group, NS group and the untreated group was determined. The differentiation of grafts was determined by TH immunohistology. High performance liquid chromatography (HPLC) was used to determine monoamine neurotransmitter levels in the striatum.Results The rotational asymmetry induced by apomorphine of the HAECs group was ameliorated significantly compared to the NS group two weeks after transplantation (P <0.01). The grafts expressed nestin and vimentin five weeks after transplantation. TH immunohistochemistry indicated that the TH positive cells in the substantia nigra of the HAECs group increased significantly compared to the NS group (P<0.01). Tyrosine hydroxylase (TH) positive

  20. Activation of Retinoid X Receptor increases dopamine cell survival in models for Parkinson's disease

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    Bergsland Maria

    2009-12-01

    Full Text Available Abstract Background Parkinson's disease (PD is caused by degeneration of dopamine (DA neurons in the ventral midbrain (vMB and results in severely disturbed regulation of movement. The disease inflicts considerable suffering for the affected and their families. Today, the opportunities for pharmacological treatment are meager and new technologies are needed. Previous studies have indicated that activation of the nuclear receptor Retinoid X Receptor (RXR provides trophic support for DA neurons. Detailed investigations of these neurotrophic effects have been hampered by the lack of readily available DA neurons in vitro. The aim of this study was to further describe the potential neurotrophic actions of RXR ligands and, for this and future purposes, develop a suitable in vitro-platform using mouse embryonic stem cells (mESCs. Results We studied the potential neurotrophic effects of the RXR ligand LG100268 (LG268 and the RXR-Nurr1 ligand XCT0139508 (XCT in neuronal cultures derived from rat primary vMB and mESCs. RXR ligands protect DA neurons from stress, such as that induced by the PD-modeling toxin 6-hydroxy dopamine (6-OHDA and hypoxia, but not from stress induced by oxidative hydrogen peroxide (H2O2 or the excitotoxic agent kainic acid (KA. The neurotrophic effect is selective for DA neurons. DA neurons from rat primary vMB and mESCs behaved similarly, but the mESC-derived cultures contained a much higher fraction of DA cells and thus provided more accessible experimental conditions. Conclusions RXR ligands rescue DA neurons from degeneration caused by the PD simulating 6-OHDA as well as hypoxia. Thus, RXR is a novel promising target for PD research. mESC-derived DA cells provide a valid and accessible in vitro-platform for studying PD inducing toxins and potential trophic agents.

  1. Changes and roles of endogenous hydrogen sulfide in the substantial nigra oxidative damage of rats%内源性硫化氢在大鼠黑质氧化损伤中的变化及作用

    Institute of Scientific and Technical Information of China (English)

    许岩; 马娜; 刘博; 王晶莹; 廖文辉; 汪胜; 王金全; 孟金兰

    2014-01-01

    Objective To observe the changes and roles of endogenous hydrogen sulfide in the substantia nigra oxida-tive damage of rats. Methods 6-hydroxydop- amine (6-OHDA) was microinjected in the unilateral substantia nigra of SD rats as the substantia nigra oxidative damage model;H2S donor, sodium hydrosulfide (NaHS) was injected intraperi-toneally for three consecutive weeks as a pretreatment before 6-OHDA injury. The experiment were divided into the control group , 7 days (D7) group, 11 days (D11) group, 17 days (D17) group after 6-OHDA injury and NaHS precondi-tioning group (deafed with NaHS + 6-OHDA); with 8 rats in each group. Cystathionine-β-synthase (CBS) activity and H2S production in substantia nigra were detected by methylene blue spectrophot-ometric method. Immunohistochemistry was used to detect tyrosine hydroxylase (tyrosine hydroxylase, TH) positive cells of the substantia nigra; Glutathione peroxidase (GSH-Px) activity and malondialdehyde (MDA) level of the substantia nigra were measured by UV spec-trophotometry. Results Compared with the control group, percentage of CBS activity was decreased re-spectively to [(96.21±8.40)%, P > 0.05], [(86.48±9.85)%, P0.05],[(86.48±9.85)%,P<0.05]和[(75.16±7.45)%,P<0.01];内源性H2S含量分别减少为[(90.12±10.03)%,P<0.05],[(82.58±9.52)%,P<0.01]和[(78.16±11.55)%,P<0.01]。 TH阳性细胞与对照组比较,在6-OHDA损伤后7 d即下降为[(84.32±6.06)%,P<0.05],同时伴随黑质GSH-Px活性降低及MDA含量升高,差异有统计学意义(P<0.05)。但早期给予NaHS预处理补充H2S之后,与单纯6-OHDA损伤后7 d比较,TH阳性细胞则增加为[(96.15±5.03)%,P<0.05],且黑质GSH-Px的活性升高,MDA的含量降低,差异有统计学意义(P<0.05)。结论6-OHDA氧化损伤导致大鼠黑质CBS酶活性及H2S含量下降,外源性H2S预处理可早期发挥抗黑质氧化损伤的神经元保护作用,这可能与其增加GSH-Px活性及减少MDA含量有关。

  2. Arachidonic acid incorporation and turnover is decreased in sympathetically denervated rat heart.

    Science.gov (United States)

    Patrick, Casey B; McHowat, Jane; Rosenberger, Thad A; Rapoport, Stanley I; Murphy, Eric J

    2005-06-01

    Heart sympathetic denervation can accompany Parkinson's disease, but the effect of this denervation on cardiac lipid-mediated signaling is unknown. To address this issue, rats were sympathetically denervated with 6-hydroxydopamine (6-OHDA, 50 mg/kg ip) and infused with 170 muCi/kg of either [1-(14)C]palmitic acid ([1-(14)C]16:0) or [1-(14)C]arachidonic acid ([1-(14)C]20:4 n-6), and kinetic parameters were assessed using a steady-state radiotracer model. Heart norepinephrine and epinephrine levels were decreased 82 and 85%, respectively, in denervated rats, and this correlated with a 34% reduction in weight gain in treated rats. Fatty acid tracer uptake was not significantly different between groups for either tracer, although the dilution coefficient lambda was increased in [1-(14)C]20:4 n-6-infused rats, which indicates that less 20:4 n-6 was recycled in denervated rats. In [1-(14)C]16:0-infused rats, incorporation rate and turnover values of 16:0 in stable lipid compartments were unchanged, which is indicative of preservation of beta-oxidation. In [1-(14)C]20:4 n-6-infused rats, there were dramatic reductions in incorporation rate (60-84%) and turnover value (56-85%) in denervated rats that were dependent upon the lipid compartment. In addition, phospholipase A(2) activity was reduced 40% in treated rats, which is consistent with the reduction observed in 20:4 n-6 turnover. These results demonstrate marked reductions in 20:4 n-6 incorporation rate and turnover in sympathetic denervated rats and thereby suggest an effect on lipid-mediated signal transduction mediated by a reduction in phospholipase A(2) activity.

  3. Acupuncture inhibits oxidative stress and rotational behavior in 6-hydroxydopamine lesioned rat.

    Science.gov (United States)

    Yu, Yong-Peng; Ju, Wei-Ping; Li, Zhen-Guang; Wang, Dao-Zhen; Wang, Yuan-Chen; Xie, An-Mu

    2010-06-08

    Increasing evidence suggests the beneficial effects of acupuncture on Parkinson's disease (PD). Although clinical evidence for the acupuncture anti-Parkinson's disease effect has been demonstrated, the precise mechanism still remains elusive. It has been suggested a relationship between PD and reactive oxygen species (ROS) can result in neurodegeneration. The aim of this study was to evaluate the status of oxidative stress, as well as the antioxidant enzyme response, and the role of acupuncture stimulation at GB34 (Yanglingquan), LR3 (Taichong), ST36 (Zusanli) and SP10 (Xuehai) acupoints on regulating oxidative stress in the nigrostriatal system in the 6-hydroxydopamine (6-OHDA) lesioned rat. Two weeks after unilateral injection of 6-OHDA into the left medial forebrain bundle (MFB), an apomorphine induced rotational behavior test was performed. The levels of enzymatic, viz., superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and nonenzymatic, viz., reduced glutathione (GSH), and the levels of malondialdehyde (MDA) in the nigrostriatal system were measured to assess the oxidative stress status. Brain MDA levels significantly increased, while GSH levels were decreased in impaired groups with 6-OHDA injection only, accompanied by a marked reduction in the level of SOD and GSH-Px. The levels of oxidative stress related parameters except CAT, as well as the rotational asymmetry, were reversed by acupuncture stimulation. These results showed that acupuncture treatment displayed antioxidative and/or neuroprotective properties in the 6-OHDA lesioned rat and these protective properties might be mediated, at least in part, by involving regulation of the antioxidant defense system.

  4. An autophagic mechanism is involved in the 6-hydroxydopamine-induced neurotoxicity in vivo.

    Science.gov (United States)

    He, Xin; Yuan, Wei; Li, Zijian; Feng, Juan

    2017-08-09

    6-hydroxydopamine (6-OHDA) is one of the most common agents for modeling dopaminergic neuron degeneration in Parkinson's disease (PD). So far, the role of autophagy in 6-OHDA-induced neurotoxicity remains controversial and most evidence is collected from in vitro studies. In this study, we determined the role of autophagy activation in 6-OHDA-induced neurotoxicity in a rat model of PD. Following 6-OHDA treatment, we observed a concomitant activation of autophagy and apoptosis. To further explore the interaction between autophagy and apoptosis induced by 6-OHDA, autophagy inhibitor 3-methylademine (3-MA) or cysteine protease inhibitor Z-FA-fmk was applied. We found that both 3-MA and Z-FA-fmk could not only exert immediate protection against 6-OHDA-induced neuronal apoptosis, but also prevent dopaminergic neuron loss in the long-term, which was related to reduced autophagosome formation. Furthermore, by monitoring the sequential changes of mTOR-related signaling pathways, we found that reactive oxygen species (ROS)-mediated AKT/AMPK-mTOR signaling pathway participated in but was not the initial cause of autophagy activation by 6-OHDA. Collectively, our data suggest that 6-OHDA-induced autophagy activation contributes to its neurotoxicity and targeting autophagy activation or cysteine proteases could be promising for developing neuroprotective agents for PD. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Protective effects of H2S on dopamine neurons in rats with Parkinson's disease%硫化氢对帕金森病模型大鼠多巴胺神经元的保护作用

    Institute of Scientific and Technical Information of China (English)

    尹蔚兰; 何剑琴; 张恺芳; 欧阳新平

    2011-01-01

    目的:观察硫化氢对帕金森病(Parkinson's disease,PD)大鼠神经行为学、氧化应激以及多巴胺及其代谢产物的影响.方法:采用6-羟基多巴胺(6-OHDA)注射于脑右侧黑质造成偏侧PD模型.将模型动物随机分为模型组、硫化氢组(硫氢化钠做供体),每组10只;另分别取10只正常大鼠为正常组及假手术组(以抗坏血酸注射).观察PD大鼠经过硫化氢处理后神经行为学、脑组织丙二醛(MDA)、谷胱甘肽(GSH)、超氧化物歧化酶(SOD)含量以及多巴胺代谢产物的变化.结果:与模型组比较硫化氧组大鼠行为学明显改善(P<0.01),同时脑组织中GSH、SOD含量均升高,MDA含量降低,多巴胺及其代谢产物升高.结论:硫化氢对PD模型大鼠多巴胺神经元具有保护作用.%Objective: To observe the effects of H2S prescription on neuroethology, oxidative stress, dopamine and its metabolites in rats with Parkinson's disease (PD).Methods: Model of hemilateral PD mt was established with injection of 6-hydroxydopamine( 6-OHDA )into the right substantia nigra of midbrain.The PD model rats were randomly divided into model group, H2S group (sodium hydrosulfide, NariS, was used as H2S donor), control group and sham-operated group( injected by ascorbic acid) ,10 rats for each group.The changes of neuroethology, the contents of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and the levels of dopamine and its metabolites were compared among groups.Results: Compared with model group, the neuroethology of rats in H2S group were significantly improved.The contents of GSH, SOD were reduced significanfiy; The contents of MDA and the levels of dopamine( DA ),HVA, dihydroxv-phenyl acetic acid (DOPAC) were elevated significantly.Conclusion: H2S can protect the dopamine neurons in rats with Parkinson's disease.

  6. G-CSF for mobilizing transplanted bone marrow stem cells in rat model of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Manouchehr Safari

    2016-12-01

    Full Text Available Objective(s: Granulocyte-colony stimulating factor (G-CSF is used in clinical practice for the treatment of neutropenia and to stimulate generation of hematopoietic stem cells in bone marrow donors. In the present study, the ability of G-CSF in mobilizing exogenous bone marrow stem cells (BMSCs from peripheral blood into the brain was tested. We for the first time injected a small amount of BMSCs through the tail vein. Materials and Methods: We choose 25 male Wistar rats (200–250 g were lesioned by 6-OHDA injected into the left substantia nigra, pars compacta (SNpc. G-CSF (70 µg/kg/day was given from the 7th day after lesion for five days. The BMSCs (2×105 were injected through the dorsal tail vein on the 7th day after lesion. Results:The number of rotations was significantly lower in the stem cell therapy group than in the control group. In the third test in the received G-CSF and G-CSF+stem cells groups, animals displayed significant behavioral recovery compared with the control group (P

  7. G-CSF for mobilizing transplanted bone marrow stem cells in rat model of Parkinson's disease.

    Science.gov (United States)

    Safari, Manouchehr; Jafari, Behnaz; Zarbakhsh, Sam; Sameni, Hamidreza; Vafaei, Abbas Ali; Mohammadi, Nasrin Khan; Ghahari, Laya

    2016-12-01

    Granulocyte-colony stimulating factor (G-CSF) is used in clinical practice for the treatment of neutropenia and to stimulate generation of hematopoietic stem cells in bone marrow donors. In the present study, the ability of G-CSF in mobilizing exogenous bone marrow stem cells (BMSCs) from peripheral blood into the brain was tested. We for the first time injected a small amount of BMSCs through the tail vein. We choose 25 male Wistar rats (200-250 g) were lesioned by 6-OHDA injected into the left substantia nigra, pars compacta (SNpc). G-CSF (70 µg/kg/day) was given from the 7(th) day after lesion for five days. The BMSCs (2×10(5)) were injected through the dorsal tail vein on the 7(th) day after lesion. The number of rotations was significantly lower in the stem cell therapy group than in the control group. In the third test in the received G-CSF and G-CSF+stem cells groups, animals displayed significant behavioral recovery compared with the control group (Pstem cells groups. We didn't detect any labeling stem cells in SNpc. G-CSF can't mobilize low amounts of exogenous BMSCs from the blood stream to injured SNpc. But G-CSF (70 µg/kg) is more neuroprotective than BMSCs (2×10(5) number[w1] of BMSCs). Results of our study suggest that G-CSF alone is more neuroprotective than BMSCs.

  8. Effect of electroacupuncture scalp point-through-point therapy on the expression of tyrosine hydroxylase and dopamine transporter mRNAs in substantia nigra of Parkinson's disease model rats%头部电针透穴疗法对帕金森病模型大鼠黑质TH及DAT基因表达的影响

    Institute of Scientific and Technical Information of China (English)

    王顺; 戚秀杰; 韩迪

    2009-01-01

    目的:探讨头部电针透穴疗法治疗帕金森病的作用机制.方法:将36只Wistar大鼠随机分为正常组、假手术组、模型组、透针组,以6-羟基多巴胺(6-OHDA)左侧纹状体注射法制备偏侧帕金森病大鼠旋转模型,透针组穴取"百会"透"太阳",每日1次,6日为一疗程.其他3组不予治疗,观察2个疗程.采用以HE染色观察大鼠黑质神经细胞组织形态变化,以RT-PCR技术检测酪氨酸羟化酶(TH)及多巴胺转运体(DAT)mRNA的表达.结果:透针组TH mRNA(1.22±0.19)及DAT mRNA(0.62±0.11)均较模型组TH mRNA(0.65±0.17)及DAT mRNA(0.41±0.08)表达明显增加(均P<0.05).大鼠黑质神经细胞透针组较模型组数量增多,细胞变性减轻.结论:头部电针透穴疗法能使帕金森病模型大鼠黑质TH及DAT mRNA表达增高,进而可以促进多巴胺的合成与重摄取,以达到治疗帕金森病的目的.%Objective To explore the mechanism of electroacupuncture scalp point-through-point therapy in the treatment of Parkinson's disease. Methods Thirty-six Wistar rats were randomly divided into a normal group, a sham-operation group, a model group and a point-through-point therapy group. 6-OHDA was injected into left stria-tum to made lateralization Parkinson's disease rat model. The point-through-point therapy group was treated with electroacupuncture at "Baihui" (GV 20)-through-"Taiyang" (EX-NH 5), once each day, 6 days constituting one course, for 2 courses, and the rats of other groups were not treated. HE staining method was used for observation of the histo-morphologic changes of the substantia nigra neurons, and RT-PCR for the expression of tyrosine hydroxylase (TH) and dopamine transporter(DAT) mRNAs. Results The expressions of TH mRNA (1.22 ± 0. 19) and DAT mRNA (0. 62 ± 0. 11) in the point-through-point therapy group were significantly higher than (0. 65 ± 0. 17) and (0. 41 ± 0. 08) in the model group, respectively (all P<0. 05). As compared with the model group

  9. Dopamine agonists increase perseverative instrumental responses but do not restore habit formation in a rat model of Parkinsonism.

    Science.gov (United States)

    Faure, A; Leblanc-Veyrac, P; El Massioui, N

    2010-06-30

    Dopamine (DA) deafferentation of the dorsolateral striatum has been shown to prevent habit development, leaving instrumental behavior under action-outcome control that is persistently sensitive to modification of the motivational value of the reward. The present experiment further explored the basis of this dysfunction by examining the ability of intrastriatal DA agonist injections (D1 SKF 38393 or D2/D3 Quinpirole) during overtraining of a signaled instrumental task to restore habit formation in rats subjected to bilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopaminergic pathway. Overtraining was followed by a test of goal sensitivity by satiety-specific devaluation of the reward. The results confirmed the impaired shift in performance from action to habit in control lesioned rats. However, lesioned rats repeatedly injected with quinpirole D2/D3 agonist showed an increase in non-rewarded instrumental responses (intertrials periods) during overtraining, suggesting the development of perseverative behavior. Following the procedure of devaluation, quinpirole D2/D3 agonist treatment, and to a lesser extent SKF 38393 D1 agonist, caused the persistence of sensitivity to reward devaluation, indicating clear goal-directed behavior despite extended training. This absence of restoration of habit formation by DA agonist treatment is discussed in the light of DA agonist effects in Parkinson patients.

  10. The effects of constraint-induced movement therapy on expression of tyrosine hydroxylase and glial cell derived neurotrophic factor in Parkinson's disease model rats%强制性运动训练对帕金森病大鼠酪氨酸羟化酶及胶质细胞源性神经营养因子表达的影响

    Institute of Scientific and Technical Information of China (English)

    黄月; 张善锋; 任秀花; 张杰文

    2012-01-01

    Objective To explore the effects of constraint-induced movement therapy (CIMT) on the expression of tyrosine hydroxylase (TH) and glial cell derived neurotrophic factor (GDNF) in Parkinson's disease (PD) model rats. Methods PD models were established by microinjection of 6-hydroxydopamine (6-OHDA) solution into substantia nigra of rats' right cerebral hemisphere.Forty-two model rats were divided randomly into an exercise group and a control group 1 week after microinjection.The exercise group rats were forced to use their impaired limbs by placing their nonimpaired fore-limbs in casts.The control group rats were housed in the same environment without any special treatment.Two weeks after 6-OHDA infusion and exercise training,the behavioral changes of rats were examined after intraperitoneal injection apomorphine ( APO).The content of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) was measured by high performance liquid chromatography with electrochemistry ( HPLAEC) ; the expressions of TH and GDNF in striatum were detected by immunohistochemical methods and TH,GDNF mRNA were detected by reverse transcription-polymerase chain reaction (RT-PCR). Results After 2 weeks of training,the rotating laps of the rats in exercise group within 30 min after APO induction,reduced to a significantly greater extent when compared to the control group (P < 0.05).The content of DA and it's metabolites DOPAC in striatum homogenate was significantly higher in exercise group than that in the control group ( P < 0.05 ),and the expression levels,of TH and GDNF protein/ mRNA were also significantly higher in the exercise group than those in control group ( P < 0.05 ). Conclusions CIMT can improve the behavioral performance of PD rats,probably through promoting the expressions of TH and GDNF protein/mRNA in striatum,and increasing DA and it's metabolites DOPAC level.%目的 观察强制性运动训练对帕金森病(PD)模型大鼠酪氨酸羟化酶(TH)及胶质细胞源性神

  11. Effect of electroacupuncture on Nestin, PCNA and Tuj1 expression in neural stem cells of substantia nigra in the Parkinson's disease model rats%电针对帕金森病模型大鼠黑质神经干细胞巢蛋白、PCNA和β-微管蛋白表达的作用

    Institute of Scientific and Technical Information of China (English)

    倪进忠; 丁艳霞; 熊克仁

    2012-01-01

    目的:研究不同频率和疗程电针对帕金森病(PD)模型大鼠黑质致密部(SNc)神经干细胞(NSC)表达的影响.方法:SD大鼠随机分为16组,正常对照组,1、2、3周假手术组、模型组、1、2、3疗程美多巴组、低频电针组、高频电针组,采用右侧纹状体内注射6-羟基多巴胺(6-OHDA)制备PD模型,取合谷和太冲穴,分别给予低频(2 Hz)和高频(100 Hz)电针治疗.免疫组织化学观察黑质致密部的巢蛋白、PCNA和β-微管蛋白(Tuj1)表达.结果:PD模型大鼠黑质致密部的巢蛋白、PCNA和Tuj1表达增加,高频电针可增加其巢蛋白、PCNA和Tuj1表达,低频电针对其没有影响.结论:高频电针可增加黑质致密部自体NSC的增殖,并诱导其向神经元前体细胞分化.%Objective; To explore the expression changes of proteins related neural stem cells (NSC) in the substantia nigra pars compacta (SNc) in Parkinson's disease (PD) model rats treated with different frequency and course of electroacupuncture (EA). Methods; Ninty-six Sprague-Dawley rats were randomly divided into sixteen groups:a normal control group; 1-. 2- and 3- week sham-operated groups, a model group; 1-, 2- and 3- course of Madopar treatment groups, a low-frequency EA treatment group, and a high-frequency EA treatment group. The PD model was prepared by injection of 6-hydroxydo-pamine (6-OHDA) into the right striatum. "Hegu" and "Taichong" were given low-frequency (2 Hz) and high-frequency (100 Hz) EA treatment Immunohistochemistry was used to observe the Nestin, proliferating cell nuclear antigen (PCNA) and β-tubulin isotype-Ⅲ (Tujl) expression in SNc. Results-. The expression of Nestin, PCNA, Tujl increased in SNc of the PD model rats. The high-frequency EA improved its Nestin, PCNA and Tujl expression, while the low-frequency EA had no effect. Conclusion-. High-frequency EA can improve the autologous NSC proliferation of SNc and induce the differentiation into neuronal precursor cells.

  12. 头部电针透穴对帕金森病模型大鼠细胞凋亡的作用机制研究%Study on the mechanism of electroacupuncture scalp point penetration therapy in action on apoptosis in the Parkinson's disease rat model

    Institute of Scientific and Technical Information of China (English)

    王顺; 蒋花; 曲龙

    2009-01-01

    Objective To explore the mechanism of electroacupuncture scalp point penetration therapy in treatment of the Parkinson's disease (PD). Methods Forty Wistar rats were randomly divided into a normal group, a sham-operation group, a model group and an electroacupuncture (EA) group. 6-OHDA was injected into the left striatum to make lateralization PD rat model. Acupuncture at "Baihui" (GV 20)-through-"Taiyang" (EX-HN 5), once each day, 6 days constituting one course. Immunohistochemical method was used to observe the facio-density and the integral optical density of brain-derived neurotrophic factor (BDNF) in the left substantia nigra, and TUNEL method was used to observe the apoptotic amount, and high performance liquid chromatography was used to observe DA contents of the left striatum in each group. Results As compared with the model group, in the acupuncture group, the facio-density and the integral optical density in the left substantia nigra increased significantly (P<0. 05), the amount of apoptosis decreased significantly (P<0. 05), and the content of striatum DA increased significantly (P<0. 05). Conclusion EA scalp point-through-point therapy may enhance BDNF protein expression level in the substantia nigra to decrease the amount of apoptosis in the PD model rat,%目的:探讨头部电针透穴治疗帕金森病(PD)的作用机制.方法:将40只Wistar大鼠随机分为正常组、假手术组、模型组、针刺组,以6-羟基多巴胺(6-OHDA)左侧纹状体注射法制备偏侧PD大鼠模型,针刺组穴取"百会"透"太阳",每日1次,6日为一疗程.其他3组不予治疗,观察2个疗程.采用免疫组织化学方法观察各组左侧黑质神经营养因子(BDNF)面密度(阳性目标总面积与统计场总面积比值)、积分光密度,用高效液相色谱观察左侧纹状体多巴胺(DA)含量,以TUNEL法观察各组细胞凋亡数.结果:针刺组与模型组比较,左侧黑质BDNF面密度、积分光密度均显著增大(P<0.05);

  13. Penile autotransplantation in rats: An animal model

    Directory of Open Access Journals (Sweden)

    Raouf M Seyam

    2013-01-01

    Conclusions: Penile autotransplantation in rats is feasible and provides the basis for evaluation of the corpora cavernosa in an allotransplantation model. Long-term urethral continuity and dorsal neurovascular bundle survival in this model is difficult to establish.

  14. Human olfactory bulb neural stem cells mitigate movement disorders in a rat model of Parkinson's disease.

    Science.gov (United States)

    Marei, Hany E S; Lashen, Samah; Farag, Amany; Althani, Asmaa; Afifi, Nahla; A, Abd-Elmaksoud; Rezk, Shaymaa; Pallini, Roberto; Casalbore, Patrizia; Cenciarelli, Carlo

    2015-07-01

    Parkinson's disease (PD) is a neurological disorder characterized by the loss of midbrain dopaminergic (DA) neurons. Neural stem cells (NSCs) are multipotent stem cells that are capable of differentiating into different neuronal and glial elements. The production of DA neurons from NSCs could potentially alleviate behavioral deficits in Parkinsonian patients; timely intervention with NSCs might provide a therapeutic strategy for PD. We have isolated and generated highly enriched cultures of neural stem/progenitor cells from the human olfactory bulb (OB). If NSCs can be obtained from OB, it would alleviate ethical concerns associated with the use of embryonic tissue, and provide an easily accessible cell source that would preclude the need for invasive brain surgery. Following isolation and culture, olfactory bulb neural stem cells (OBNSCs) were genetically engineered to express hNGF and GFP. The hNFG-GFP-OBNSCs were transplanted into the striatum of 6-hydroxydopamin (6-OHDA) Parkinsonian rats. The grafted cells survived in the lesion environment for more than eight weeks after implantation with no tumor formation. The grafted cells differentiated in vivo into oligodendrocyte-like (25 ± 2.88%), neuron-like (52.63 ± 4.16%), and astrocyte -like (22.36 ± 1.56%) lineages, which we differentiated based on morphological and immunohistochemical criteria. Transplanted rats exhibited a significant partial correction in stepping and placing in non-pharmacological behavioral tests, pole and rotarod tests. Taken together, our data encourage further investigations of the possible use of OBNSCs as a promising cell-based therapeutic strategy for Parkinson's disease. © 2014 Wiley Periodicals, Inc.

  15. Role of putative neurotransmitters in the central gastric antisecretory effect of prostaglandin E2 in rats.

    OpenAIRE

    Puurunen, J.

    1985-01-01

    The role of putative neurotransmitters of the central nervous system in the central gastric antisecretory effect of prostaglandin E2 (PGE2) was investigated in pylorus-ligated rats. Pretreatment of the rats with an intracerebroventricular (i.c.v.) injection of 6-hydroxydopamine (6-OHDA) prevented the antisecretory effect of the i.c.v. administration of PGE2, whereas pretreatment with 5,6-dihydroxytryptamine (5,6-DHT) plus p-chlorophenylalanine (PCPA) had no effect. I.c.v.-administered phentol...

  16. Influence on behavior of rats with Parkinson's disease treated by bone mesenchymal stem cell modified by plasmid pIRESneo-EGFP-BDNF%转染pIRESneo-EGFP-BDNF的骨髓间充质干细胞侧脑室注射对帕金森大鼠行为学的影响

    Institute of Scientific and Technical Information of China (English)

    张平; 赵钢勇; 宋月平; 苏立凯

    2012-01-01

    [目的]观察转染pIRESneo- EGFP-BDNF的骨髓间充质干细胞(MSCs)侧脑室注射对帕金森病(PD)大鼠行为学的影响.[方法]将pEGFP(N1)-BDNF与pIRESneo进行双酶切后再连接,构建高拷贝质粒pIRESneo-EGFPBDNF,采用电穿孔法将其转染MSCs.采用6-羟多巴(6-OHDA)制备PD大鼠模型(36只),造模成功后将其随机分为3组,每组12只.B组为模型组:侧脑室注射生理盐水;C组:侧脑室注射MSCs;D组:侧脑室注射转染pIRESneoEGFP-BDNF的MSCs;A组(12只大鼠,为假手术组):以生理盐水代替6-OHDA后,侧脑室注射生理盐水.分别于侧脑室注射后2、4、8周腹腔注射阿扑吗啡(APO)诱导大鼠旋转,观察各组大鼠行为学变化.[结果]经双酶切鉴定,pIRESneo-EGFP-BDNF构建成功.侧脑室注射细胞干预PD大鼠模型后2、4、8周,大鼠旋转次数D组<C组<B组(P均<0.05);D组大鼠旋转次数明显减少,但仍较A组多.[结论]侧脑室注射转染plRESneo-EGFP-BDNF的MSCs能明显改善PD大鼠的行为能力.%Objective To observe influence on behavior of Parkinson's disease( PD) model treated by bone mesen-chymal stem cells ( MSCs) modified by plasmid pIRESneo-EGFP-BDNF. Methods pEGFP-BDNF and pIRESneo were double enzymed and then were reconstructed into pIRESneo-EGFP-BDNF which was transfected to MSCs with electroproa-lion. 36 rat models of PD were set up by 6-OHDA and divided into three groups randomly; group B( group model): inlrac-erebrovenlricular injection of saline; group C: intracerebroventricular injection of bone MSCs; group D: intracerebroventric-ular injection of bone MSCs modefied by pIRESneo-ECFP-BDNF. Group A (12 rats, sham opreation groups): saline instead of 6-OHDA, than intracerebroventricular injection of saline. The rotating behavior of rat models induced by Apomor-phine intraperitoneally which transplanting bone MSCs or MSCs modified by plasmid pIRESneo-EGFP-BDNF through cerebral lateral ventricle after 2, 4 and 8 weeks. Results Pbsmids p

  17. 6-羟多巴胺毁损的帕金森病模型大鼠脚桥核神经元放电频率和放电形式的变化%Increase of firing rate with changes in firing pattern of neurons of the pedunculopontine nucleus in 6-hydrodopamine lesioned rats

    Institute of Scientific and Technical Information of China (English)

    王勇; 张巧俊; 刘健; 冯洁; 褚玉霞; 高蕊; 刘娅萍

    2005-01-01

    Objective To explore the change in the firing rate and firing pattern of pedunculopontine nucleus (PPN)neurons in 6-hydrodopamine (6-OHDA) unilaterally lesiond rats. Methods Electrophysiological recordings of PPN neurons were done in normal rats and 6-OHDA lesiond rats with standard single unit glass microelectrode method in vivo. Results The firing rate of PPN neurons in normal rats and 6-OHDA lesiond rats were (9.0 ± 0.8 ) Hz [ (0.5-25.2) Hz, n = 56 ] and ( 16. 1 ± 1.6) Hz [ (1.2-49.7) Hz, n= 57), respectively. The firing rate of 6-OHDA lesioned rats was significantly increased when compared to control rats (P < 0. 001 ). Concerning the firing pattern, 68% (38/56) of the neurons recorded discharged regularly, 27% (15/56) exhibited an irregular pattern and 5% (3/56) discharged in bursts in normal rats. In 6-OHDA lesioned rats, 39% (22/57) discharged regularly, 47% (27/57) exhibited an irregular pattern and 14% (8/57) in bursts. The number of PPN neurons in 6-OHDA lesioned rats fired irregularly was significantly higher than in control rats ( P < 0.05). Conclusion The firing rate and the percentage of the irregularly firing neuron in PPN of 6-OHDA lesioned rats increased significantly, which may be contributed to the pathophysiological changes of Parkinson's disease.%目的观察6-羟多巴胺毁损的帕金森病(Parkinson's disease,PD)模型大鼠脚桥核(pedunculopontine nucleus,PPN)神经元放电频率和放电形式的变化.方法采用在体玻璃微电极细胞外记录法,记录正常对照组和PD模型组大鼠PPN神经元的电活动.结果对照组和PD组大鼠PPN神经元的放电频率分别为(9.0±0.8)Hz[(0.5-25.2)Hz,n=56]和(16.1±1.6)Hz[(1.2-49.7)Hz,n=57],PD组大鼠的放电频率显著高于对照组(P<0.001).在对照组大鼠脚桥核,68%(38/56)的神经元呈现规则放电,27%(15/56)呈现不规则放电,5%(3/56)为爆发式放电;在PD组大鼠脚桥核,具有规则、不规则和爆发式放电的神经元比例分别为39

  18. Behavioral effects of lesions in the A10 dopaminergic area of the rat.

    Science.gov (United States)

    Galey, D; Simon, H; Le Moal, M

    1977-03-18

    Experiments have been carried out with 150 rats in order to study some psychophysiological functions of the mesencephalocortico limbic dopaminergic A10 group. Lesions in the A10 area were made by using 6-hydroxydopamine (6-OHDA) local injections; 2 small volumes of injections were used at the same concentration (2 mug/1 mul or 1 mug/0.5 mul). In a first experiment the effects of these two injections were tested on locomotor activity measured in a circular corridor, 10 and 30 days after surgery. Injections provoked hyperactivity, mainly during nocturnal basal activity periods, but not during initial exploratory activity periods. The larger the injection, the more important the hyperactivity was. The larger injections induced important food spillage evidence through the wire floor of the home cage and perturbation in a passive avoidance learning. There was no change in body weight or in amount of ingested food. In a second experiment, the effects of local injection of 6-OHDA in the other CA structures or bundles situated in or near the ventral tegmental area were tested. Injections in the substantia nigra compacta, in the noradrenergic ventral bundle, in the dorsal periventricular system-tegmental radiations did not provoke locomotor hyperactivity. In a third experiment, a possible role of the median raphe (MR) nucleus in the A10-lesion induced hyperactivity was tested: first, radiofrequency MR lesions were made and no durable significant hyperactivity was recorded; secondly, 6-OHDA (1 mug/0.5 mul) was injected into the A10 area and activity was measured 10 days later: these injections provoked significant hyperactivity during the nocturnal basal and the diurnal basal activity periods. It might be concluded that neither the neighboring CA fibers nor the MR were directly involved in the ventral tegmental -- 6-OHDA lesions syndrome. Anatomical controls by using the Fink-Heimer silver impregnating method have demonstrated, first, that the 6-OHDA injections did not

  19. The NLRP3 Inflammasome is Involved in the Pathogenesis of Parkinson's Disease in Rats.

    Science.gov (United States)

    Mao, Zhijuan; Liu, Chanchan; Ji, Suqiong; Yang, Qingmei; Ye, Hongxiang; Han, Haiyan; Xue, Zheng

    2017-02-28

    The etiology and pathogenesis of Parkinson's disease (PD) are complicated and have not been fully elucidated, but an important association has been identified between inflammation and PD. In this study, we investigated the role of the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing (NLRP) 3 inflammasome, consisting of NLRP3, caspase-1 and cytokines of the IL-1 family, in lipopolysaccharide (LPS)-induced and 6-hydroxydopamine (6-OHDA)-induced PD rats. Microinjection of different doses of caspase-1 inhibitor (Ac-YVAD-CMK, 300 or 1200 ng/rat) was performed for seven consecutive days. Then, rotational behavior, the number of dopamine (DA) neurons in the substantia nigra pars compacta (SNc), and the mRNA and protein expression levels of NLRP3 inflammasome components were measured 14 days after the microinjection setup was established. Results showed that high mRNA and protein expression levels of NLRP3 inflammasome components were observed in the injected side of the LPS- and 6-OHDA-induced PD rats; Ac-YVAD-CMK inhibited the mRNA and protein expression of NLRP3 inflammasome components in both LPS- and 6-OHDA-induced PD rats. Moreover, the number of rotations was significantly decreased, and the number of DA neurons in the SNc improved. Our data indicate that the NLRP3 inflammasome participates in the pathogenesis of PD and that inhibiting the downstream pathway of the NLRP3/caspase-1/IL-1β axis can alleviate the occurrence of PD symptoms, providing a new basis for the prevention and treatment of PD.

  20. Effect of Buspirone, Fluoxetine and 8-OH-DPAT on Striatal Expression of Bax, Caspase-3 and Bcl-2 Proteins in 6-Hydroxydopamine-Induced Hemi-Parkinsonian Rats.

    Science.gov (United States)

    Sharifi, Hamdollah; Mohajjel Nayebi, Alireza; Farajnia, Safar; Haddadi, Rasool

    2015-11-01

    The exact pathogenesis of sporadic parkinson's disease (PD) is still unclear. Numerous evidences suggest involvement of apoptosis in the death of dopaminergic neurons. In this study we investigated the effect of sub-chronic administration of buspirone, fluoxetine and 8-hydroxy-2-[di-n-propylamino]tetralin (8-OH-DPAT) in 6-hydroxydopamine (6-OHDA)-lesioned rats and assayed striatal concentrations of apoptotic (Bax, Caspase3) and anti-apoptotic (Bcl-2) proteins. 6-OHDA (8μg/2μl/rat) was injected unilaterally into the central region of the substantia nigra pars copmacta (SNc) of male Wistar rats and then, after 21 days lesioned rats were treated with intraperitonel (i.p) 1 mg/kg injections of buspirone, fluoxetine and 8-OH-DPAT for 10 consecutive days. Striatum of rats was removed at tenth day of drugs administration and were analyzed by western blotting method to measure Bax, caspase3 and Bcl-2 expression. The results showed that the expression of Bax and caspase3 proteins was increased three weeks after 6-OHDA injection while they were decreased significantly in parkinsonian rats which were treated by buspirone, fluoxetine and 8-OH-DPAT. Bcl-2 was decreased and increased in parkinsonian rats and parkinsonian rats treated with buspirone, fluoxetine and 8-OH-DPAT, respectively. Our study indicates that sub-chronic administration of serotonergic drugs such as buspirone, fluoxetine and 8-OH-DPAT restores striatal concentration of apoptotic and anti-apoptotic factors to the basal levels of normal non-lesioned rats. We suggest that these drugs can be used as a potential adjunctive therapy in PD through attenuating neuronal apoptotic process.

  1. Adenoviral vector-mediated GDNF gene therapy in a rodent lesion model of late stage Parkinson's disease.

    Science.gov (United States)

    Lapchak, P A; Araujo, D M; Hilt, D C; Sheng, J; Jiao, S

    1997-11-28

    A recombinant adenoviral vector encoding the human glial cell line-derived neurotrophic factor (GDNF) gene (Ad-GDNF) was used to express the neurotrophic factor GDNF in the unilaterally 6-hydroxydopamine (6-OHDA) denervated substantia nigra (SN) of adult rats ten weeks following the 6-OHDA injection. 6-OHDA lesions significantly increased apomorphine-induced (contralateral) rotations and reduced striatal and nigral dopamine (DA) levels by 99% and 70%, respectively. Ad-GDNF significantly (P weight gain which persisted for approximately two weeks following the injection. Consistent with the behavioral changes, levels of DA and the metabolite dihydroxyphenylacetic acid (DOPAC) were elevated (by 98% and 65%, respectively) in the SN, but not the striatum of Ad-GDNF-injected rats. Overall, a single Ad-GDNF injection had significant effects for 2-3 weeks following administration. These results suggest that virally delivered GDNF promotes the recovery of nigral dopaminergic tone (i.e.: increased DA and DOPAC levels) and improves behavioral performance (i.e.: decreased rotations, increased locomotion) in rodents with extensive nigrostriatal dopaminergic denervation. Moreover, our results suggest that viral delivery of trophic factors may be used eventually to treat neurodegenerative diseases such as Parkinson's disease.

  2. Experimental model of anal fistula in rats

    OpenAIRE

    Arakaki, Mariana Sousa; Santos,Carlos Henrique Marques dos; Falcão, Gustavo Ribeiro; Cassino,Pedro Carvalho; Nakamura, Ricardo Kenithi; Gomes,Nathália Favero; Santos,Ricardo Gasparin Coutinho dos

    2013-01-01

    INTRODUCTION: the management of anal fistula remains debatable. The lack of a standard treatment free of complications stimulates the development of new options. OBJECTIVE: to develop an experimental model of anal fistula in rats. METHODS: to surgically create an anal fistula in 10 rats with Seton introduced through the anal sphincter musculature. The animals were euthanized for histological fistula tract assessment. RESULTS: all ten specimens histologically assessed had a lumen and surroundi...

  3. Modeling Alzheimer's disease in transgenic rats.

    Science.gov (United States)

    Do Carmo, Sonia; Cuello, A Claudio

    2013-10-25

    Alzheimer's disease (AD) is the most common form of dementia. At the diagnostic stage, the AD brain is characterized by the accumulation of extracellular amyloid plaques, intracellular neurofibrillary tangles and neuronal loss. Despite the large variety of therapeutic approaches, this condition remains incurable, since at the time of clinical diagnosis, the brain has already suffered irreversible and extensive damage. In recent years, it has become evident that AD starts decades prior to its clinical presentation. In this regard, transgenic animal models can shed much light on the mechanisms underlying this "pre-clinical" stage, enabling the identification and validation of new therapeutic targets. This paper summarizes the formidable efforts to create models mimicking the various aspects of AD pathology in the rat. Transgenic rat models offer distinctive advantages over mice. Rats are physiologically, genetically and morphologically closer to humans. More importantly, the rat has a well-characterized, rich behavioral display. Consequently, rat models of AD should allow a more sophisticated and accurate assessment of the impact of pathology and novel therapeutics on cognitive outcomes.

  4. Progesterone Exerts a Neuromodulatory Effect on Turning Behavior of Hemiparkinsonian Male Rats: Expression of 3α-Hydroxysteroid Oxidoreductase and Allopregnanolone as Suggestive of GABAA Receptors Involvement

    Directory of Open Access Journals (Sweden)

    Roberto Yunes

    2015-01-01

    Full Text Available There is a growing amount of evidence for a neuroprotective role of progesterone and its neuroactive metabolite, allopregnanolone, in animal models of neurodegenerative diseases. By using a model of hemiparkinsonism in male rats, injection of the neurotoxic 6-OHDA in left striatum, we studied progesterone’s effects on rotational behavior induced by amphetamine or apomorphine. Also, in order to find potential explanatory mechanisms, we studied expression and activity of nigrostriatal 3α-hydroxysteroid oxidoreductase, the enzyme that catalyzes progesterone to its active metabolite allopregnanolone. Coherently, we tested allopregnanolone for a possible neuromodulatory effect on rotational behavior. Also, since allopregnanolone is known as a GABAA modulator, we finally examined the action of GABAA antagonist bicuculline. We found that progesterone, in addition to an apparent neuroprotective effect, also increased ipsilateral expression and activity of 3α-hydroxysteroid oxidoreductase. It was interesting to note that ipsilateral administration of allopregnanolone reversed a clear sign of motor neurodegeneration, that is, contralateral rotational behavior. A possible GABAA involvement modulated by allopregnanolone was shown by the blocking effect of bicuculline. Our results suggest that early administration of progesterone possibly activates genomic mechanisms that promote neuroprotection subchronically. This, in turn, could be partially mediated by fast, nongenomic, actions of allopregnanolone acting as an acute modulator of GABAergic transmission.

  5. Creation of Reversible Cholestatic Rat Model

    Science.gov (United States)

    Subhas, Gokulakkrishna

    2011-01-01

    Cholestasis is a clinical condition commonly encountered by both surgeons and gastroenterologists. Cholestasis can cause various physiological changes and affect the nutritional status and surgical outcomes. Study of the pathophysiological changes occurring in the liver and other organs is of importance. Various studies have been done in cholestatic rat models. We used a reversible cholestatic rat model in our recent study looking at the role of methylprednisolone in the ischemia reperfusion injury. Various techniques for creation of a reversible cholestatic model have been described. Creation of a reversible cholestatic rat model can be challenging in view of the smaller size and unique hepatopancreatobiliary anatomy in rats. This video article demonstrates the creation of a reversible cholestatic model. This model can be used in various studies, such as looking at the changes in nutritional, physiological, pathological, histological and immunological changes in the gastrointestinal tract. This model can also be used to see the effects of cholestasis and various therapeutic interventions on major hepatic surgeries. PMID:21633335

  6. Organotypic Cultures as a Model of Parkinson´s Disease. A Twist to an Old Model

    Directory of Open Access Journals (Sweden)

    Katja Stahl

    2009-01-01

    Full Text Available Organotypic cultures from the ventral mesencephalon (VM are widely used to model Parkinson's disease (PD. In this method, neurotoxic compounds have traditionally been applied to the media to induce a uniform dopaminergic (DAergic cell death in the tissue slices, regardless of the variation existing among slices. This study demonstrates a refinement of the toxic induction technique. We show that unilateral application of 6-hydroxydopamine (6-OHDA at the tissue surface by means of a microelectrode causes a precisely localized cell death that closely resembles an in vivo stereotactic model. This technique introduces an internal control that accounts for variation between slices and enables a precise quantification of the cell loss due to the toxin in use. We characterized organotypic VM cultures in terms of effects of 6-OHDA toxicity and number of DAergic neurons as judged by immunofluorescence and Western blots. Our findings illustrate that this new application technique greatly improves the representativeness of organotypic cultures as a model for PD.We characterized organotypic VM cultures in terms of effects of 6-OHDA toxicity and number of DAergic neurons as judged by immunofluorescence and Western blots. Our findings illustrate that this new application technique greatly improves the representativeness of organotypic cultures as a model for PD.

  7. A rat model for hepatitis E virus

    Science.gov (United States)

    Mishra, Niraj; Verbeken, Erik; Ramaekers, Kaat; Dallmeier, Kai

    2016-01-01

    ABSTRACT Hepatitis E virus (HEV) is one of the prime causes of acute viral hepatitis, and chronic hepatitis E is increasingly recognized as an important problem in the transplant setting. Nevertheless, the fundamental understanding of the biology of HEV replication is limited and there are few therapeutic options. The development of such therapies is partially hindered by the lack of a robust and convenient animal model. We propose the infection of athymic nude rats with the rat HEV strain LA-B350 as such a model. A cDNA clone, pLA-B350, was constructed and the infectivity of its capped RNA transcripts was confirmed in vitro and in vivo. Furthermore, a subgenomic replicon, pLA-B350/luc, was constructed and validated for in vitro antiviral studies. Interestingly, rat HEV proved to be less sensitive to the antiviral activity of α-interferon, ribavirin and mycophenolic acid than genotype 3 HEV (a strain that infects humans). As a proof-of-concept, part of the C-terminal polymerase sequence of pLA-B350/luc was swapped with its genotype 3 HEV counterpart: the resulting chimeric replicon replicated with comparable efficiency as the wild-type construct, confirming that LA-B350 strain is amenable to humanization (replacement of certain sequences or motifs by their counterparts from human HEV strains). Finally, ribavirin effectively inhibited LA-B350 replication in athymic nude rats, confirming the suitability of the rat model for antiviral studies. PMID:27483350

  8. A rat model for hepatitis E virus

    Directory of Open Access Journals (Sweden)

    Yannick Debing

    2016-10-01

    Full Text Available Hepatitis E virus (HEV is one of the prime causes of acute viral hepatitis, and chronic hepatitis E is increasingly recognized as an important problem in the transplant setting. Nevertheless, the fundamental understanding of the biology of HEV replication is limited and there are few therapeutic options. The development of such therapies is partially hindered by the lack of a robust and convenient animal model. We propose the infection of athymic nude rats with the rat HEV strain LA-B350 as such a model. A cDNA clone, pLA-B350, was constructed and the infectivity of its capped RNA transcripts was confirmed in vitro and in vivo. Furthermore, a subgenomic replicon, pLA-B350/luc, was constructed and validated for in vitro antiviral studies. Interestingly, rat HEV proved to be less sensitive to the antiviral activity of α-interferon, ribavirin and mycophenolic acid than genotype 3 HEV (a strain that infects humans. As a proof-of-concept, part of the C-terminal polymerase sequence of pLA-B350/luc was swapped with its genotype 3 HEV counterpart: the resulting chimeric replicon replicated with comparable efficiency as the wild-type construct, confirming that LA-B350 strain is amenable to humanization (replacement of certain sequences or motifs by their counterparts from human HEV strains. Finally, ribavirin effectively inhibited LA-B350 replication in athymic nude rats, confirming the suitability of the rat model for antiviral studies.

  9. Acetyl-L-Carnitine via Upegulating Dopamine D1 Receptor and Attenuating Microglial Activation Prevents Neuronal Loss and Improves Memory Functions in Parkinsonian Rats.

    Science.gov (United States)

    Singh, Sonu; Mishra, Akanksha; Srivastava, Neha; Shukla, Rakesh; Shukla, Shubha

    2016-12-14

    Parkinson's disease is accompanied by nonmotor symptoms including cognitive impairment, which precede the onset of motor symptoms in patients and are regulated by dopamine (DA) receptors and the mesocorticolimbic pathway. The relative contribution of DA receptors and astrocytic glutamate transporter (GLT-1) in cognitive functions is largely unexplored. Similarly, whether microglia-derived increased immune response affects cognitive functions and neuronal survival is not yet understood. We have investigated the effect of acetyl-L-carnitine (ALCAR) on cognitive functions and its possible underlying mechanism of action in 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian rats. ALCAR treatment in 6-OHDA-lesioned rats improved memory functions as confirmed by decreased latency time and path length in the Morris water maze test. ALCAR further enhanced D1 receptor levels without altering D2 receptor levels in the hippocampus and prefrontal cortex (PFC) regions, suggesting that the D1 receptor is preferentially involved in the regulation of cognitive functions. ALCAR attenuated microglial activation and release of inflammatory mediators through balancing proinflammatory and anti-inflammatory cytokines, which subsequently enhanced the survival of mature neurons in the CA1, CA3, and PFC regions and improved cognitive functions in hemiparkinsonian rats. ALCAR treatment also improved glutathione (GSH) content, while decreasing oxidative stress indices, inducible nitrogen oxide synthase (iNOS) levels, and astrogliosis resulting in the upregulation of GLT-1 levels. Additionally, ALCAR prevented the loss of dopaminergic (DAergic) neurons in ventral tagmental area (VTA)/substantia nigra pars compacta (SNpc) regions of 6-OHDA-lesioned rats, thus maintaining the integrity of the nigrostriatal pathway. Together, these results demonstrate that ALCAR treatment in hemiparkinsonian rats ameliorates neurodegeneration and cognitive deficits, hence suggesting its therapeutic potential in

  10. Effect of electroacupuncture on nNOS ex-pression at hippocampal CA1 in the model rat of Parkinson′s disease%电针对帕金森病模型大鼠海马CA1区nNOS表达的影响

    Institute of Scientific and Technical Information of China (English)

    倪进忠; 熊克仁

    2013-01-01

      Objective:To observe the variation of neuronal nitric oxidesynthase (nNOS) expression at the hippocampal CA1 region in model ratswith Parkinson′s disease (PD) by electroacupuncture (EA) stimulationat different frequency.Methods:Twenty four Sprague-Dawley rats were equallyrandomized into groups of normal controls,models,low-frequencyEA and high-frequency EA treatment.PD models of rats were developedby injection of 6-hydroxyl-dopamine (6-OHDA) into the right striatum,and undergone electrotherapy with EA at low-frequency (2 Hz) and highfrequency(100 Hz) via acupuncture point of Hegu or Taichong.immunohistochemicalmethod was used to observe the changes of nNOS expressionat hippocampal CA1.Results:Increased nNOS expression was found athippocampal CA1 region in PD model rats as compared with the controls.High-frequency EA resulted in decrease of nNOS expression,yet the stimulationby low-frequency EA produced no effect.Conclusion:Effectivestimulation via high-frequency EA for PD may be associated with one ofthe potential mechanisms of decreased nNOS expression at hippocampalCA1 region.%  目的:观察不同频率电针对帕金森病(PD)模型大鼠海马CA1区神经元型一氧化氮合酶(nNOS)表达的影响。方法:将24只SD大鼠随机分为4组:正常对照组、模型组、PD模型低频电针组和高频电针组。采用右侧纹状体内注射6-羟基多巴胺(6-OHDA)制备PD模型,取合谷和太冲穴,分别给予低频(2 Hz)和高频(100 Hz)电针治疗。免疫组织化学方法观察海马CA1区nNOS表达。结果:与正常对照组相比,PD模型大鼠海马CA1区nNOS表达增加,高频电针可降低其nNOS表达,低频电针对其没有影响。结论:高频电针治疗PD的机制之一可能是通过降低PD模型大鼠海马 CA1区nNOS表达。

  11. Long-term survival of encapsulated GDNF secreting cells implanted within the striatum of parkinsonized rats.

    Science.gov (United States)

    Grandoso, Laura; Ponce, Sara; Manuel, Ivan; Arrúe, Aurora; Ruiz-Ortega, Jose A; Ulibarri, Isabel; Orive, Gorka; Hernández, Rosa M; Rodríguez, Alicia; Rodríguez-Puertas, Rafael; Zumárraga, Mercedes; Linazasoro, Gurutz; Pedraz, Jose Luis; Ugedo, Luisa

    2007-10-01

    Several findings suggest that glial cell line-derived neurotrophic factor (GDNF) may be a useful tool to treat parkinsonism by acting as a neuroprotective and neurotrophic factor for dopaminergic neurotransmission systems. In the present study, we implanted alginate-poly-L-lysine-alginate microcapsules containing immobilized Fischer rat 3T3 fibroblasts transfected to produce GDNF in vitro into the striatum of 6-hydroxydopamine (6-OHDA) lesioned rats. Microencapsulated GDNF secreting cells were stable for at least 3 weeks in vitro. Intrastriatal implantation of microencapsulated GDNF secreting cells into 6-OHDA lesioned rats resulted in a decrease in apomorphine-induced rotations by 84%, 64%, 84%, 60% and 52% (2, 5, 8, 16 and 24 weeks, respectively) with respect to the value before implantation and with respect to the value obtained from the empty microcapsule implanted-group at each time point. Six months after transplantation, immunohistochemical detection of GDNF revealed strong immunoreactivity in the striatal tissue surrounding the microcapsules in the absence of tissue damage due to microcapsule implantation. No changes in the levels of dopamine and its metabolites or of tyrosine hydroxylase immunoreactivity were detected in the striatum. In summary, the implantation of microencapsulated GDNF secreting cells allows the delivery of this molecule into the rat striatum for at least 6 months and results in substantial behavioral improvement.

  12. Creation of Reversible Cholestatic Rat Model

    OpenAIRE

    2011-01-01

    Cholestasis is a clinical condition commonly encountered by both surgeons and gastroenterologists. Cholestasis can cause various physiological changes and affect the nutritional status and surgical outcomes. Study of the pathophysiological changes occurring in the liver and other organs is of importance. Various studies have been done in cholestatic rat models.

  13. Digital replantation teaching model in rats.

    Science.gov (United States)

    Ad-El, D D; Harper, A; Hoffman, L A

    2000-01-01

    Replant surgery is a complex procedure that requires advanced microsurgical skills and is usually performed as an emergency operation, lasting many hours. For these reasons, teaching replantation is difficult. Although teaching models exist, they are often too general or complicated for routine use and do not simulate the stages and the pitfalls of human replant surgery. We have designed a model that is simple and imitates human replant surgery. After reviewing the rat anatomy, students dissect and replant a rat hind limb that has been sharply amputated by the instructor. They follow the same principles of "real" surgery like debridement, minimizing ischemia time, and stable fixation before anatomosis of vessels. After marking the structures, bony fixation followed by vessel and nerve anastomosis are performed. Muscle is reattached to the skin and limb vascularity evaluated. After we designed this model, plastic surgery residents performed the technique on 10 rats. An 80% limb viability rate was achieved. This model is simple to perform, simulates all the relevant structures and pitfalls of human surgery, and the rats are relatively cheap and can be used for other parallel projects.

  14. Pharmacologically controlled, discontinuous GDNF gene therapy restores motor function in a rat model of Parkinson's disease.

    Science.gov (United States)

    Tereshchenko, Julia; Maddalena, Andrea; Bähr, Mathias; Kügler, Sebastian

    2014-05-01

    Neurotrophic factors have raised hopes to be able to cure symptoms and to prevent progressive neurodegeneration in devastating neurological diseases. Gene therapy by means of viral vectors can overcome the hurdle of targeted delivery, but its current configuration is irreversible and thus much less controllable than that of classical pharmacotherapies. We thus aimed at developing a strategy allowing for both curative and controllable neurotrophic factor expression. Therefore, the short-term, intermittent and reversible expression of a neutrophic factor was evaluated for therapeutic efficacy in a slowly progressive animal model of Parkinson's disease (PD). We demonstrate that short-term induced expression of glial cell line derived neurotrophic factor (GDNF) is sufficient to provide i) substantial protection of nigral dopaminergic neurons from degeneration and ii) restoration of dopamine supply and motor behaviour in the partial striatal 6-OHDA model PD. These neurorestorative effects of GDNF lasted several weeks beyond the time of its expression. Later on, therapeutic efficacy ceased, but was restored by a second short induction of GDNF expression, demonstrating that monthly application of the inducing drug mifepristone was sufficient to maintain neuroprotective and neurorestorative GDNF levels. These findings suggest that forthcoming gene therapies for PD or other neurodegenerative disorders can be designed in a way that low frequency application of an approved drug can provide controllable and therapeutically efficient levels of GDNF or other neurotrophic factors. Neurotrophic factor expression can be withdrawn in case of off-target effects or sufficient clinical benefit, a feature that may eventually increase the acceptance of gene therapy for less advanced patients, which may profit better from such approaches.

  15. Experimental model to induce obesity in rats

    OpenAIRE

    von Diemen,Vinicius; Trindade, Eduardo Neubarth; Trindade, Manoel Roberto Maciel

    2006-01-01

    The etiology of obesity is multifactorial and is becoming a problem of public health, due to its increased prevalence and the consequent repercussion of its comorbidities on the health of the population. The great similarity and homology between the genomes of rodents and humans make these animal models a major tool to study conditions affecting humans, which can be simulated in rats. Obesity can be induced in animals by neuroendocrine, dietary or genetic changes. The most widely used models ...

  16. IMPACTS OF PENETRATION THERAPY WITH HEAD ELECTRICAL ACUPUNCTURE ON PROLIFERATION OF NEURAL STEM CELLS IN SUBSTANTIA NIGRA OF RAT MODEL OF PARKINSON'S DISEASE%头部电针透穴疗法对帕金森病模型大鼠黑质神经干细胞增殖的影响

    Institute of Scientific and Technical Information of China (English)

    王顺; 戚秀杰; 韩迪

    2008-01-01

    Objective To probe into the function mechanism of penetration therapy with head electrical acupuncture on Parkinson's disease.Methods Microinjection of 6-hydroxydopamin(6-OHDA)on the left corpus striatum was adopted to prepare rotation model of Parkinson's disease in rat.Penetration therapy with head electrical acupuncture was administered in treatment.Normal group,sham-operation group,model group and penetration therapy group were set up.①Immunohistochemical(IHC)method was used to test the morphology and count of positive cell of tyrosine hydroxylase(TH).②RT-PCR technology was used to detect the expression of nestin mRNA of neural stem cell(NSC).Results ①Compared with model group,in penetration therapy group,the expressions of TH-positive neurons in immune response were increased in areal densitv(AD),numerical density(ND)and integrating optic density(P<0.05).②Compared with model group,in penetration therapy group,the expression of nestin mRNA was increased(P<0.05).Conclusion Penetration therapy with head electrical acupuncture promotes the proliferation of endogenous neural stem cells in substantia nigra of rat model of Parkinson's disease.%目的:探讨头部电针透穴疗法治疗帕金森病的作用机制.方法:以6-羟基多巴胺左侧纹状体微量注射法制备偏侧帕金森病大鼠旋转模型,采用头部电针透穴疗法进行治疗,设立正常组、假手术组、模型组和透针组:①以免疫组织化学方法检测酪氨酸羟化酶阳性细胞的形态、数量;②以RT-PCR技术检测神经干细胞巢蛋白mRNA的表达.结果:①透针组与模型组比较络氨酸羟化酶免疫反应阳性神经元在面密度、数密度及积分光密度方面表达增加(P<0.05);②透针组与模型组比较巢蛋白mRNA表达增加(P<0.05).结论:头部电针透穴疗法能促进帕金森病模型大鼠黑质内源性神经干细胞的增殖.

  17. Gastrointestinal dysfunction and dopaminergic, cholinergic neurotransmitte changes of myenteric plexus in a rodent model of Parkinson' s disease%帕金森病大鼠胃肠功能障碍和肌间神经丛多巴胺能、胆碱能神经递质的变化

    Institute of Scientific and Technical Information of China (English)

    朱红灿; 赵静; 段东晓; 罗常月; 李倩倩; 张华; 任秀花; 臧卫东

    2011-01-01

    Objective To observe the gastrointestinal dysfunction and the changes of dopaminergic and cholinergic neurons in the myenteric plexuses of Sprague-Dawley (SD) rats model with parkinson' s disease (PD). Methods A rat model of PD was induced by 6-hydroxydopamine (6-OHDA). The one-h fecal output, stool water content and residual solid food in the stomach at 2 h after feeding were measured.Contractile activity of isolated antrum and colon smooth muscle were recorded. Changes in tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT) in the gastrointestinal myenteric plexus were studied by immunohistochemistry. Changes in TH and ChAT mRNA levels in the gastric antrum and colon tissue were determined by reverse transcription-polymerase chain reaction ( RT-PCR). Results In the 6-OHDA group, the wet weight, dry weight and water content of the feces within 1 h were (1. 047 ± 0. 124) g,(0. 812 ±0.093) g, (22.442 ±1. 180)% respectively, which were lower than in the control group (P<0.01); The percentage of residual solid food was (72. 316 ±3. 834)% , that was higher than in the control group (P <0. 01); The contractile amplitude of gastric antrum and colon smooth muscle strips was (0. 824 ±0. 152) g and (1. 541 ±0. 103) g respectively, that were lower than in the control group (P <0.01);The average integrated absorbance values of TH-positive areas in the myenteric plexus of gastric antrum and colon tissue were 147. 74 ± 13. 92 and 150. 45 ± 10. 09 respectively, that were higher than in the control group (P <0. 01); There was no significant difference in ChAT immunoreactivity between 6-OHDA group (109. 36 ± 3. 37 and 104. 73 ± 5. 93) and control group ( P > 0. 05); The mRNA expression levels of TH in the gastric antrum and colon tissue were 0. 662 ±0. 011 and 0. 585 ±0.012 respectively, that were lower than in the control group (P < 0. 01). There was no significant difference in ChAT mRNA expression levels between 6-OHDA group (1.157 ± 0. 037

  18. AAV.shRNA-mediated downregulation of ROCK2 attenuates degeneration of dopaminergic neurons in toxin-induced models of Parkinson's disease in vitro and in vivo.

    Science.gov (United States)

    Saal, Kim-Ann; Koch, Jan C; Tatenhorst, Lars; Szegő, Eva M; Ribas, Vinicius Toledo; Michel, Uwe; Bähr, Mathias; Tönges, Lars; Lingor, Paul

    2015-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder with prominent neuronal cell death in the substantia nigra (SN) and other parts of the brain. Previous studies in models of traumatic and neurodegenerative CNS disease showed that pharmacological inhibition of Rho-associated kinase (ROCK), a molecule involved in inhibitory signaling in the CNS, by small-molecule inhibitors improves neuronal survival and increases regeneration. Most small-molecule inhibitors, however, offer only limited target specificity and also inhibit other kinases, including both ROCK isoforms. To establish the role of the predominantly brain-expressed ROCK2 isoform in models of regeneration and PD, we used adeno-associated viral vectors (AAV) to specifically knockdown ROCK2 in neurons. Rat primary midbrain neurons (PMN) were transduced with AAV expressing short-hairpin-RNA (shRNA) against ROCK2 and LIM-domain kinase 1 (LIMK1), one of the downstream targets of ROCK2. While knock-down of ROCK2 and LIMK1 both enhanced neurite regeneration in a traumatic scratch lesion model, only ROCK2-shRNA protected PMN against 1-methyl-4-phenylpyridinium (MPP+) toxicity. Moreover, AAV.ROCK2-shRNA increased levels of the pro-survival markers Bcl-2 and phospho-Erk1. In vivo, AAV.ROCK2-shRNA vectors were injected into the ipsilateral SN and a unilateral 6-OHDA striatal lesion was performed. After four weeks, behavioral, immunohistochemical and biochemical alterations were investigated. Downregulation of ROCK2 protected dopaminergic neurons in the SN from 6-OHDA-induced degeneration and resulted in significantly increased TH-positive neuron numbers. This effect, however, was confined to nigral neuronal somata as striatal terminal density, dopamine and metabolite levels were not significantly preserved. Interestingly, motor behavior was improved in the ROCK2-shRNA treated animals compared to control after four weeks. Our studies thus confirm ROCK2 as a promising therapeutic target in models of PD and

  19. A model of subarachnoid hemorrhage in rats

    Institute of Scientific and Technical Information of China (English)

    Liao-liaoLI; Xiao-liangWANG

    2004-01-01

    AIM: To build a simple and repeatable animal model of subarachnoid hemorrhage (SAH). METHODS: SAH was introduced by passing a nylon thread up through the right internal carotid artery and piercing a hone in the right anterior cerebral artery. At 12 and 24 h, the rats were evaluated with rotarod test and the behavior scale (5-point scale). RESULTS: The ratswere trained through rotarod test and then randomly divided into

  20. Rat Model of Parkes Weber Syndrome.

    Directory of Open Access Journals (Sweden)

    Krzysztof Bojakowski

    Full Text Available The Parkes Weber syndrome is a congenital vascular malformation, characterized by varicose veins, arterio-venous fistulas and overgrown limbs. No broadly accepted animal model of Parkes Weber syndrome has been described. We created side-to-side arterio-venous fistula between common femoral vessels with proximal non-absorbable ligature on common femoral vein limiting the enlargement of the vein diameter in Wistar rats. Contralateral limb was sham operated. Invasive blood pressure measurements in both iliac and inferior cava veins were performed in rats 30 days after fistula creation. Tight circumference and femoral bone length were measured. Histopathology and morphology of soleus muscle, extensor digitorum longus muscle, and the common femoral vessel were analyzed. 30 days following arterio-venous fistula creation, a statistically significant elevation of blood pressure in common iliac vein and limb overgrowth was observed. Limb enlargement was caused by muscle overgrowth, varicose veins formation and bone elongation. Arterio-venous fistula with proximal outflow limitation led to significant increase of femoral vein circumference and venous wall thickness. Our study indicates that the described rat model mimics major clinical features characteristic for the human Parkes Weber syndrome: presence of arterio-venous fistula, venous hypertension and dilatation, varicose veins formation, and the limb hypertrophy. We reveal that limb overgrowth is caused by bone elongation, muscle hypertrophy, and venous dilatation. The newly established model will permit detailed studies on the mechanisms underlying the disease and on the efficacy of novel therapeutic strategies for the Parkes Weber syndrome treatment.

  1. [Effect of astaxanthin on preeclampsia rat model].

    Science.gov (United States)

    Xuan Rong-rong; Gao Xin; Wu, Wei; Chen, Hai-min

    2014-10-01

    The effect of astaxanthin on N(Ω)-nitro-L-arginine methyl ester (L-NAME) induced preeclampsia disease rats was investigated. Thirty pregnant Sprague-Dawley rats were randomly divided into three groups (n = 10): blank group, L-NAME group and astaxanthin group. From day 5 to 20, astaxanthin group rats were treated with astaxanthin (25 mg x kg(-1) x d(-1) x bw(-1)) from pregnancy (day 5). To establish the preeclamptic rat model, L-NAME group and astaxanthin group rats were injected with L-NAME (125 mg x kg(-1) x d(-1) x bw(-1)) from days 10-20 of pregnancy. The blood pressure and urine protein were recorded. Serum of each group was collected and malondialdehyde (MDA), superoxide dismutase (SOD) and nitric oxide synthase (NOS) activities were analyzed. Pathological changes were observed with HE stain. The expression of NF-κB (nuclear factor kappa B), ROCK II (Rho-associated protein kinase II), HO-1 (heme oxygenase-1) and Caspase 3 were analyzed with immunohistochemistry. L-NAME induced typical preeclampsia symptoms, such as the increased blood pressure, urinary protein, the content of MDA, etc. Astaxanthin significantly reduced the blood pressure (P astaxanthin, the thickness of basilal membrane was improved and the content of trophoblast cells and spiral arteries was reduced. Immunohistochemistry results revealed that the expressions of NF-κB, ROCK II and Caspase 3 in placenta tissue were effectively decreased, and HO-1 was increased. Results indicated that astaxanthin can improve the preeclampsia symptoms by effectively reducing the oxidative stress and inflammatory damages of preeclampsia. It revealed that astaxanthin may be benefit for prevention and treatment of preeclampsia disease.

  2. BIOCHEMICAL ESTIMATIONS IN 6-HYDROXYDOPAMINE-INDUCED RAT MODEL OF PARKINSON’S DISEASE

    Directory of Open Access Journals (Sweden)

    Alin Ciobica

    2007-12-01

    OHDA (8µg/4µl was right-unilateral injected in substantia nigra (SN and ventral tegmental area (VTA, and 20 days after neurosurgery the activity of superoxid dismutase (SOD and glutathione peroxidase (GPX from the temporal lobe homogenate was assessed. A significant decrease in both markers was found in the temporal lobe 20 days after neurotoxin administration. These results support that an early event in the course of dopamine depletion following 6-OHDA administration is the generation of oxidative stress.

  3. Behavioral responses and Fos activation following painful stimuli in a rodent model of Parkinson's disease.

    Science.gov (United States)

    Tassorelli, Cristina; Armentero, Marie-Therese; Greco, Rosaria; Fancellu, Roberto; Sandrini, Giorgio; Nappi, Giuseppe; Blandini, Fabio

    2007-10-24

    In Parkinson's disease (PD), the motor dysfunction caused by degeneration of the nigrostriatal pathway is often associated with alterations of pain perception. This is likely related to the role that the nigrostriatal system may play in the processing of noxious, somatosensory stimuli. To further address this issue, we used a rodent model of PD, based on the unilateral, intrastriatal injection of neurotoxin 6-hydroxydopamine (6-OHDA). We investigated the effects of the nigrostriatal lesion on behavioral responses to pain tests designed to explore different aspects of nociception, such as the formalin test and the tail flick test; we also explored modifications in the expression of Fos protein, a marker of neuronal activation, in supraspinal nuclei involved in the integration of pain perception and stress-related behavior. Rats bearing the nigrostriatal lesion showed complex alterations in pain perception, including hyperalgesic responses to the tonic, inflammatory pain elicited by formalin injection, but only when the stimulus was delivered ipsilaterally to the lesion. This phenomenon was associated with delayed responses to the phasic, thermal stimulus induced by the tail flick test. The hyperalgesic response to the formalin test was accompanied by reduced Fos expression in the paraventricular nucleus of the hypothalamus, which is part of a network (the medial pain system) that mediates motivational-affective aspects of pain. Our results confirm that a unilateral alteration of central dopaminergic transmission disrupts the neural mechanisms underlying proper integration of painful stimuli, particularly in the hemibody ipsilateral to the dopaminergic denervation.

  4. Inhibition by anandamide of 6-hydroxydopamine-induced cell death in PC12 cells.

    LENUS (Irish Health Repository)

    Mnich, Katarzyna

    2010-01-01

    6-hydroxydopamine (6-OHDA) is a selective neurotoxin that is widely used to investigate cell death and protective strategies in models of Parkinson\\'s disease. Here, we investigated the effects of the endogenous cannabinoid, anandamide, on 6-OHDA-induced toxicity in rat adrenal phaeochromocytoma PC12 cells. Morphological analysis and caspase-3 activity assay revealed that anandamide inhibited 6-OHDA-induced apoptosis. The protection was not affected by antagonists of either cannabinoid receptors (CB(1) or CB(2)) or the vanilloid receptor TRPV1. Anandamide-dependent protection was reduced by pretreatment with LY294002 (inhibitor of phosphatidylinositol 3-kinase, PI3K) and unaffected by U0126 (inhibitor of extracellularly-regulated kinase). Interestingly, phosphorylation of c-Jun-NH2-terminal kinase (JNK) in cells exposed to 6-OHDA was strongly reduced by anandamide pre-treatment. Furthermore, 6-OHDA induced c-Jun activation and increased Bim expression, both of which were inhibited by anandamide. Together, these data demonstrate antiapoptotic effects of anandamide and also suggest a role for activation of PI3K and inhibition of JNK signalling in anandamide-mediated protection against 6-OHDA.

  5. Cardiovascular effects of (-)-11-OH-delta 8-tetrahydrocannabinol-dimethylheptyl in rats.

    Science.gov (United States)

    Vidrio, H; Sánchez-Salvatori, M A; Medina, M

    1996-08-01

    The effects of the stereochemically pure psychoactive cannabinoid (-)-11-OH-delta 8-tetrahydrocannabinol-dimethylheptyl (HU-210) on blood pressure (BP) and heart rate (HR) were determined in rats. In pentobarbital-anesthetized animals, the compound produced dose-related, long-lasting hypotension and bradycardia at doses between 10 and 1,000 micrograms/kg. BP began to decrease immediately after drug administration, and in no case was an initial pressor response observed. Previous vagotomy (VX) or pretreatment with 6-hydroxydopamine (6-OHDA) did not affect hypotension. Bradycardia was inhibited by VX, but only 60 min after administration of HU-210; it was enhanced by 6-OHDA. The cannabinoid blocked reflex bradycardia induced by phenylephrine (PE). HU-210 also decreased BP and HR in conscious rats. Hypotension lasted 2 h, whereas bradycardia was still present 8 h after drug administration. HU-210 thus shares with delta 9-tetrahydrocannabinol (THC) the ability to decrease BP and HR, but is 5-10 times more potent than the natural compound. Its lack of an initial pressor effect, such as that described for THC, could be related to its specificity for the type-1 cannabinoid (CB1) receptor. Hypotension and bradycardia after HU-210 administration are not due to sympathetic withdrawal. Enhanced parasympathetic tone is involved in bradycardia only at a late stage of the response.

  6. Caffeic acid phenethyl ester protects against the dopaminergic neuronal loss induced by 6-hydroxydopamine in rats.

    Science.gov (United States)

    Barros Silva, R; Santos, N A G; Martins, N M; Ferreira, D A S; Barbosa, F; Oliveira Souza, V C; Kinoshita, A; Baffa, O; Del-Bel, E; Santos, A C

    2013-03-13

    Caffeic acid phenethyl ester (CAPE) is a botanical compound abundant in honeybees' propolis. It has anti-inflammatory, antiviral, antioxidant, immunomodulatory and antitumor properties. Its beneficial effects against neurodegenerative diseases, including Parkinson's disease, have also been suggested and some mechanisms have been proposed. Mitochondrial damage and oxidative stress are critical events in neurodegeneration. Release of cytochrome c from mitochondria to cytosol and the downstream activation of caspase-3 have been suggested as targets of the protective mechanism of CAPE. Most of the studies addressing the protective effect of CAPE have been performed in cell culture. This is the first study to demonstrate the protective effect of CAPE against the dopaminergic neuronal loss induced by 6-hydroxydopamine (6-OHDA) in rats. It also demonstrates, for the first time, the inhibitory effect of CAPE on mitochondrial permeability transition (MPT), a mediator of neuronal death that triggers cytochrome c release and caspase-3 activation. Scavenging of reactive oxygen species (ROS) and metal chelation was demonstrated in the brain-affected areas of the rats treated with 6-OHDA and CAPE. Additionally, we demonstrated that CAPE does not affect brain mitochondrial function. Based on these findings and on its ability to cross the blood-brain barrier, CAPE is a promising compound to treat Parkinson's and other neurodegenerative diseases.

  7. EGF enhances the effect of GDNF on protecting dopamine neurons in substantia nigra of Parkinson's disease model in rats%表皮生长因子加强胶质细胞系源性神经营养因子对PD模型大鼠黑质多巴胺能神经元的保护作用

    Institute of Scientific and Technical Information of China (English)

    刘洪梅; 丁艳霞; 王炎强; 高殿帅

    2011-01-01

    目的:研究表皮生长因子(EGF)能否加强胶质细胞系源性神经营养因子(GDNF)保护帕金森病(PD)模型大鼠黑质内多巴胺(DA)能神经元.方法:大鼠右侧纹状体内注射6-羟多巴胺(6-OHDA)并行为学分析筛选PD动物模型.将动物模型随机分为EGF+GDNF组(右侧黑质内注射EGF+GDNF)和GDNF组(右侧黑质内注射GDNF).动物继续存活至第21天,取一部分动物中脑黑质节段,用免疫组织化学显色方法,以抗钙结合蛋白D28K(CB)和胶质源纤维酸性蛋白(GFAP)抗体免疫反应阳性分别检测右侧黑质含CB的神经元及激活的星形胶质细胞,光镜下观察并进行细胞计数;另一部分动物被快速断头取脑,分离右侧黑质,用免疫印迹法分析黑质CB及GFAP蛋白的表达,蛋白条带用图像处理仪扫描,结果用LabWorks软件分析处理.结果:免疫组织化学显色显示,EGF+GDNF组大鼠黑质内CB及GFAP反应阳性细胞数量均高于GDNF组;免疫印迹法检测表明EGF+ GDNF组大鼠黑质内CB及GFAP蛋白表达量高于GDNF组.结论:EGF可能通过促进PD模型大鼠黑质内神经元表达CB和激活星形胶质细胞,从而加强GDNF对黑质内DA能神经元的保护作用.%Objective: To explore whether epidermal growth factor (EGF) is capable of enhancing the effect of glial cell line-derived neurotropic factor (GDNF) on protecting dopamine (DA) neurons in substantia nigra (SN) of PD model rats. Methods-. 6-hydroxydopamine (6-OHDA) was injected into rats' right striatum and behavioral tests were performed Parkinson's disease (PD) rats were selected according to the result of behavioral tests. Then, the PD rats were randomly divided into two groups: GDNF group (intranigral GDNF injection) and EGF+GDNF group (intranigral EGF+GDNF injection). The rats were allowed to survive for another 21 days. Then some PD rats were sacrificed, and the midbrain substantia nigra (SN) were performed for analyses of cal-bindin D28 K (CB) and glial fibrillary

  8. Treatment with a substance P receptor antagonist is neuroprotective in the intrastriatal 6-hydroxydopamine model of early Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Emma Thornton

    Full Text Available Neuroinflammation and blood brain barrier (BBB dysfunction have been implicated in the pathogenesis of Parkinson's disease (PD. The neuropeptide substance P (SP is an important mediator of both neuroinflammation and BBB dysfunction through its NK1 receptor in a process known as neurogenic inflammation. Increased SP content has previously been reported following 6-OHDA treatment in vitro, with the levels of SP correlating with cell death. The present study used an in vivo 6-OHDA lesion model to determine if dopaminergic degeneration was associated with increased SP in the substantia nigra and whether this degeneration could be prevented by using a SP, NK1 receptor antagonist. Unilateral, intrastriatal 6-OHDA lesions were induced and SP (10 µg/2 µL or the NK1 receptor antagonists, N-acetyl-L-tryptophan (2 µL at 50 nM or L-333,060 (2 µL at 100 nM, administered immediately after the neurotoxin. Nigral SP content was then determined using immunohistochemical and ELISA methods, neuroinflammation and barrier integrity was assessed using Iba-1, ED-1, GFAP and albumin immunohistochemistry, while dopaminergic cell loss was assessed with tyrosine hydroxylase immunohistochemistry. Motor function in all animals was assessed using the rotarod task. Intrastriatal 6-OHDA lesioning produced an early and sustained increase in ipsilateral nigral SP content, along with a breakdown of the BBB and activation of microglia and astrocytes. Further exacerbation of SP levels accelerated disease progression, whereas NK1 receptor antagonist treatment protected dopaminergic neurons, preserved barrier integrity, reduced neuroinflammation and significantly improved motor function. We propose that neurogenic inflammation contributes to dopaminergic degeneration in early experimental PD and demonstrate that an NK1 receptor antagonist may represent a novel neuroprotective therapy.

  9. The rat as an animal model of Alzheimer's disease

    DEFF Research Database (Denmark)

    Benedikz, Eirikur; Kloskowska, Ewa; Winblad, Bengt

    2009-01-01

    As a disease model, the laboratory rat has contributed enormously to neuroscience research over the years. It has also been a popular animal model for Alzheimer's disease but its popularity has diminished during the last decade, as techniques for genetic manipulation in rats have lagged behind...... as an animal model of Alzheimer's disease....

  10. 骨髓间充质干细胞黑质内移植对帕金森病大鼠的治疗作用%Therapeutic effects of transplantation of bone marrow mesenchymal stem cells into substantia nigra on the rat model of Parkinson's disease

    Institute of Scientific and Technical Information of China (English)

    陈丹丹; 付文玉; 庄宝祥; 李锋杰; 吕翠

    2013-01-01

    目的 探索骨髓间充质干细胞(BMSCs)移植到帕金森病(Parkinson's disease,PD)大鼠毁损侧黑质内,PD模型大鼠的姿势不对称性和黑质及纹状体内酪氨酸羟化酶(tyrosine hydroxylase,TH)表达的改变,以及BMSCs在大鼠脑内的存活、分化情况.方法 黑质、前脑内侧束两点法注射6-羟多巴胺(6-OHDH)并行为学分析筛选PD模型大鼠.将PD模型大鼠随机分为移植组和对照组.BMSCs移植术后4周和8周,观察大鼠姿势不对称性,免疫组织化学及免疫荧光显色方法检测黑质和纹状体酪氨酸羟化酶 (tyrosine hydroxylase,TH) 的表达变化以及BMSCs在大鼠体内的存活、迁移及分化情况.结果 BMSCs黑质内移植可使PD模型大鼠的转动频率由(10.62±2.97)r/min降至(4.65±1.08)r/min(P<0.01),显著增加毁损侧黑质TH阳性细胞数量和纹状体内TH阳性纤维密度.BMSCs在大鼠黑质内可以存活至少8周,部分细胞分化为神经干细胞、神经元和神经胶质细胞.结论 黑质内移植BMSCs对PD模型大鼠有一定的治疗作用.%Objective To explore the effect of bone marrow mesenchymal stem cells (BMSCs) transplanted into the unilateral lesioned substantia nigra (SN) , the changes of postural asymmetry and expression of tyrosine hydroxylase in SN of Parkinson's disease ( PD) model rats, and the survival and differentiation of BMSCs in the brain tissue. Methods Model of Parkinson's dieases (PD) was induced by 6-hydroxydopamine (6-OHDA) injection into the right SN and medial forebrain bundle in the rat brains. The PD rats were randomly divided into transplantation group and control group. The PD rat rotational behavior was induced by apomorphine ( APO) at 4 weeks and 8 weeks after BMSCs transplantation. The rat behavior was tested, and the expression of tyrosine hydroxylase ( TH ) and the survival, migration and differentiation of transplanted BMSCs in the SN and ST were examined using immunohistochemical and immunofluorescence

  11. Effects of squalene/squalane on dopamine levels, antioxidant enzyme activity, and fatty acid composition in the striatum of Parkinson's disease mouse model.

    Science.gov (United States)

    Kabuto, Hideaki; Yamanushi, Tomoko T; Janjua, Najma; Takayama, Fusako; Mankura, Mitsumasa

    2013-01-01

    Active oxygen has been implicated in the pathogenesis of Parkinson's disease (PD); therefore, antioxidants have attracted attention as a potential way to prevent this disease. Squalene, a natural triterpene and an intermediate in the biosynthesis of cholesterol, is known to have active oxygen scavenging activities. Squalane, synthesized by complete hydrogenation of squalene, does not have active oxygen scavenging activities. We examined the effects of oral administration of squalene or squalane on a PD mouse model, which was developed by intracerebroventricular injection of 6-hydroxydopamine (6-OHDA). Squalene administration 7 days before and 7 days after one 6-OHDA injection prevented a reduction in striatal dopamine (DA) levels, while the same administration of squalane enhanced the levels. Neither squalene nor squalane administration for 7 days changed the levels of catalase, glutathione peroxidase, or superoxide dismutase activities in the striatum. Squalane increased thiobarbituric acid reactive substances, a marker of lipid peroxidation, in the striatum. Both squalane and squalene increased the ratio of linoleic acid/linolenic acid in the striatum. These results suggest that the administration of squalene or squalane induces similar changes in the composition of fatty acids and has no effect on the activities of active oxygen scavenging enzymes in the striatum. However, squalane increases oxidative damage in the striatum and exacerbates the toxicity of 6-OHDA, while squalene prevents it. The effects of squalene or squalane treatment in this model suggest their possible uses and risks in the treatment of PD.

  12. Sensory innervation of rat contracture shoulder model.

    Science.gov (United States)

    Ochiai, Nobuyasu; Ohtori, Seiji; Kenmoku, Tomonori; Yamazaki, Hironori; Ochiai, Satoko; Saisu, Takashi; Matsuki, Keisuke; Takahashi, Kazuhisa

    2013-02-01

    To date, few studies have investigated the cause of pain experienced by patients with frozen shoulder. The purposes of this study were to establish a rat contracture model and clarify the innervation pattern of the glenohumeral (GH) joint and subacromial bursa (SAB) using immunohistochemistry in the dorsal root ganglion (DRG) neurons. The rat contracture models were made by tying the animal's humerus and scapula with No. 2-0 FiberWire (Arthrex, Naples, FL, USA). Contracture was confirmed on x-ray images taken 8 weeks after the operation. Subsequently, two kinds of neurotracers, Fluoro-Gold (FG) (Fluorochrome, Denver, CO, USA) and 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (DiI) (Molecular Probes, Eugene, OR, USA), were used to detect the GH joints and SAB separately. FG tracers were injected into GH joints, and DiI tracers were injected into the SAB. At 7 days after injection, DRGs were harvested between C1 and T1. Immunohistochemistry by use of calcitonin gene-related peptide (CGRP) was performed. CGRP is thought to be one of the causes of pain sensation in joint disease. We evaluated the percentages of FG-labeled CGRP-immunoreactive (CGRP-ir) neurons in the total number of FG-labeled neurons and of DiI-labeled CGRP-ir neurons in the total number of DiI-labeled neurons. Abduction and total arc of the rotation were statistically significantly decreased in the contracture group. Furthermore, the percentage of CGRP-ir DRG neurons was significantly higher in the contracture group in both the GH joint and SAB. These results show that pain sensation in rat shoulder contracture may be induced by the up-regulation of CGRP expression in DRG neurons. Copyright © 2013 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved.

  13. Striatal grafts in a rat model of Huntington's disease

    DEFF Research Database (Denmark)

    Guzman, R; Meyer, M; Lövblad, K O;

    1999-01-01

    Survival and integration into the host brain of grafted tissue are crucial factors in neurotransplantation approaches. The present study explored the feasibility of using a clinical MR scanner to study striatal graft development in a rat model of Huntington's disease. Rat fetal lateral ganglionic...... eminences grown as free-floating roller-tube cultures can be successfully grafted in a rat Huntington model and that a clinical MR scanner offers a useful noninvasive tool for studying striatal graft development....

  14. A Novel Rat Model of Type 2 Diabetes: The Zucker Fatty Diabetes Mellitus ZFDM Rat

    Directory of Open Access Journals (Sweden)

    Norihide Yokoi

    2013-01-01

    Full Text Available The Zucker fatty (ZF rat harboring a missense mutation (fatty, fa in the leptin receptor gene (Lepr develops obesity without diabetes; Zucker diabetic fatty (ZDF rats derived from the ZF strain exhibit obesity with diabetes and are widely used for research on type 2 diabetes (T2D. Here we establish a novel diabetic strain derived from normoglycemic ZF rats. In our ZF rat colony, we incidentally found fa/fa homozygous male rats having reproductive ability, which is generally absent in these animals. During maintenance of this strain by mating fa/fa males and fa/+ heterozygous females, we further identified fa/fa male rats exhibiting diabetes. We then performed selective breeding using the fa/fa male rats that exhibited relatively high blood glucose levels at 10 weeks of age, resulting in establishment of a diabetic strain that we designated Hos:ZFDM-Leprfa (ZFDM. These fa/fa male rats developed diabetes as early as 10 weeks of age, reaching 100% incidence by 21 weeks of age, while none of the fa/+ male rats developed diabetes. The phenotypic characteristics of this diabetic strain are distinct from those of normoglycemic ZF rats. ZFDM rat strain having high reproductive efficiency should serve as a more useful animal model of T2D.

  15. [MAM-E17 schizophrenia rat model].

    Science.gov (United States)

    Kállai, Veronika; Tóth, Attila; Gálosi, Rita; Szabó, Imre; Petykó, Zoltán; Karádi, Zoltán; Kállai, János; Lénárd, László

    2015-01-01

    Schizophrenia is a serious neuropsychiatric disorder. Several brain structures, neurotransmitter systems, genetic and environmental risk factors are suspected in the background. Because of its complexity the mechanism of the disorder is not known exactly, so the treatment of patients is unsolved. In the research of schizophrenia application of the rodent models is widespread. In this study one of these models based on the effect of methylazoxymethanol- acetate (MAM) is described, which is a neurodevelopmental, validated rat model. This antimitotic agent is able to evoke a number of schizophrenic symptomes temporarily disrupting the prenatal neurogenesis. The model reproduces numerous histological and neurophysiological changes of the human disorder, moreover it also represents several behavioral and cognitive phenomena resembling those in schizophrenia. A salient advantage of the model is the demonstration of the diachronic feature of the disorder, that is, postpubertal appearance of the positive symptoms. This model provides widespread opportunities for manipulations of the symptoms, so that using it in the future investigations can lead to a better understanding of this disorder.

  16. APLICACIÓN DEL TEST DE LA BARRA TRANSVERSAL MODIFICADO PARA EVALUAR RATAS HEMIPARKINSONIZADAS. Modify Beam Transversal Test to Evauate Hemiparkinsonian Rats.

    Directory of Open Access Journals (Sweden)

    LISETTE BLANCO LEZCANO

    Full Text Available La degeneración nigroestriatal que caracteriza a la enfermedad de Parkinson (EP es estudiada en modelos experimentales en roedores por inyección de 6-hidroxidopamina (6-OHDA. El presente estudio presenta una versión modificada del test de la barra transversal (TBT que permite la cuantificación del déficit motor a través de: tiempo que demora la rata en alcanzar una de las plataformas (latencia de escape, LE; tiempo que demora en caer de la barra (latencia de caída, LC; número total de errores cometidos durante la ejecución en cada barra (número de errores, NE. La forma y el diámetro de la sección transversal de la barra se modificaron desde barras rectangulares y circulares de 2,5 cm de diámetro hasta barras con esta misma forma y 1 cm de diámetro respectivamente lo cual impuso la mayor dificultad a la ejecución del test. Tres grupos de ratas Wistar fueron evaluados: no tratadas (n=15, lesionadas con 6-OHDA (n=14 y falsas operadas (n=14. Todas las variables estudiadas mostraron diferencias signifi-cativas entre ratas controles y hemiparkinsonizadas. Para todos los tipos de barras, las variables LE y NE se incrementaron mientras que la LC disminuyó significativamente en las ratas hemiparkinsonizadas en comparación con las ratas controles. La LC mostró diferencias altamente significativas (pThe nigrostriatal degeneration underlying Parkinson’s disease (PD is commonly studied in experimental animals by injection of the neurotoxin 6-hydroxydopamine. The present study describes a modified version of a beam traversal test which allows the quantification of the motor deficit through the time spent to arrive to the platform once all four paws of the animals are in contact with the beam (escape latency, EL, the time spent before falling (tumbled down latency, TDL and the number of errors (NE committed for the animals in each beam. The shape and the diameter of the cross section of the beams were modified from rectangular and circular

  17. Comparison of mesencephalic free-floating tissue culture grafts and cell suspension grafts in the 6-hydroxydopamine-lesioned rat

    DEFF Research Database (Denmark)

    Meyer, Morten; Widmer, H R; Wagner, B

    1998-01-01

    improvements in terms of significant reductions in amphetamine-induced rotations were observed in rats grafted with FFRT cultures (127%) and rats grafted with cell suspensions (122%), while control animals showed no normalization of rotational behavior. At 84 days after transplantation, there were similar...... days in culture or directly as dissociated cell suspensions, and compared with regard to neuronal survival and ability to normalize rotational behavior in adult rats with unilateral 6-hydroxydopamine (6-OHDA) lesions. Other lesioned rats received injections of cell-free medium and served as controls...... numbers of TH-immunoreactive (TH-ir) neurons in grafts of cultured tissue (775 +/- 98, mean +/- SEM) and grafts of fresh, dissociated cell suspension (806 +/- 105, mean +/- SEM). Cell counts in fresh explants, 7-day-old cultures, and grafted cultures revealed a 68.2% loss of TH-ir cells 7 days after...

  18. Variation in rat sciatic nerve anatomy: implications for a rat model of neuropathic pain.

    Science.gov (United States)

    Asato, F; Butler, M; Blomberg, H; Gordh, T

    2000-03-01

    We discovered a variation of rat sciatic nerve anatomy as an incidental finding during the anatomical exploration of the nerve lesion site in a rat neuropathic pain model. To confirm the composition and distribution of rat sciatic nerve, macroscopic anatomical investigation was performed in both left and right sides in 24 adult Sprague-Dawley rats. In all rats, the L4 and L5 spinal nerves were fused tightly to form the sciatic nerve. However, the L6 spinal nerve did not fuse with this nerve completely as a part of the sciatic nerve, but rather sent a thin branch to it in 13 rats (54%), whereas in the remaining 11 rats (46%), L6 ran separately along with the sciatic nerve. Also, the L3 spinal nerve sent a thin branch to the L4 spinal nerve or sciatic nerve in 6 rats (25%). We conclude that the components of sciatic nerve in Sprague-Dawley rats vary from L3 to L6; however, the major components are L4 and L5 macroscopically. This finding is in contrast to the standard textbooks of rat anatomy which describe the sciatic nerve as having major contributions from L4, L5, and L6.

  19. Effect of selective and non-selective serotonin receptor activation on L-DOPA-induced therapeutic efficacy and dyskinesia in parkinsonian rats.

    Science.gov (United States)

    Tronci, E; Fidalgo, C; Stancampiano, R; Carta, M

    2015-10-01

    Selective activation of 5-HT1 receptors has been shown to produce near to full suppression of L-DOPA-induced dyskinesia (LID) in animal models of Parkinson's disease; however, a reduction of the therapeutic effect of L-DOPA has been reported in several studies. Conversely, we recently found that increasing the serotonergic tone with chronic administration of the serotonin precursor 5-hydroxy-tryptophan (5-HTP) can reduce LID in 6-OHDA-lesioned rats, without affecting L-DOPA efficacy. To directly compare the effects of selective versus non-selective serotonin receptor activation, here we first tested different acute doses of the 5-HT1A/1B receptor agonist eltoprazine and 5-HTP on LID in order to identify doses of the individual compounds showing similar anti-dyskinetic efficacy in L-DOPA-primed dyskinetic rats. About 50% reduction of LID was observed with 0.1 mg/kg and 24 mg/kg of eltoprazine and 5-HTP, respectively; we then compared the effect of the two drugs, individually and in combination, on L-DOPA-induced stepping test in L-DOPA-naïve parkinsonian animals and LID over three weeks of L-DOPA treatment. Results showed that eltoprazine induced significant worsening of L-DOPA-mediated performance in the stepping test, while 5-HTP did not. Interestingly, combination of 5-HTP with eltoprazine prevented the reduction in the forelimb use induced by eltoprazine. Moreover, 5-HTP and eltoprazine given individually showed similar efficacy also upon chronic treatment, and had additive effect in dampening the appearance of LID when given in combination. Finally, chronic administration of eltoprazine and/or 5-HTP did not affect striatal serotonin innervation, compared to l-DOPA alone, as measured by serotonin transporter expression.

  20. Effect of 5-HT7 receptor agonist on pyramidal neurons in the medial frontal cortex in a rat model of Parkinson's disease%5-羟色胺-7受体激动剂对帕金森病模型大鼠内侧前额叶皮层锥体神经元兴奋性的影响

    Institute of Scientific and Technical Information of China (English)

    范玲玲; 邓博; 闫君宝; 胡志红; 任爱红; 胡咏梅; 杨东伟

    2016-01-01

    Objective To investigate the activity of pyramidal neurons in the medial prefrontal cortex (mPFC) of normal and 6-OHDA-lesioned rats and the responses of the neurons to 5-hydroxytryptamine-7 (5-HT7) receptor stimulation. Methods The changes in spontaneous firing of the pyramidal neurons in the mPFC in response to 5-HT7 receptor stimulation were observed by extracellular recording in normal and 6-OHDA-lesioned rats. Results Both systemic and local administration of 5-HT7 receptor agonist AS 19 resulted in 3 response patterns (excitation, inhibition and no change) of the pyramidal neurons in the mPFC of normal and 6-OHDA-lesioned rats. In normal rats, the predominant response of the pyramidal neurons to AS 19 stimulation was excitatory, and the inhibitory effect of systemically administered AS 19 was reversed by GABAA receptor antagonist picrotoxinin. In the lesioned rats, systemic administration of AS 19 also increased the mean firing rate of the pyramidal neurons, but the cumulative dose for producing excitation was higher than that in normal rats. Systemic administration of AS 19 produced an inhibitory effect in the lesioned rats, which was partially reversed by picrotoxinin. Local administration of AS 19 at the same dose did not change the fi ring rate of the neurons in the lesioned rats. Conclusion The activity of mPFC pyramidal neurons is directly or indirectly regulated by 5-HT7 receptor, and degeneration of the nigrostriatal pathway leads to decreased response of these neurons to AS 19.%目的:探讨5-羟色胺(5-hydroxytryptamine,5-HT)-7受体对帕金森病(Parkinson's disease, PD)模型大鼠内侧前额叶皮层(medial prefrontal cortex, mPFC)中锥体神经元兴奋性的影响。方法以正常大鼠和6-羟多巴胺单侧损毁黑质致密部建立的PD模型大鼠为研究对象,采用在体细胞外生物电记录的方法,观察5-HT7受体激动剂AS 19对mPFC中锥体神经元电活动的影响。结果无论是

  1. Experimental model of osteosarcomas in rats

    Energy Technology Data Exchange (ETDEWEB)

    Jasmin, C.; Allouche, M.; Jude, J.G.; Klein, B. (Institut de Cancerologie et d' Immunogenetique, Villejuif (France)); Thiery, J.P.; Perdereau, B.; Gongora, R.; Gongora, G.; Mazabraud, A. (Institut Curie, Paris (France))

    1982-07-08

    Satisfactory experimental models for preclinical prediction in cancerology must answer the following criteria: reproducibility of the method used for inducing tumors; clinical, pathological and kinetic similarity with the corresponding human tumors. We have developed a model of osteosarcoma locally induced by insoluble radioactive cerium chloride (/sup 144/Ce Cl/sub 3/) in Sprague Dawley rats. This method yields over 80% of bone tumors at the injection site, of which approximately half are histologically similar to human tumors. These tumors double their volume fairly slowly (in approximately 20 days); lung metastases occur both early and frequently (80% of animals). A transplantable tumor was developed from an induced osteosarcoma and adapted to the Curie strain. Transplantation in the bone, next to the bone, or under the skin is followed by widespread metastatic dissemination. The kinetics and histological features of the primary tumor are maintained. Tumor /sup 85/strontium uptake is similar to that seen in human osteosarcomas. These new models of osteosarcomas are being used for evaluating new cancer chemotherapeutic agents and interferon, etc.

  2. Neuroprotective Effects of Liraglutide for Stroke Model of Rats

    Directory of Open Access Journals (Sweden)

    Kenichiro Sato

    2013-10-01

    Full Text Available The number of diabetes mellitus (DM patients is increasing, and stroke is deeply associated with DM. Recently, neuroprotective effects of glucagon-like peptide-1 (GLP-1 are reported. In this study, we explored whether liraglutide, a GLP-1 analogue exerts therapeutic effects on a rat stroke model. Wistar rats received occlusion of the middle cerebral artery for 90 min. At one hour after reperfusion, liraglutide or saline was administered intraperitoneally. Modified Bederson’s test was performed at 1 and 24 h and, subsequently, rats were euthanized for histological investigation. Peripheral blood was obtained for measurement of blood glucose level and evaluation of oxidative stress. Brain tissues were collected to evaluate the level of vascular endothelial growth factor (VEGF. The behavioral scores of liraglutide-treated rats were significantly better than those of control rats. Infarct volumes of liraglutide-treated rats at were reduced, compared with those of control rats. The level of derivatives of reactive oxygen metabolite was lower in liraglutide-treated rats. VEGF level of liraglutide-treated rats in the cortex, but not in the striatum significantly increased, compared to that of control rats. In conclusion, this is the first study to demonstrate neuroprotective effects of liraglutide on cerebral ischemia through anti-oxidative effects and VEGF upregulation.

  3. Thrombolytic and anticoagulation treatment in a rat embolic stroke model

    DEFF Research Database (Denmark)

    Rasmussen, Rune Skovgaard; Overgaard, K; Meden, P

    2003-01-01

    OBJECTIVES: The effects of pentasaccharide (PENTA), given alone or combined with thrombolysis using recombinant tissue plasminogen activator (rt-PA), on infarct size and clinical outcome were evaluated in a rat embolic stroke model. MATERIALS AND METHODS: Ninety-two rats were embolized unilaterally...

  4. A Rat Excised Larynx Model of Vocal Fold Scar

    Science.gov (United States)

    Welham, Nathan V.; Montequin, Douglas W.; Tateya, Ichiro; Tateya, Tomoko; Choi, Seong Hee; Bless, Diane M.

    2009-01-01

    Purpose: To develop and evaluate a rat excised larynx model for the measurement of acoustic, aerodynamic, and vocal fold vibratory changes resulting from vocal fold scar. Method: Twenty-four 4-month-old male Sprague-Dawley rats were assigned to 1 of 4 experimental groups: chronic vocal fold scar, chronic vocal fold scar treated with 100-ng basic…

  5. Characterization of Fetal Antigen 1/Delta-Like 1 Homologue Expressing Cells in the Rat Nigrostriatal System

    DEFF Research Database (Denmark)

    Liechti, Rémy; Ducray, Angélique D; Jensen, Pia;

    2015-01-01

    Fetal antigen 1/delta-like 1 homologue (FA1/dlk1) belongs to the epidermal growth factor superfamily and is considered to be a non-canonical ligand for the Notch receptor. Interactions between Notch and its ligands are crucial for the development of various tissues. Moreover, FA1/dlk1 has been su...... adult rats. FA1/dlk1-ir cells were predominantly distributed in the substantia nigra (SN) pars compacta (SNc) and in the ventral tegmental area. Interestingly, the expression of FA1/dlk1 significantly increased in tyrosine hydroxylase (TH)-ir cells during early postnatal development. Co......-localization and tracing studies demonstrated that FA1/dlk1-ir cells in the SNc were nigrostriatal dopaminergic neurons, and unilateral 6-OHDA lesions resulted in loss of both FA1/dlk1-ir and TH-ir cells in the SNc. Surprisingly, increased numbers of FA1/dlk1-ir cells (by 70%) were detected in dopamine-depleted striata...... as compared to unlesioned controls. The higher number of FA1/dlk1-ir cells was likely not due to neurogenesis as colocalization studies for proliferation markers were negative. This suggests that FA1/dlk1 was up-regulated in intrinsic cells in response to the 6-OHDA-mediated loss of FA1/dlk1-expressing SNc...

  6. Leptin Influences Healing in the Sprague Dawley Rat Fracture Model

    Science.gov (United States)

    Liu, Pengcheng; Cai, Ming

    2017-01-01

    Background Leptin plays a crucial role in bone metabolism, and its level is related to bone callus formation in the fracture repair process. The objective of this study was to evaluate the effect of recombinant leptin on the healing process of femoral fractures in rats. Material/Methods Forty-eight male Sprague Dawley (SD) rats with an average body weight of 389 g (range: 376–398 g) and an average age of 10 weeks were included in this animal research, and all rats were randomly divided into two major groups. Then standardized femur fracture models were implemented in all SD rats. Rats in the control group were treated with only 0.5 mL of physiological saline, and rats in the experimental group were treated with recombinant leptin 5 μg/kg/d along with the same 0.5 mL of physiological saline for 42 days intraperitoneally. At the same time, each major group was evenly divided into three parallel subgroups for each parallel bone evaluation separately at the second, fourth, and sixth weeks. Each subgroup included eight rats. Results The total radiological evaluation results showed that the healing progress of femoral fracture in the experimental group was superior to that in the control group from the fourth week. At the sixth week, experimental group rats began to present significantly better femoral fracture healing progress than that of the control group rats. Results of biomechanics show the ultimate load (N) and deflection ultimate load (mm) of the experimental group rats was significantly increased compared with that of the control group rats from the fourth week. Conclusions Our results suggest that leptin may have a positive effect on SD rat femur fracture healing. PMID:28088810

  7. Use of surgical techniques in the rat pancreas transplantation model

    National Research Council Canada - National Science Library

    Ma, Yi; Guo, Zhi-Yong

    2008-01-01

    ... (also called type 1 diabetes). With the improvement of microsurgical techniques, pancreas transplantation in rats has been the major model for physiological and immunological experimental studies in the past 20 years...

  8. Effects of garlicin on apoptosis in rat model of colitis

    Institute of Scientific and Technical Information of China (English)

    Xi-Ming Xu; Jie-Ping Yu; Xiao-Fei He; Jun-Hua Li; Liang-Liang Yu; Hong-Gang Yu

    2005-01-01

    AIM: To investigate the effects of garlicin on apoptosis and expression of bcl-2 and bax in lymphocytes in rat model of ulcerative colitis (UC).METHODS: Healthy adult Sprague-Dawley rats of both sexes, weighing 180±30 g, were employed in the present study. The rat model of UC was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) enema. The experimental animals were randomly divided into garlicin treatment group (including high and low concentration), model control group, and normal control group. Rats in garlicin treatment group and model control group received intracolic garlicin daily at doses of 10.0 and 30.0 mg/kg and equal amount of saline respectively 24 h after colitis model was induced by alcohol and TNBS co-enema. Rats in normal control group received neither alcohol nor only TNBS but only saline enema in this study. On the 28th d of the experiment, rats were executed, the expression of bcl-2 and bax protein was determined immunohistochemically and the apoptotic cells were detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate fluorescence nick end labeling (TUNEL) method. At the same time, the rat colon mucosal damage index (CMDI) was calculated.RESULTS: In garlicin treatment group, the positive expression of bcl-2 in lymphocytes decreased and the number of apoptotic cells was more than that in model control group, CMDI was lower than that in model control group. The positive expression of bax in lymphocytes had no significant difference.CONCLUSION: Garlicin can protect colonic mucosa against damage in rat model of UC induced by TNBS enema.

  9. Antioxidant Activity of Oral Administration of Rosmarinus Officinalis Leaves Extract on Rat's Hippocampus which Exposed to 6-Hydroxydopamine

    Directory of Open Access Journals (Sweden)

    Arashpour Rasoul

    2016-01-01

    Full Text Available Carnosic acid, a diterpene of Rosemarinus officinalis leaves extract (RE, has potent antioxidant activity in vitro. The dopaminergic connection of substantia nigra pars compacta to the hippocampus might be affected by oxidative stress which caused cognitive impairment observed in the early phase of Parkinson's disease (PD. Adult male Wistar rats were lesioned bilaterally by intra-nigral injection of 6-OHDA, and divided into six groups: four groups that orally given RE containing 40% of carnosic acid, at doses of 25, 50 and 100 mg/kg (treated rats and distilled water (H2O, once daily for a period of 14 days before and after the injury. There were also two another groups as control rats which injected by normal saline and untreated lesion group. The injured animals were evaluated for their spatial memory performance by Morris Water Maze test. Lesioned rats showed significant increase in escape latency, as compared with control group. Two weeks after injury, tissue samples were collected from the hippocampus. Levels of catalase (CAT, glutathione peroxidase (GPX and superoxide dismutase (SOD, malondialdehyde (MDA and reactive oxygen species (ROS were determined. There were significant increase of SOD, GPX and CAT enzymes activities in RE50 treated group as compared to lesioned rats. We found a significant decrease of ROS in RE50 treated group as compared to Lesioned rats. These findings provide evidence that 50 mg/kg of RE decreased oxidative damage of the hippocampus induced by 6-OHDA and serve as potential candidate for the treatment of PD.

  10. Dietary models for inducing hypercholesterolemia in rats

    Directory of Open Access Journals (Sweden)

    Sheyla Leite Matos

    2005-03-01

    Full Text Available The present work aimed at finding a dietetical model capable of promoting the highest hypercholesterolemia without affecting the development of the rats. Sixty female Fisher rats were divided into five groups. The first one was fed a control diet; the remaining four were fed hypercholesterolemic diets with cholesterol and different contents of soybean oil, starch, casein, micronutrients and fiber and, consequently, different caloric values. After eight weeks animals were evaluated in relation to growth, fecal excretion, liver weight and fat, cholesterol and its fractions, serum biochemical parameters and sistolic pressure and compared with controls. The best result was obtained with the diet containing 25 % soybean oil, 1.0 % cholesterol, 13 % fiber and 4,538.4 Kcal/Kg, since it promoted an increase in LDL-cholesterol, a decrease in the HDL fraction and affected less the hepatic function of the animals.Modelos animais têm sido usados para investigar a relação entre desordens no metabolismo do colesterol e a aterogênese. A estratégia utilizada a fim de induzir hipercolesterolemia (dietas com alto teor de gordura e com colesterol adicionado leva à redução de sua ingestão pelos animais, o que induz desnutrição. O presente trabalho objetivou encontrar um modelo dietético capaz de promover a maior hipercolesterolemia, sem afetar o desenvolvimento dos animais. Sessenta ratas Fisher foram divididas em cinco grupos. O primeiro foi alimentado com uma dieta controle; os quatros restantes receberam dietas hipercolesterolêmicas, com colesterol e diferentes teores de óleo de soja, amido, caseína, micronutrientes e fibra e, conseqüentemente, diferentes valores calóricos. Após oito semanas os animais foram avaliados em relação ao crescimento, excreção fecal, peso e teor de gordura do fígado, colesterol e suas frações, parâmetros bioquímicos séricos e pressão sistólica. Os melhores resultados foram obtidos com a dieta contendo 25

  11. Ovariectomized rats as a model of postmenopausal osteoarthritis

    DEFF Research Database (Denmark)

    Høegh-Andersen, Pernille; Tankó, László B; Andersen, Thomas L

    2004-01-01

    inhibited the ovariectomy-induced acceleration of cartilage and bone turnover and significantly suppressed cartilage degradation and erosion seen in vehicle-treated OVX rats. The study indicates that estrogen deficiency accelerates cartilage turnover and increases cartilage surface erosion. OVX rats provide......We aimed to assess the effect of ovariectomy on cartilage turnover and degradation, to evaluate whether ovariectomized (OVX) rats could form an experimental model of postmenopausal osteoarthritis. The effect of ovariectomy on cartilage was studied using two cohorts of female Sprague-Dawley rats...... for collagen type II degradation products (CTX-II), and bone resorption was quantified in serum using an assay for bone collagen type I fragments (CTX-I). Surface erosion in the cartilage of the knee was more severe in OVX rats than in sham-operated animals, particularly in the 7-month-old cohort (P = 0...

  12. Modeling diabetic sensory neuropathy in rats.

    Science.gov (United States)

    Calcutt, Nigel A

    2004-01-01

    The procedures to induce insulin-deficient diabetes in rats using streptozotocin are described along with a number of insulin treatment regimes that can be used to maintain these animals at different degrees of glycemia for periods of weeks to months. Streptozotocin-diabetic rats develop tactile allodynia, hyperalgesia following paw formalin injection and abnormal responses to thermal stimulation and the detailed methods used to evaluate these behavioral indices of abnormal sensory function are provided.

  13. Pioglitazone treatment restores in vivo muscle oxidative capacity in a rat model of diabetes

    NARCIS (Netherlands)

    Wessels, B.; Ciapaite, J.; van den Broek, N. M. A.; Houten, S. M.; Nicolay, K.; Prompers, J. J.

    2015-01-01

    Aim: To determine the effect of pioglitazone treatment on in vivo and ex vivo muscle mitochondrial function in a rat model of diabetes. Methods: Both the lean, healthy rats and the obese, diabetic rats are Zucker Diabetic Fatty (ZDF) rats. The homozygous fa/fa ZDF rats are obese and diabetic. The he

  14. Changes of the anti-oxidation capability of rat model of Parkinson disease after acupuncture at subthalamus%针刺丘脑底核后帕金森病模型大鼠抗氧化能力的变化

    Institute of Scientific and Technical Information of China (English)

    金泽; 刘婷婷; 周伯旭

    2006-01-01

    BACKGROUND: Acupuncture has been confirmed to be effective in treating Parkinson disease both clinically and experimentally, but there is still lack of systematical and complete therapeutic principle and law to be followed in clinic.OBJECTIVE: To observe the influence on glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), malondialdehyde(MDA)and nitric oxide synthase (NOS) in corpus striatum of the damaged side in rat models of Parkinson disease by acupuncture at subthalamus.DESIGN: A randomized controlled animal experiment.SETTING: The Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine.MATERIALS: The experiment was performed in the Experimental Animal Center of Heilongjiang University of Traditional Chinese Medicine from January to June in 2003. Eighteen healthy adult Wistar rats of pure breed were randomly divided into 3 groups with 6 rats in each:electroacupuncture group, model group and normal saline group.METHODS: ① Model group: The rats were made into models of Parkinson disease with damaged corpus striatum by injecting 6-hydroxydopamine (6-OHDA, 12 μg), which was dissolved in 5 μL normal saline containing 2 g/L ascorbic acid, slowly into caudal putamen. without intervention. ②Normal saline group: 6-OHDA was replaced by normal saline of the same dosage, and other treatments were the same as those in the model group. ③ Electroacupuncture group: The model preperation was the same as that in the model group. The needles were embedded in subthalamus at 6 weeks postoperatively, and then electroacupuncture (in frequency of 100 Hz, and the intensity about 1 mA) was given one week later for 2 weeks, once a day,15 minutes for each time.MAIN OUTCOME MEASURES: All the rats were killed by cutting heads to remove brain under anesthesia at 2 weeks after electroacupuncture, and the activities of GSH, GSH-Px, SOD and NOS and the concentration of MDA were detected with chromatometry.RESULTS: All the 18

  15. Immunohistochemical changes of nigrostriatal tyrosine hydroxylase and dopamine transporter in the golden hamster after a single intrastriatal injection of 6-hydroxydopamine.

    Science.gov (United States)

    Rodríguez, Sebastián; Uchida, Kazuyuki; Nakayama, Hiroyuki

    2013-05-01

    One of the most important models for analyzing the pathomorphological aspects of Parkinson's disease (PD) is the 6-hydroxydopamine (6-OHDA) model where lesions of the nigrostriatal axis are observed when 6-OHDA is intrastriatally injected. Despite the widespread use in rats, only few studies about the toxicity of 6-OHDA have been carried out in other species. In the present study, we evaluated for the first time the effects of a single intrastriatal injection of 6-OHDA (20 μg dissolved in 2 μl of vehicle) in the young-adult golden hamster (GH). Significant decreases in tyrosine hydroxylase (TH)-positive area and dopamine transporter (DAT)-positive area were found in the ipsilateral striatum 3 days after the injection. These decreases in immunoreactivity continued for 7 days and a recovery trend was found at days 15 and 21 post injection. On the other hand, no effect of injection was found on the contralateral side. In the substantia nigra pars compacta (SNpc), a significant decrease in the number of TH-positive cells appeared one week after the injection with the peak in the loss of TH-positive immunoreactivity being recorded two weeks post-injection. On the basis of the results herein reported, we believe that the GH is a suitable model for studying the patterns of spontaneous recovery of striatal axons following the 6-OHDA intrastriatal injection.

  16. Establishment of intramedullary spinal cord glioma model in rats

    Institute of Scientific and Technical Information of China (English)

    REN Tian-jian; WANG Zhong-cheng; ZHANG Ya-zhuo; LI Dan; WANG Hong-yun; LI Zhen-zong

    2010-01-01

    Background Treating intramedullary spinal cord gliomas is a big challenge because of limited options, high recurrence rate and poor prognosis. An intramedullary glioma model is prerequisite for testing new treatments. This paper describes the establishment of a rodent intramedullary glioma model and presents functional progression, neuroimaging and histopathological characterization of the tumour model.Methods Fischer344 rats (n=24) were randomized into two groups. Group 1 (n=16) received a 5 μl intramedullary implantation of 9L gliosarcomal (105) cells. Group 2 (n=8) received a 5 μl intramedullary injection of Dulbecco's modified Eagle medium. The rats were anesthetized, the spinous process of the T10 vertebra and the ligamentum flavum were removed to expose the T10-11 intervertebral space and an intramedullary injection was conducted into the spinal cord. The rats were evaluated preoperatively and daily postoperatively for neurological deficits using the Basso, Beattie and Bresnahan scale. High resolution magnetic resonance images were acquired preoperatively and weekly postoperatively.When score equal to 0, rats were sacrificed for histopathological examination.Results Rats implanted with 9L gliosarcoma cells had a statistically significant median onset of hind limb paraplegia at (16.0±0.4) days, compared with rats in the control group in which neurological deficits were absent. Imaging and pathological cross sections confirmed intramedullary 9L gliosarcoma invading the spinal cord. Rats in the control group showed no significant functional, radiological or histopathological findings of tumour.Conclusions Rats implanted with 9L cells regularly develop paraplegia in a reliable and reproducible manner. The progression of neurological deficits, neuroimaging and histopathological characteristics of intramedullary spinal cord gliomas in rats is comparable with the behaviour of infiltrative intramedullary spinal cord gliomas in patients.

  17. Altered pallido-pallidal synaptic transmission leads to aberrant firing of globus pallidus neurons in a rat model of Parkinson's disease.

    Science.gov (United States)

    Miguelez, Cristina; Morin, Stéphanie; Martinez, Audrey; Goillandeau, Michel; Bezard, Erwan; Bioulac, Bernard; Baufreton, Jérôme

    2012-11-15

    The pattern of activity of globus pallidus (GP) neurons is tightly regulated by GABAergic inhibition. In addition to extrinsic inputs from the striatum (STR-GP) the other source of GABA to GP neurons arises from intrinsic intranuclear axon collaterals (GP-GP). While the contribution of striatal inputs has been studied, notably its hyperactivity in Parkinson's disease (PD), the properties and function of intranuclear inhibition remain poorly understood. Our objective was therefore to test the impact of chronic dopamine depletion on pallido-pallidal transmission. Using patch-clamp whole-cell recordings in rat brain slices, we combined electrical and optogenetic stimulations with pharmacology to differentiate basic synaptic properties of STR-GP and GP-GP GABAergic synapses. GP-GP synapses were characterized by activity-dependent depression and insensitivity to the D(2) receptor specific agonist quinpirole and STR-GP synapses by frequency-dependent facilitation and quinpirole modulation. Chronic dopamine deprivation obtained in 6-OHDA lesioned animals boosted the amplitude of GP-GP IPSCs but did not modify STR-GP transmission and increased the amplitude of miniature IPSCs. Replacement of calcium by strontium confirmed that the quantal amplitude was increased at GP-GP synapses. Finally, we demonstrated that boosted GP-GP transmission promotes resetting of autonomous activity and rebound-burst firing after dopamine depletion. These results suggest that GP-GP synaptic transmission (but not STR-GP) is augmented by chronic dopamine depletion which could contribute to the aberrant GP neuronal activity observed in PD.

  18. Phenotypic Characterization of LEA Rat: A New Rat Model of Nonobese Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Tadashi Okamura

    2013-01-01

    Full Text Available Animal models have provided important information for the genetics and pathophysiology of diabetes. Here we have established a novel, nonobese rat strain with spontaneous diabetes, Long-Evans Agouti (LEA rat derived from Long-Evans (LE strain. The incidence of diabetes in the males was 10% at 6 months of age and 86% at 14 months, while none of the females developed diabetes. The blood glucose level in LEA male rats was between 200 and 300 mg/dl at 120 min according to OGTT. The glucose intolerance in correspondence with the impairment of insulin secretion was observed in male rats, which was the main cause of diabetes in LEA rats. Histological examination revealed that the reduction of β-cell mass was caused by progressive fibrosis in pancreatic islets in age-dependent manner. The intracytoplasmic hyaline droplet accumulation and the disappearance of tubular epithelial cell layer associated with thickening of basement membrane were evident in renal proximal tubules. The body mass index and glycaemic response to exogenous insulin were comparable to those of control rats. The unique characteristics of LEA rat are a great advantage not only to analyze the progression of diabetes, but also to disclose the genes involved in type 2 diabetes mellitus.

  19. A modified rat model of isolated bilateral pulmonary contusion

    OpenAIRE

    Wang, Shaohua; Ruan, Zheng; Jie ZHANG; ZHENG, JIN

    2012-01-01

    The aim of the present study was to create a feasible specific rat model of isolated bilateral pulmonary contusion (PC) and to evaluate the relationship between severity of hypoxemia and quantity of contusion lesions. Anesthetized rats were placed in a prone position. Injury energy ranging from 2.1 to 3.0 J was produced by a falling weight passed through a specially designed arched shield to the bilateral chest wall of rats. After injury (4 h), the contusion volume was measured using computer...

  20. Spontaneous trigeminal allodynia in rats: a model of primary headache.

    Science.gov (United States)

    Oshinsky, Michael L; Sanghvi, Menka M; Maxwell, Christina R; Gonzalez, Dorian; Spangenberg, Rebecca J; Cooper, Marnie; Silberstein, Stephen D

    2012-10-01

    Animal models are essential for studying the pathophysiology of headache disorders and as a screening tool for new therapies. Most animal models modify a normal animal in an attempt to mimic migraine symptoms. They require manipulation to activate the trigeminal nerve or dural nociceptors. At best, they are models of secondary headache. No existing model can address the fundamental question: How is a primary headache spontaneously initiated? In the process of obtaining baseline periorbital von Frey thresholds in a wild-type Sprague-Dawley rat, we discovered a rat with spontaneous episodic trigeminal allodynia (manifested by episodically changing periorbital pain threshold). Subsequent mating showed that the trait is inherited. Animals with spontaneous trigeminal allodynia allow us to study the pathophysiology of primary recurrent headache disorders. To validate this as a model for migraine, we tested the effects of clinically proven acute and preventive migraine treatments on spontaneous changes in rat periorbital sensitivity. Sumatriptan, ketorolac, and dihydroergotamine temporarily reversed the low periorbital pain thresholds. Thirty days of chronic valproic acid treatment prevented spontaneous changes in trigeminal allodynia. After discontinuation, the rats returned to their baseline of spontaneous episodic threshold changes. We also tested the effects of known chemical human migraine triggers. On days when the rats did not have allodynia and showed normal periorbital von Frey thresholds, glycerol trinitrate and calcitonin gene related peptide induced significant decreases in the periorbital pain threshold. This model can be used as a predictive model for drug development and for studies of putative biomarkers for headache diagnosis and treatment.

  1. Early increase in dopamine release in the ipsilateral striatum after unilateral intranigral administration of lactacystin produces spontaneous contralateral rotations in rats.

    Science.gov (United States)

    Konieczny, J; Lenda, T; Czarnecka, A

    2016-06-02

    Since the discovery of the role of the ubiquitin-proteasome system (UPS) in the pathogenesis of Parkinson's disease, UPS inhibitors, such as lactacystin have been used to investigate the relationship between UPS impairment and degeneration of dopamine (DA) neurons. However, mostly long-term neurotoxic effects of lactacystin have been studied in animal models. Therefore, the aim of our study was to investigate behavioral and biochemical changes related to the DA system during the first week following unilateral intranigral injection of lactacystin to rats. We found that lactacystin produced early spontaneous contralateral rotations which were inhibited by combined administration of DA D1 and D2 receptor antagonists. Simultaneously, an increase in the extracellular level of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) was found in the ipsilateral striatum. In contrast, one week after lesion, when turning behavior was no longer visible, a decrease in the extracellular level of DA, DOPAC and HVA was demonstrated. It was accompanied by a substantial reduction in the tissue levels of DA and its metabolites in the lesioned substantia nigra and striatum. We concluded that unilateral intranigral administration of lactacystin produces an early increase in DA neurotransmission which precedes a decrease in the striatal and nigral tissue DA content. It is manifested by the appearance of spontaneous contralateral rotations and an elevation of the extracellular DA level in the ipsilateral striatum. Since similar behavior was previously observed after intranigral administration of rotenone and MPP(+) but not 6-hydroxydopamine (6-OHDA), it may indicate a common mechanism of action shared by these neurotoxins.

  2. Evaluation of Buprenorphine in a Postoperative Pain Model in Rats

    OpenAIRE

    Curtin, Leslie I; Grakowsky, Julie A.; Suarez, Mauricio; Thompson, Alexis C; DiPirro, Jean M.; Martin, Lisa BE; Kristal, Mark B.

    2009-01-01

    We evaluated the commonly prescribed analgesic buprenorphine in a postoperative pain model in rats, assessing acute postoperative pain relief, rebound hyperalgesia, and the long-term effects of postoperative opioid treatment on subsequent opioid exposure. Rats received surgery (paw incision under isoflurane anesthesia), sham surgery (anesthesia only), or neither and were treated postoperatively with 1 of several doses of subcutaneous buprenorphine. Pain sensitivity to noxious and nonnoxious m...

  3. Experimental cell transplantation therapy in rat myocardial infarction model including nude rat preparation.

    Science.gov (United States)

    Dai, Wangde; Kloner, Robert A

    2010-01-01

    As a novel potential therapeutic strategy for cardiac disease, cell transplantation therapy has been extensively investigated in experimental studies and clinical trials. Although encouraging results have been demonstrated, a number of critical questions still remain to be answered. For example, what kind of stem cell and how many cells should be used; what is the best time for cell transplantation after acute myocardial infarction; which delivery approach is better, intravenous injection or direct intramyocardial injection? Transplantation of cells derived from human tissues into experimental animals may elicit an immune rejection. Immunodeficient nude rats provide a useful myocardial infarction model for cell transplantation therapy studies. We introduce our detailed methods of direct intramyocardial injection of immature heart cells and stem cells into the myocardial infarction region of rats and nude rats. Careful maintenance under aseptic conditions and proper surgical technique are essential to improve the survival of immunodeficient rats after surgery.

  4. Development of a Rat Model of Hypothermia

    Science.gov (United States)

    2005-06-01

    general measure of activity, since it can not distinguish the type of locomotor action. Dataloggers are 1.5 cm diameter x 0.5 cm thick cylinders...rat Tc when challenged by cold. Small mammals employ BAT to generate heat to sustain body temperature during cold exposure (1). Moreover, blood...water swims in rats. Physiol. Behav. 54:1081-1084, 1993. 12. Ricco, D.C., E.A. MacArdy and S.C. Kissinger. Association processes in adaptation

  5. Novel Rat Model for Neurocysticercosis Using Taenia solium

    Science.gov (United States)

    Verastegui, Manuela R.; Mejia, Alan; Clark, Taryn; Gavidia, Cesar M.; Mamani, Javier; Ccopa, Fredy; Angulo, Noelia; Chile, Nancy; Carmen, Rogger; Medina, Roxana; García, Hector H.; Rodriguez, Silvia; Ortega, Ynes; Gilman, Robert H.

    2016-01-01

    Neurocysticercosis is caused by Taenia solium infecting the central nervous system and is the leading cause of acquired epilepsy and convulsive conditions worldwide. Research into the pathophysiology of the disease and appropriate treatment is hindered by lack of cost-effective and physiologically similar animal models. We generated a novel rat neurocysticercosis model using intracranial infection with activated T. solium oncospheres. Holtzman rats were infected in two separate groups: the first group was inoculated extraparenchymally and the second intraparenchymally, with different doses of activated oncospheres. The groups were evaluated at three different ages. Histologic examination of the tissue surrounding T. solium cysticerci was performed. Results indicate that generally infected rats developed cysticerci in the brain tissue after 4 months, and the cysticerci were observed in the parenchymal, ventricle, or submeningeal brain tissue. The route of infection did not have a statistically significant effect on the proportion of rats that developed cysticerci, and there was no dependence on infection dose. However, rat age was crucial to the success of the infection. Epilepsy was observed in 9% of rats with neurocysticercosis. In histologic examination, a layer of collagen tissue, inflammatory infiltrate cells, perivascular infiltrate, angiogenesis, spongy change, and mass effect were observed in the tissue surrounding the cysts. This study presents a suitable animal model for the study of human neurocysticercosis. PMID:26216286

  6. Novel rat model for neurocysticercosis using Taenia solium.

    Science.gov (United States)

    Verastegui, Manuela R; Mejia, Alan; Clark, Taryn; Gavidia, Cesar M; Mamani, Javier; Ccopa, Fredy; Angulo, Noelia; Chile, Nancy; Carmen, Rogger; Medina, Roxana; García, Hector H; Rodriguez, Silvia; Ortega, Ynes; Gilman, Robert H

    2015-08-01

    Neurocysticercosis is caused by Taenia solium infecting the central nervous system and is the leading cause of acquired epilepsy and convulsive conditions worldwide. Research into the pathophysiology of the disease and appropriate treatment is hindered by lack of cost-effective and physiologically similar animal models. We generated a novel rat neurocysticercosis model using intracranial infection with activated T. solium oncospheres. Holtzman rats were infected in two separate groups: the first group was inoculated extraparenchymally and the second intraparenchymally, with different doses of activated oncospheres. The groups were evaluated at three different ages. Histologic examination of the tissue surrounding T. solium cysticerci was performed. Results indicate that generally infected rats developed cysticerci in the brain tissue after 4 months, and the cysticerci were observed in the parenchymal, ventricle, or submeningeal brain tissue. The route of infection did not have a statistically significant effect on the proportion of rats that developed cysticerci, and there was no dependence on infection dose. However, rat age was crucial to the success of the infection. Epilepsy was observed in 9% of rats with neurocysticercosis. In histologic examination, a layer of collagen tissue, inflammatory infiltrate cells, perivascular infiltrate, angiogenesis, spongy change, and mass effect were observed in the tissue surrounding the cysts. This study presents a suitable animal model for the study of human neurocysticercosis.

  7. Surgical Intervention to Rescue Hirschsprung Disease in a Rat Model

    Science.gov (United States)

    Stamp, Lincon A; Obermayr, Florian; Pontell, Louise; Young, Heather M; Xie, Dan; Croaker, David H; Song, Zan-Min; Furness, John B

    2015-01-01

    Background/Aims Rats with a spontaneous null mutation in endothelin receptor type B or Ednrb (sl/sl; spotting lethal) lack enteric neurons in the distal bowel and usually die within the first week after birth. This early postnatal lethality limits their use for examining the potential of cell therapy to treat Hirschsprung disease, and for studies of the influence of EDNRB on the mature CNS and vascular systems. Methods We have developed a surgical intervention to prolong the life of the spotting lethal sl/sl rat, in which we perform a colostomy on postnatal (P) day 4–6 rats to avoid the fatal obstruction caused by the lack of colonic enteric neurons. Results The stomas remained patent and functional and the rats matured normally following surgery. Weight gains were comparable between control and Hirschsprung phenotype (sl/sl) rats, which were followed until 4 weeks after surgery (5 weeks old). We confirmed the absence of enteric neurons in the distal colon of rats whose lives were saved by the surgical intervention. Conclusions This study provides a novel approach for studying EDNRB signalling in multiple organ systems in mature rats, including an animal model to study the efficacy of cell therapy to treat Hirschsprung disease. PMID:26424040

  8. Cannabis exacerbates depressive symptoms in rat model induced by reserpine.

    Science.gov (United States)

    Khadrawy, Yasser A; Sawie, Hussein G; Abdel-Salam, Omar M E; Hosny, Eman N

    2017-05-01

    Cannabis sativa is one of the most widely recreational drugs and its use is more prevalent among depressed patients. Some studies reported that Cannabis has antidepressant effects while others showed increased depressive symptoms in Cannabis users. Therefore, the present study aims to investigate the effect of Cannabis extract on the depressive-like rats. Twenty four rats were divided into: control, rat model of depression induced by reserpine and depressive-like rats treated with Cannabis sativa extract (10mg/kg expressed as Δ9-tetrahydrocannabinol). The depressive-like rats showed a severe decrease in motor activity as assessed by open field test (OFT). This was accompanied by a decrease in monoamine levels and a significant increase in acetylcholinesterase activity in the cortex and hippocampus. Na(+),K(+)-ATPase activity increased in the cortex and decreased in the hippocampus of rat model. In addition, a state of oxidative stress was evident in the two brain regions. This was indicated from the significant increase in the levels of lipid peroxidation and nitric oxide. No signs of improvement were observed in the behavioral and neurochemical analyses in the depressive-like rats treated with Cannabis extract. Furthermore, Cannabis extract exacerbated the lipid peroxidation in the cortex and hippocampus. According to the present findings, it could be concluded that Cannabis sativa aggravates the motor deficits and neurochemical changes induced in the cortex and hippocampus of rat model of depression. Therefore, the obtained results could explain the reported increase in the depressive symptoms and memory impairment among Cannabis users. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. A novel model of invasive fungal rhinosinusitis in rats.

    Science.gov (United States)

    Zhang, Fang; An, Yunfang; Li, Zeqing; Zhao, Changqing

    2013-01-01

    Invasive fungal rhinosinusitis (IFRS) is a life-threatening inflammatory disease that affects immunocompromised patients, but animal models of the disease are scarce. This study aimed to develop an IFRS model in neutropenic rats. The model was established in three consecutive steps: unilateral nasal obstruction with Merocel sponges, followed by administration of cyclophosphamide (CPA), and, finally, nasal inoculation with Aspergillus fumigatus. Fifty healthy Wistar rats were randomly divided into five groups, with group I as the controls, group II undergoing unilateral nasal obstruction alone, group III undergoing nasal obstruction with fungal inoculation, group IV undergoing nasal obstruction with administration of CPA, and group V undergoing nasal obstruction with administration of CPA and fungal inoculation. Hematology, histology, and mycology investigations were performed. The changes in the rat absolute neutrophil counts (ANCs) were statistically different across the groups. The administration of CPA decreased the ANCs, whereas nasal obstruction with fungal inoculation increased the ANCs, and nasal obstruction did not change them. Histological examination of the rats in group V revealed the hyphal invasion of sinus mucosa and bone, thrombosis, and tissue infarction. No pathology indicative of IFRS was observed in the remaining groups. Positive rates of fungal culture in tissue homogenates from the maxillary sinus (62.5%) and lung (25%) were found in group V, whereas groups I, II, III, and IV showed no fungal culture in the homogenates. A rat IFRS model was successfully developed through nasal obstruction, CPA-induced neutropenia, and fungal inoculation. The disease model closely mimics the pathophysiology of anthropic IFRS.

  10. Cerebral microbleeds in a neonatal rat model

    Science.gov (United States)

    Carusillo Theriault, Brianna; Woo, Seung Kyoon; Karimy, Jason K.; Keledjian, Kaspar; Stokum, Jesse A.; Sarkar, Amrita; Coksaygan, Turhan; Ivanova, Svetlana; Gerzanich, Volodymyr

    2017-01-01

    Background In adult humans, cerebral microbleeds play important roles in neurodegenerative diseases but in neonates, the consequences of cerebral microbleeds are unknown. In rats, a single pro-angiogenic stimulus in utero predisposes to cerebral microbleeds after birth at term, a time when late oligodendrocyte progenitors (pre-oligodendrocytes) dominate in the rat brain. We hypothesized that two independent pro-angiogenic stimuli in utero would be associated with a high likelihood of perinatal microbleeds that would be severely damaging to white matter. Methods Pregnant Wistar rats were subjected to intrauterine ischemia (IUI) and low-dose maternal lipopolysaccharide (mLPS) at embryonic day (E) 19. Pups were born vaginally or abdominally at E21-22. Brains were evaluated for angiogenic markers, microhemorrhages, myelination and axonal development. Neurological function was assessed out to 6 weeks. Results mRNA (Vegf, Cd31, Mmp2, Mmp9, Timp1, Timp2) and protein (CD31, MMP2, MMP9) for angiogenic markers, in situ proteolytic activity, and collagen IV immunoreactivity were altered, consistent with an angiogenic response. Vaginally delivered pups exposed to prenatal IUI+mLPS had spontaneous cerebral microbleeds, abnormal neurological function, and dysmorphic, hypomyelinated white matter and axonopathy. Pups exposed to the same pro-angiogenic stimuli in utero but delivered abdominally had minimal cerebral microbleeds, preserved myelination and axonal development, and neurological function similar to naïve controls. Conclusions In rats, pro-angiogenic stimuli in utero can predispose to vascular fragility and lead to cerebral microbleeds. The study of microbleeds in the neonatal rat brain at full gestation may give insights into the consequences of microbleeds in human preterm infants during critical periods of white matter development. PMID:28158198

  11. Ototoxicity of boric acid powder in a rat animal model.

    Science.gov (United States)

    Salihoglu, Murat; Dogru, Salim; Cesmeci, Enver; Caliskan, Halil; Kurt, Onuralp; Kuçukodaci, Zafer; Gungor, Atila

    2017-04-22

    Boric acid, which has antiseptic and acidic properties, is used to treat external and middle ear infections. However, we have not found any literature about the effect of boric acid powder on middle ear mucosa and inner ear. The purpose of this study is to investigate possible ototoxic effects of boric acid powder (BAP) on cochlear outer hair cell function and histological changes in middle ear mucosa in a rat animal model. Twenty healthy, mature Wistar albino rats were used in this study. The rats were divided into two groups, Group A and Group B, each of which consisted of 10 rats. Initially, the animals in each group underwent distortion product otoacoustic emissions (DPOAE) testing of their right and left ears. After the first DPOAE test, a surgical microscope was used to make a small perforation in both ears of the rats in each group, and a second DPOAE test was used to measure both ears in all of the rats. BAP was applied to the right middle ear of the rats using tympanic membrane perforation, and the DPOAEs were measured immediately after the BAP application. The histological changes and DPOAEs were evaluated three days later in Group A and 40 days later in Group B. No significant differences were found at all of the DPOAE frequencies. In Group A, mild inflammation of the middle ear mucosa was found on the third day after BAP application. In Group B, BAP caused mild inflammatory changes on the 40th day, which declined over time. Those changes did not lead to significant fibrosis within the mucosa. In rats, BAP causes mild inflammation in middle ear mucosa and it has no ototoxic effects on cochlear outer hair cell function in the inner ear of rats. Copyright © 2017 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

  12. Establishment of a rat model for canine necrotizing meningoencephalitis (NME).

    Science.gov (United States)

    Park, E-S; Uchida, K; Nakayama, H

    2014-11-01

    The pathogenesis of necrotizing meningoencephalitis (NME), necrotizing leukoencephalitis (NLE), and granulomatous meningoencephalomyelitis (GME) is still uncertain, although they are considered immune-mediated diseases. The purpose of the present study is to generate a rodent model(s) of these diseases. Rats were injected with rat cerebral or cerebellar homogenate. Rats injected with cerebral homogenate (Cbr) exhibited vacuolar or malacic changes mainly in the cerebral cortex. CD3-positive T cells and Iba-1-positive and CD163-negative microglia infiltrated and activated around the lesions. IgG deposited in the glial fibrillary acid protein (GFAP)-positive glia limitans from the early phase, and CD3-positive T cells attached to GFAP-positive astrocytes. Autoantibodies against GFAP were detected in the sera. These pathological features of Cbr rats were consistent with those of canine NME. In contrast, rats injected with cerebral homogenate (Cbe) exhibited demyelinating lesions with inflammatory reactions in the cerebellum, brainstem, and spinal cord. The presence of demyelination and autoantibodies against myelin proteins in Cbe rats was similar to murine experimental autoimmune encephalitis and differed from NME, NLE, and GME. All the present findings indicate that autoantibodies together with microglia and T cells may play a major role in the pathogenesis of idiopathic canine meningoencephalomyelitis. © The Author(s) 2014.

  13. Increased GABAB receptor signaling in a rat model for schizophrenia.

    Science.gov (United States)

    Selten, Martijn M; Meyer, Francisca; Ba, Wei; Vallès, Astrid; Maas, Dorien A; Negwer, Moritz; Eijsink, Vivian D; van Vugt, Ruben W M; van Hulten, Josephus A; van Bakel, Nick H M; Roosen, Joey; van der Linden, Robert J; Schubert, Dirk; Verheij, Michel M M; Kasri, Nael Nadif; Martens, Gerard J M

    2016-09-30

    Schizophrenia is a complex disorder that affects cognitive function and has been linked, both in patients and animal models, to dysfunction of the GABAergic system. However, the pathophysiological consequences of this dysfunction are not well understood. Here, we examined the GABAergic system in an animal model displaying schizophrenia-relevant features, the apomorphine-susceptible (APO-SUS) rat and its phenotypic counterpart, the apomorphine-unsusceptible (APO-UNSUS) rat at postnatal day 20-22. We found changes in the expression of the GABA-synthesizing enzyme GAD67 specifically in the prelimbic- but not the infralimbic region of the medial prefrontal cortex (mPFC), indicative of reduced inhibitory function in this region in APO-SUS rats. While we did not observe changes in basal synaptic transmission onto LII/III pyramidal cells in the mPFC of APO-SUS compared to APO-UNSUS rats, we report reduced paired-pulse ratios at longer inter-stimulus intervals. The GABAB receptor antagonist CGP 55845 abolished this reduction, indicating that the decreased paired-pulse ratio was caused by increased GABAB signaling. Consistently, we find an increased expression of the GABAB1 receptor subunit in APO-SUS rats. Our data provide physiological evidence for increased presynaptic GABAB signaling in the mPFC of APO-SUS rats, further supporting an important role for the GABAergic system in the pathophysiology of schizophrenia.

  14. Detection of visual signals by rats: A computational model

    Science.gov (United States)

    We applied a neural network model of classical conditioning proposed by Schmajuk, Lam, and Gray (1996) to visual signal detection and discrimination tasks designed to assess sustained attention in rats (Bushnell, 1999). The model describes the animals’ expectation of receiving fo...

  15. The Use of Perinatal 6-Hydroxydopamine to Produce a Rodent Model of Lesch-Nyhan Disease.

    Science.gov (United States)

    Knapp, Darin J; Breese, George R

    Lesch-Nyhan disease is a neurologically, metabolically, and behaviorally devastating condition that has eluded complete characterization and adequate treatment. While it is known that the disease is intimately associated with dysfunction of the hypoxanthine phosphoribosyltransferase 1 (HPRT1) gene that codes for an enzyme of purine metabolism (hypoxanthine-guanine phosphoribosyltransferase) and is associated with neurological, behavioral, as well as metabolic dysfunction, the mechanisms of the neurobehavioral manifestations are as yet unclear. However, discoveries over the past few decades not only have created useful novel animal models (e.g., the HPRT-deficient mouse and the serendipitously discovered perinatal 6-hydroxydopamine (6-OHDA lesion model), but also have expanded into epigenetic, genomic, and proteomic approaches to better understand the mechanisms underlying this disease. The perinatal 6-OHDA model, in addition to modeling self-injury and dopamine depletion in the clinical condition, also underscores the profound importance of development in the differential course of maladaptive progression in the face of a common/single neurotoxic insult at different ages. Recent developments from clinical and basic science efforts attest to the fact that while the disease would seem to have a simple single gene defect at its core, the manifestations of this defect are profound and unexpectedly diverse. Future efforts employing the 6-OHDA model and others in the context of the novel technologies of genome editing, chemo- and opto-genetics, epigenetics, and further studies on the mechanisms of stress-induced maladaptations in brain all hold promise in taking our understanding of this disease to the next level.

  16. Infrared Thermography in Serotonin-Induced Itch Model in Rats

    DEFF Research Database (Denmark)

    Jasemian, Yousef; Gazerani, Parisa; Dagnæs-Hansen, Frederik

    2012-01-01

    The study validated the application of infrared thermography in a serotonin-induced itch model in rats since the only available method in animal models of itch is the count of scratching bouts. Twenty four adult Sprague-Dawley male rats were used in 3 experiments: 1) local vasomotor response...... with no scratching reflex was investigated. Serotonin elicited significant scratching and lowered the local temperature at the site of injection. A negative dose-temperature relationship of serotonin was found by thermography. Vasoregulation at the site of serotonin injection took place in the absence of scratching...... reflexes. Thermography is a reliable, non-invasive, and objective method for assessment in serotonin-induced itch model in rat....

  17. Infrared Thermography in Serotonin-Induced Itch Model in Rats

    DEFF Research Database (Denmark)

    Jasemian, Yousef; Gazerani, Parisa; Dagnæs-Hansen, Frederik

    2012-01-01

    The study validated the application of infrared thermography in a serotonin-induced itch model in rats since the only available method in animal models of itch is the count of scratching bouts. Twenty four adult Sprague-Dawley male rats were used in 3 experiments: 1) local vasomotor response...... with no scratching reflex was investigated. Serotonin elicited significant scratching and lowered the local temperature at the site of injection. A negative dose-temperature relationship of serotonin was found by thermography. Vasoregulation at the site of serotonin injection took place in the absence of scratching...... reflexes. Thermography is a reliable, non-invasive, and objective method for assessment in serotonin-induced itch model in rat....

  18. Characterizing a Rat Brca2 Knockout Model

    Science.gov (United States)

    2007-05-01

    this treatment (Figure 2b). Aspermatogenesis Meiosis in Brca2/ rats proceeds normally through leptotene and early zygotene (Figure 3a) with 40...Zygotene Late Zygotene Scp3Scp3 Scp3 Scp3 Scp1 CREST CRESTCREST Merge a b Figure 3 (a) Meiosis in Brca2/ spermatocytes does not progress beyond late...control of noncrossover and crossover recombination during meiosis . Cell 106: 47–57. Barlow C, Liyanage M, Moens PB, Tarsounas M, Nagashima K, Brown K

  19. ISOLATION OF HEPATIC OVAL CELLS FROM DIFFERENT MODEL RATS INCLUDING DIABETIC RATS

    Institute of Scientific and Technical Information of China (English)

    LU Ying-li; YE Ting-ting; XIA Fang-zhen; WANG Ning-jian; YANG Hua; CHEN Yi

    2009-01-01

    Objective To acquire oval cells (progenitor stem cells) from adult rat liver of different models including diabetic rats. Methods Thirty Sprague-Dawley (SD) rats were divided into 5 groups randomly: control, 2-acetylaminofluorene (2-AAF), 2-AAF+partial hepatectomy (PH), 2-AAF+carbon tetrachloride (CCl4), and diabetic groups. As two-step collagenase perfusion protocol of Seglen, oval cells were isolated by Percoll density gradient centrifugation. Thy1.1 positive cells were sorted by flow cytometry, and then cultured in Dulbeccos minimum Eagles medium (DMEM). Immunofluorescence staining was applied to labelling Thy1.1. Results Different rates of Thy1.1 positive oval cells were found in different rat model groups: 0.5% in 2-AAF, 0.3% in 2-hAAF+PH, 0.2% in 2-AAF+CCl4 , 0.1% in diabetic, and 0.0% in control. Isolated cells adhered to plate with fusiform or polygon as epithelial cells. Conclusion Progenitor stem cells exist in injured liver tissue including those from diabetic rats.

  20. 帕金森病动物模型的研究进展%Research Development of Animal Models of Parkinson Disease

    Institute of Scientific and Technical Information of China (English)

    陈丽

    2011-01-01

    Parkinson disease( PD )is a common neurodegenerative disease in the central nervous system of old people,whose quality of life decline sharply,calling for more and more attention on PD research. Both the research on pathogenesis or treatment need the animal models. Reserpine model is the earliest PD model, followed by plenty of other animal models such as methylamthetamine model,6-OHDA model,MTPT model, rotenone model,and herbicide model etc. ,among which 6-OHDA and MTPT models are used more widely.%帕金森病(PD)是老年人常见的中枢神经系统退行性疾病,导致患者的生活质量急剧下降.目前对PD的研究越来越受到关注.无论研究其发病机制还是探索新的治疗方法都离不开PD动物模型.利血平模型是最早建立的PD模型,后来又逐渐出现了甲基苯丙胺模型、6-羟基多巴胺(6-OHDA)模型、1-甲基-4-苯基-1,2,4,6-四氢吡啶(MPTP)模型、鱼藤酮模型、除草剂模型等众多动物模型,其中以6-OHDA模型和MTPT模型应用较多.

  1. Gait Impairment in a Rat Model of Focal Cerebral Ischemia

    Directory of Open Access Journals (Sweden)

    Saara Parkkinen

    2013-01-01

    Full Text Available The availability of proper tests for gait evaluation following cerebral ischemia in rats has been limited. The automated, quantitative CatWalk system, which was initially designed to measure gait in models of spinal cord injury, neuropathic pain, and peripheral nerve injury, is said to be a useful tool for the study of motor impairment in stroke animals. Here we report our experiences of using CatWalk XT with rats subjected to transient middle cerebral artery occlusion (MCAO, during their six-week followup. Large corticostriatal infarct was confirmed by MRI in all MCAO rats, which was associated with severe sensorimotor impairment. In contrast, the gait impairment was at most mild, which is consistent with seemingly normal locomotion of MCAO rats. Many of the gait parameters were affected by body weight, walking speed, and motivation despite the use of a goal box. In addition, MCAO rats showed bilateral compensation, which was developed to stabilize proper locomotion. All of these interferences may confound the data interpretation. Taken together, the translational applicability of CatWalk XT in evaluating motor impairment and treatment efficacy remains to be limited at least in rats with severe corticostriatal infarct and loss of body weight.

  2. A novel rat contact lens model for Fusarium keratitis

    Science.gov (United States)

    Abou Shousha, Mohamed; Santos, Andrea Rachelle C.; Oechsler, Rafael A.; Iovieno, Alfonso; Maestre-Mesa, Jorge; Ruggeri, Marco; Echegaray, Jose J.; Dubovy, Sander R.; Perez, Victor L.; Miller, Darlene; Alfonso, Eduardo C.

    2013-01-01

    Purpose The aim of this study was to develop and characterize a new contact lens–associated fungal keratitis rat model and to assess the ability of non-invasive spectral-domain optical coherence tomography (SD-OCT) to detect pathological changes in vivo in fungal keratitis. Methods We used SD-OCT to image and measure the cornea of Sprague Dawley rats. Fusarium infection was initiated in the rat eye by fitting Fusarium solani–soaked contact lenses on the experimental eye, while the control animals received contact lenses soaked in sterile saline. The fungal infection was monitored with periodic slit-lamp examination and in vivo SD-OCT imaging of the rat eye, and confirmed by histology, counting of viable fungi in the infected rat cornea, and PCR with specific primers for Fusarium sp. Results We imaged and measured the rat cornea with SD-OCT. Custom-made contact lenses were developed based on the OCT measurements. Incubation of contact lenses in a F. solani suspension resulted in biofilm formation. We induced contact lens–associated Fusarium keratitis by fitting the rat eyes for 4 h with the Fusarium-contaminated contact lenses. The SD-OCT images of the cornea correlated well with the slit-lamp and histopathological results and clearly defined clinical signs of infection, namely, increased corneal thickening, loss of epithelial continuity, hyper-reflective areas representing infiltrates, and endothelial plaques characteristic of fungal infection. Moreover, in three cases, SD-OCT detected the infection without any clear findings on slit-lamp examination. Infection was confirmed with histological fungal staining, PCR, and microbiological culture positivity. Conclusions We developed a highly reproducible rat contact lens model and successfully induced contact lens–associated Fusarium keratitis in this model. The clinical presentation of contact lens–associated Fusarium keratitis in the rat model is similar to the human condition. SD-OCT is a valuable tool that

  3. Development of Wistar rat model of insulin resistance

    Institute of Scientific and Technical Information of China (English)

    Jing Ai; Ning Wang; Mei Yang; Zhi-Min Du; Yong-Chun Zhang; Bao-Feng Yang

    2005-01-01

    AIM: To establish a simplified and reliable animal model of insulin resistance with low cost in Wistar rats. METHODS: Wistar rats were treated with a high fat emulsion by ig for 10 d. Changes of the diets, drinking and body weight were monitored every day and insulin resistance was evaluated by hyperinsulinemic-euglycemicclamp techniques and short insulin tolerance test using capillary blood glucose. Morphologic changes of liver, fat, skeletal muscles, and pancreatic islets were assessed under light microscope. mRNA expressions of GLUT2 and α-glucosidase in small intestine epithelium, GLUT4 in skeletal muscles and Kir6.2 in beta cell of islets were determined by in situ hybridization.RESULTS: KITT was smaller in treated animals (4.5±0.9)than in untreated control Wistar rats (6.8±1.5), and so was glucose injection rate. Both adipocyte hypertrophy and large pancreatic islets were seen in high fat fed rats,but no changes of skeletal muscles and livers wereobserved. mRNA levels of GLUT2, α-glucosidase in small intestinal epithelium and Kir6.2 mRNA in beta cells of islets increased, whereas that of GLUT4 in skeletal muscles decreased in high fat fed group compared with normal control group.CONCLUSION: An insulin resistance animal model in Wistar rats is established by ig special fat emulsion.

  4. Palmitoyl Serotonin Inhibits L-dopa-induced Abnormal Involuntary Movements in the Mouse Parkinson Model.

    Science.gov (United States)

    Park, Hye-Yeon; Ryu, Young-Kyoung; Go, Jun; Son, Eunjung; Kim, Kyoung-Shim; Kim, Mee Ree

    2016-08-01

    L-3,4-dihydroxyphenylalanine (L-DOPA) is the most common treatment for patients with Parkinson's disease (PD). However, long term use of L-DOPA for PD therapy lead to abnormal involuntary movements (AIMs) known as dyskinesia. Fatty acid amide hydrolase (FAAH) is enriched protein in basal ganglia, and inhibition of the protein reduces dyskinetic behavior of mice. Palmitoyl serotonin (PA-5HT) is a hybrid molecule patterned after arachidonoyl serotonin, antagonist of FAAH. However, the effect of PA-5HT on L-DOPA-induced dyskinesia (LID) in PD have not yet been elucidated. To investigate whether PA-5HT relieve LID in PD and decrease hyperactivation of dopamine D1 receptors, we used the 6-hydroxydopomine (6-OHDA)-lesioned mouse model of PD and treated the L-DOPA (20 mg/kg) for 10 days with PA-5HT (0.3 mg/kg/day). The number of wall contacts with the forelimb in the cylinder test was significantly decreased by 6-OHDA lesion in mice and the pharmacotherapeutic effect of L-DOPA was also revealed in PA-5HT-treated mice. Moreover, in AIMs test, PA-5HT-treated mice showed significant reduction of locomotive, axial, limb, and orofacial AIMs score compared to the vehicle-treated mice. LID-induced hyper-phosphorylation of ERK1/2 and overexpression of FosB/ΔFosB was markedly decreased in 6-OHDA-lesioned striatum of PA-5HT-treated mice, indicating that PA-5HT decreased the dopamine D1 receptor-hyperactivation induced by chronic treatment of L-DOPA in dopamine-denervated striatum. These results suggest that PA-5HT effectively attenuates the development of LID and enhance of ERK1/2 phosphorylation and FosB/ΔFosB expression in the hemi-parkinsonian mouse model. PA-5HT may have beneficial effect on the LID in PD.

  5. A New Rat Model for Orthotopic Abdominal Wall Allotransplantation

    Directory of Open Access Journals (Sweden)

    William W. Lao, MD

    2014-04-01

    Conclusions: Technical, histological, and immunological aspects of a new rat model are described. These results give clues to what occurs in human abdominal wall transplantation. In addition, Th1, a proinflammatory cell, was found to be a potential biomarker for allograft rejection.

  6. Reducing Fear of the Laboratory Rat: A Participant Modeling Approach.

    Science.gov (United States)

    Barber, Nigel

    1994-01-01

    Reports on the use of participant modeling in a study of 56 college-level students to reduce fear of laboratory rats. Discovers that even mild exposure reduced fear significantly. Finds that women were more fearful initially but that their fear reduction was equal to that of men. (CFR)

  7. A rat model with an isolated bladder in situ

    DEFF Research Database (Denmark)

    Thulesen, J; Olsen, P S; Grevstad, J U

    1997-01-01

    This paper describes our method for producing a rat model with an isolated bladder in situ in which the bladder makes no contact with urine. First, the right kidney was removed, then an external catheter was placed in the right ureter for bladder infusions, and next the left ureter was anatomosed...

  8. Pharmacokinetics of Dexamethasone in a Rat Model of Rheumatoid Arthritis

    OpenAIRE

    Earp, Justin C; Pyszczynski, Nancy A.; Molano, Diana S.; Jusko, William J.

    2008-01-01

    Dexamethasone (DEX) is often given for the treatment of rheumatoid arthritis and clinical dosing regimens of DEX have often been based empirically. This study tests whether the inflammation processes in a rat model of rheumatoid arthritis alters the clearance and volume of distribution of DEX when compared with healthy controls. Groups of healthy and arthritic male Lewis rats received either a low (0.225 mg/kg) or high (2.25 mg/kg) intramuscular dose of DEX. Arthritis was induced by intraderm...

  9. OPTIMIZATION OF TETRANDRINE TREATMENT IN RAT HEPATIC FIBROSIS MODEL

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Objective To optimize the therapeutic dosage of tetrandrine (Tet) in rat hepatic fibrosis model. Methods 50 Wistar rats were divided into 5 groups at random including normal control, model control, Tettreated model groups of l0mg·kg-1 ·d-1, 5mg·kg-1 ·d-1 and 2.5mg·kg-1 ·d-1 ( n =10 in each group). All rats,except for the normal controls, were injected with axenic porcine serum (0. 5ml each time, twice a week) intraperitoneally for 8 weeks to establish hepatic fibrosis. After the 8th week, rats of Tet-treated model groups were given by gavage once a day with different doses of Tet for another 8 weeks. Then the liver function, serum levels of hyaluronic acid (HA) , laminin ( LM) , and procollagen type Ⅲ (PCⅢ) were tested. Collagen type Ⅰ and Ⅲ, pathological changes in liver tissue were also assessed. Results Most indices of liver function including alanine minotransferase (ALT), aspartate aminotransferase ( AST), albumin (ALB), albumin/globulin ratio (A/G) and alkaline phosphatase (ALP) improved significantly in Tet-treated groups with the exception of γ-glutamyl transpeptidase (γ-GT) and total bilirubin (TBIL). Secondly, markedly lowered levels of HA, LM and collagen type Ⅰ, Ⅲ were also detected by radioimmunology and immunohistochemistry in the 5 mg · kg- 1 · d- 1 Tet-treated model group. Moreover, pathological findings confirmed the statistically significant improvement in hepatofibrotic degree resulted from the treatment of 5mg · kg- 1 · d-1 rather than other doses of Tet. Conclusion For experimental Wistar rats, Tet exhibited an anti-hepatofibrotic action in doses within the range of 2.5mg·kg-1 ·d-1 to 10mg·kg 1 ·d-1, and 5mg·kg-1 ·d-1 may be theoptimum one among all doses.

  10. A new rat model for studies of hypokinesia and antiorthostasis

    Science.gov (United States)

    Musacchia, X. J.; Deavers, D. R.

    1982-01-01

    A new rat model (suspension and immobilization) is described for induction of hypokinesia and orthostatic manipulations. Hypokinetic responses were comparable to those in prolonged bed rest and weightlessness in humans, body or limb casted and small cage restrained animals. Responses to antiorthostasis (15 to 20 deg head down tilt) in rats were similar to those in neutral bouyancy tests in humans and animals and to those in prolonged bed rest in humans. During seven days of hypokinesia there was an atrophy of the gastrocnemius and increased excretion of urinary nitrogeneous end products. The antiorthostatic (AOH) 15 to 20 deg head down tilt resulted in diuresis, natriuresis and kaliuresis. No comparable responses were observed in orthostatic hypokinetic (OH) rats. Readaptation from AOH and OH occurred during one week recovery in metabolic cage conditions.

  11. Establishment of novel rat models for premalignant breast disease

    Institute of Scientific and Technical Information of China (English)

    Wang Feng; Ma Zhongbing; Wang Fei; Fu Qinye; Fang Yunzhi; Zhang Qiang; Gao Dezong

    2014-01-01

    Background Breast cancer has become one of the most common malignant tumors among females over the past several years.Breast carcinogenesis is a continuous process,which is featured by the normal epithelium progressing to premalignant lesions and then to invasive breast cancer (IBC).Targeting premalignant lesions is an effective strategy to prevent breast cancer.The establishment of animal models is critical to study the mechanisms of breast carcinogenesis,which will facilitate research on breast cancer prevention and drug behaviors.In this study,we established a feasible chemically-induced rat model of premalignant breast cancer.Methods Following the administration of the drugs (carcinogen,estrogen,and progestogen) to Sprague-Dawley (SD) rats,tumors or suspicious tumors were identified by palpation or ultrasound imaging,and were surgically excised for pathological evaluation.A series of four consecutive steps were carried out in order to determine the carcinogen:7,12-dimethylbenzaanthracene (DMBA) or 1-methyl-1-nitrosourea,the route of carcinogen administration,the administration period of estrogen and progestogen,and the DMBA dosage.Results Stable premalignant lesions can be induced in SD rats on administration of DMBA (15 mg/kg,administered three times) followed by administration of female hormones 5-day cycle.Results were confirmed by ultrasound and palpation.Conclusion Under the premise of drug dose and cycle,DMBA combined with estrogen and progestogen can be used as a SD rat model for breast premalignant lesions.

  12. New rat models of iron sucrose-induced iron overload.

    Science.gov (United States)

    Vu'o'ng Lê, Bá; Khorsi-Cauet, Hafida; Villegier, Anne-Sophie; Bach, Véronique; Gay-Quéheillard, Jérôme

    2011-07-01

    The majority of murine models of iron sucrose-induced iron overload were carried out in adult subjects. This cannot reflect the high risk of iron overload in children who have an increased need for iron. In this study, we developed four experimental iron overload models in young rats using iron sucrose and evaluated different markers of iron overload, tissue oxidative stress and inflammation as its consequences. Iron overload was observed in all iron-treated rats, as evidenced by significant increases in serum iron indices, expression of liver hepcidin gene and total tissue iron content compared with control rats. We also showed that total tissue iron content was mainly associated with the dose of iron whereas serum iron indices depended essentially on the duration of iron administration. However, no differences in tissue inflammatory and antioxidant parameters from controls were observed. Furthermore, only rats exposed to daily iron injection at a dose of 75 mg/kg body weight for one week revealed a significant increase in lipid peroxidation in iron-treated rats compared with their controls. The present results suggest a correlation between iron overload levels and the dose of iron, as well as the duration and frequency of iron injection and confirm that iron sucrose may not play a crucial role in inflammation and oxidative stress. This study provides important information about iron sucrose-induced iron overload in rats and may be useful for iron sucrose therapy for iron deficiency anemia as well as for the prevention and diagnosis of iron sucrose-induced iron overload in pediatric patients.

  13. Groove model of tibia-femoral osteoarthritis in the rat.

    Science.gov (United States)

    de Visser, Huub M; Weinans, Harrie; Coeleveld, Katja; van Rijen, Mattie H P; Lafeber, Floris P J G; Mastbergen, Simon C

    2017-03-01

    Several experimental models of osteoarthritis in rats are used to study the pathophysiology of osteoarthritis. Many mechanically induced models have the limitation that permanent joint instability is induced by, for example, ligament transection or meniscal damage. This permanent instability will counteract the potential beneficial effects of therapy. The groove model of osteoarthritis uses a one-time trigger, surgically induced cartilage damage on the femoral condyles, and has been validated for the canine tibia-femoral compartment. The present study evaluates this model for the rat knee joint. The articular cartilage of the weight bearing surface of both femoral condyles and trochlea were damaged (grooved) without damaging the underlying subchondral bone. Severity of joint degeneration was histologically assessed, in addition to patella cartilage damage, and subchondral bone characteristics by means of (contrast-enhanced) micro-CT. Mild histological degeneration of the surgically untouched tibial plateau cartilage was observed in addition to damage of the femoral condyles, without clear synovial tissue inflammation. Contrast enhanced micro-CT demonstrated proteoglycan loss of the surgically untouched patella cartilage. Besides, a more sclerotic structure of the subchondral bone was observed. The tibia-femoral groove model in a rat results in mild knee joint degeneration, without permanent joint instability and joint inflammation. This makes the rat groove model a useful model to study the onset and progression of post-traumatic non-inflammatory osteoarthritis, creating a relatively sensitive model to study disease modifying osteoarthritic drugs. © 2016 The Authors. Journal of Orthopaedic Research published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 35:496-505, 2017.

  14. 钙调激酶Ⅱ抑制剂对帕金森病运动并发症大鼠谷氨酸受体GluR1亚基特性的影响%The research on the property of GluR1 subunit in rat models of motor complication of Parkinson' s disease after CaMKⅡ inhibitor KN-93 treatment

    Institute of Scientific and Technical Information of China (English)

    巴茂文; 孔敏; 于国平; 孙旭文; 刘竹丽

    2010-01-01

    Objective To investigate the alteration of phosphorylated GluR1Ser831 and behavioural effects in a rat model of levodopa-induced motor complications after Ca2 +/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) inhibitor KN-93 treatment. Methods The hemi-parkinsonian rat model was produced by injecting stereotaxically 6-OHDA to right medial forebrain bundle. Then, rats were intraperitoneally treated with levodopa ( 50 mg/kg with benserazide 12.5 mg/kg,twice daily) for 22 days. On day 23 ,rats received KN-93 before levodopa administration. Rotational duration was estimated. After sacrificed, subcellualr distribution of GluR1 and phosphorylated GluR1Ser831 were observed by western blot. Results The study showed that CaMKⅡ inhibitor KN-93 prolonged rotational duration. Moreover, KN-93 could regulate subcellular distribution of GluR1 and reduce hyperphosphorylation of GluR1 Ser831, which was closely associated with levodopa-induced motor complications. The expression of membrane GluR1 and phosphorylated GluR1Ser831 was (83.4 ±4.2)% and (47.2 ±5.2)% ,respectively. Conclusions These results indicated that activation of CaMKⅡ contributed to development of motor complications, through a mechanism that involved an increase in phosphorylated GluR1 Ser831. Pharmaceuticals which act to inhibit CaMKⅡ may be useful in the treatment of the motor complications in parkinsonian patients.%目的 探讨钙调激酶Ⅱ抑制剂KN-93对帕金森病运动并发症大鼠行为学及GluR1831位丝氨酸磷酸化的影响.方法 将6-羟基多巴立体定向注射于大鼠前脑内侧束建立帕金森病动物模型.对模型成功的帕金森病大鼠接受每日2次左旋多巴(每公斤体质量50mg左旋多巴加每公斤体质量12.5 mg苄丝肼)腹腔注射,持续22d.在第23天左旋多巴注射前,帕金森病大鼠给予KN-93处理.评估旋转反应时间,采用蛋白印迹法及免疫组织化学检测纹状体区GluR1和GluR1831位丝氨酸磷酸化表达情况.结果

  15. Molecular mechanism of icariin on rat asthmatic model

    Institute of Scientific and Technical Information of China (English)

    XU Chang-qing; LE Jing-jing; DUAN Xiao-hong; DU Wei-jing; LIU Bao-jun; WU Jing-feng; CAO Yu-xue; DONG Jing-cheng

    2011-01-01

    Background Effects of icariin on airway inflammation in asthmatic rats and the intervention of LPS induced inflammation are interfered with the machanism of icariin. Our study aimed to observe the effect of icariin on ovalbumin-induced imbalance of Th1/Th2 cytokine expression and its mechanism.Methods Sixty male SD rats were randomly divided into control group (PBS), asthma group (ovalbumin (OVA)-induced),dexamethasone group, and OVA+icariin low, medium and high dose groups (5, 10, 20 mg/kg, respectively). Each group had ten rats. The model of OVA sensitization was a rat asthma model. Enzyme-linked immunosorbent assay (ELISA)method was used to observe the effects of icariin on interleukin-4 (IL-4) and inerferon Y (IFN-Y) in rats' lung tissue.Immunohistochemical staining was applied to detect the intervention effects of icariin on T cells (T-bet) and gatabinding protein 3 (GATA-3) in rat pulmonary tissue. Realtime RT-PCR was used to observe the intervention effects of icariin on T-bet and GATA-3 mRNA expression in rat pulmonary tissue and spleen lymphocytes. Western blotting was used to observe the icariin intervention effects on T-bet, GATA-3 and nuclear factor-Kappa B (NF-κB) p65 protein expressions in rat pulmonary tissue.Results The ELISA results from pulmonary tissue showed that IL-4 expression was significantly reduced (P <0.05),while the IFN-y expression increased but not significantly when we compared OVA+icariin medium and high dose groups with the asthma group. Immunohistochemical staining of pulmonary tissue showed that the GATA-3 decreased significantly while the T-bet staining did not change in the OVA+icariin high dose group. In pulmonary tissue and spleen lymphocytes T-bet and GATA-3 mRNA expressions were significantly reduced (P <0.05) in icariin treatment groups compared with the asthma model group. GATA-3 and T-bet mRNA in rat spleen lymphocytes in the asthma group were higher than in the control group. GATA-3 mRNA expression in pulmonary

  16. Generation and characterization of rat liver stem cell lines and their engraftment in a rat model of liver failure.

    Science.gov (United States)

    Kuijk, Ewart W; Rasmussen, Shauna; Blokzijl, Francis; Huch, Meritxell; Gehart, Helmuth; Toonen, Pim; Begthel, Harry; Clevers, Hans; Geurts, Aron M; Cuppen, Edwin

    2016-02-26

    The rat is an important model for liver regeneration. However, there is no in vitro culture system that can capture the massive proliferation that can be observed after partial hepatectomy in rats. We here describe the generation of rat liver stem cell lines. Rat liver stem cells, which grow as cystic organoids, were characterized by high expression of the stem cell marker Lgr5, by the expression of liver progenitor and duct markers, and by low expression of hepatocyte markers, oval cell markers, and stellate cell markers. Prolonged cultures of rat liver organoids depended on high levels of WNT-signalling and the inhibition of BMP-signaling. Upon transplantation of clonal lines to a Fah(-/-) Il2rg(-/-) rat model of liver failure, the rat liver stem cells engrafted into the host liver where they differentiated into areas with FAH and Albumin positive hepatocytes. Rat liver stem cell lines hold potential as consistent reliable cell sources for pharmacological, toxicological or metabolic studies. In addition, rat liver stem cell lines may contribute to the development of regenerative medicine in liver disease. To our knowledge, the here described liver stem cell lines represent the first organoid culture system in the rat.

  17. A chronic ulcerative colitis model in rats

    Institute of Scientific and Technical Information of China (English)

    Li Zheng; Zhen Qiang Gao; Shu Xian Wang

    2000-01-01

    @@ INTRODUCTION In recent years, there have been many reports about animal model to investigate drugs for inflammatory bowel diseases (IBD). The experimental animal model often used is acetic acid-induced damage of colonic muscosa. In the present study, this animal model was investigated by administering various concentrations of TNBS.

  18. Signal attenuation as a rat model of obsessive compulsive disorder.

    Science.gov (United States)

    Goltseker, Koral; Yankelevitch-Yahav, Roni; Albelda, Noa S; Joel, Daphna

    2015-01-09

    In the signal attenuation rat model of obsessive-compulsive disorder (OCD), lever-pressing for food is followed by the presentation of a compound stimulus which serves as a feedback cue. This feedback is later attenuated by repeated presentations of the stimulus without food (without the rat emitting the lever-press response). In the next stage, lever-pressing is assessed under extinction conditions (i.e., no food is delivered). At this stage rats display two types of lever-presses, those that are followed by an attempt to collect a reward, and those that are not. The latter are the measure of compulsive-like behavior in the model. A control procedure in which rats do not experience the attenuation of the feedback cue serves to distinguish between the effects of signal attenuation and of extinction. The signal attenuation model is a highly validated model of OCD and differentiates between compulsive-like behaviors and behaviors that are repetitive but not compulsive. In addition the measures collected during the procedure eliminate alternative explanations for differences between the groups being tested, and are quantitative, unbiased and unaffected by inter-experimenter variability. The major disadvantages of this model are the costly equipment, the fact that it requires some technical know-how and the fact that it is time-consuming compared to other models of OCD (11 days). The model may be used for detecting the anti- or pro-compulsive effects of pharmacological and non-pharmacological manipulations and for studying the neural substrate of compulsive behavior.

  19. Experimental model of distraction osteogenesis in edentulous rats.

    Science.gov (United States)

    Bigi, Maria Montserrat Pujadas; Lewicki, Marianela; Ubios, Angela Matilde; Mandalunis, Patricia Monica

    2011-01-01

    Distraction osteogenesis (DO) is a surgical technique producing bone lengthening by distraction of the fracture callus. Although a large number of experimental studies on the events associated with DO of craniofacial skeleton have been reported, the few employing rat mandibular bone DO used complicated designs and produced a small volume of newly formed bone. Thus, this study aims to present an original experimental model of mandibular DO in edentulous rats that produces a sufficient quantity and quality of intramembranous bone. Eight male Wistar rats, weighing 75 g, underwent extraction of lower molars. With rats weighing 350 g, right mandibular osteotomy was performed and the distraction device was placed. The distraction device was custom made using micro-implants, expansion screws, and acrylic resin. latency: 6 days, distraction: ¼ turn (0.175 mm) once a day during 6 d, consolidation: 28 d after distraction phase, sacrifice. DO-treated and contralateral hemimandibles were dissected and compared macroscopically and using radiographic studies. Histological sections were obtained and stained with H&E. A distraction gap filled with newly formed and mature bone tissue was obtained. This model of mandibular DO proved useful to obtain adequate quantity and quality of bone to study bone regeneration.

  20. Experimental model of distraction osteogenesis in edentulous rats

    Directory of Open Access Journals (Sweden)

    Maria Montserrat Pujadas Bigi

    2011-06-01

    Full Text Available Distraction osteogenesis (DO is a surgical technique producing bone lengthening by distraction of the fracture callus. Although a large number of experimental studies on the events associated with DO of craniofacial skeleton have been reported, the few employing rat mandibular bone DO used complicated designs and produced a small volume of newly formed bone. Thus, this study aims to present an original experimental model of mandibular DO in edentulous rats that produces a sufficient quantity and quality of intramembranous bone. Eight male Wistar rats, weighing 75 g, underwent extraction of lower molars. With rats weighing 350 g, right mandibular osteotomy was performed and the distraction device was placed. The distraction device was custom made using micro-implants, expansion screws, and acrylic resin. Study protocol: latency: 6 days, distraction: ¼ turn (0.175 mm once a day during 6 d, consolidation: 28 d after distraction phase, sacrifice. DO-treated and contralateral hemimandibles were dissected and compared macroscopically and using radiographic studies. Histological sections were obtained and stained with H&E. A distraction gap filled with newly formed and mature bone tissue was obtained. This model of mandibular DO proved useful to obtain adequate quantity and quality of bone to study bone regeneration.

  1. Rat gingival model for testing drugs influencing inflammation

    Directory of Open Access Journals (Sweden)

    Shaju P Jacob

    2013-07-01

    Full Text Available Preclinical drug testing is an important areain new drug development where animals are used.An ideal animal model for this is one which is simple,reliable and can be extrapolated to humans. Topicaldrugs for inflammation are conventionally tested onthe skin of animals after induction of inflammation.A gingival model would be simple as inflammation canbe induced naturally by the action of plaque. Rats area popular animal model for testing drugs as well as tostudy various diseases of the periodontium. Periodontaldisease including gingival inflammation develops inrats in relation to indigenous plaque or experimentallyinduced bacterial products. A number of features ofrats ranging from anatomy, histology and response tobacterial insult can be seen mirrored to a great extentin humans. There is a lot similarity in the developmentand resolution of inflammation as well as the gingivalwound healing of rats and humans. This paper tries toexplore the feasibility of using the rat gingival modelfor preclinical testing of drugs acting on or influencinginflammation and concludes by identifying potentialareas of research using this model. The addition of sucha simple and inexpensive model for preclinical testing ofdrugs will be welcomed by the drug developers.

  2. Combating Combination of Hypertension and Diabetes in Different Rat Models

    Directory of Open Access Journals (Sweden)

    Talma Rosenthal

    2010-03-01

    Full Text Available Rat experimental models are used extensively for studying physiological mechanisms and treatments of hypertension and diabetes co-existence. Each one of these conditions is a major risk factor for cardiovascular disease (CVD, and the combination of the two conditions is a potent enhancer of CVD. Five major animal models that advanced our understanding of the mechanisms and therapeutic approaches in humans are discussed in this review: Zucker, Goto-Kakizaki, SHROB, SHR/NDmcr-cp and Cohen Rosenthal diabetic hypertensive (CRDH rats. The use of various drugs, such as angiotensin-converting enzyme (ACE inhibitors (ACEIs, various angiotensin receptor blockers (ARBs, and calcium channel blockers (CCBs, to combat the effects of concomitant pathologies on the combination of diabetes and hypertension, as well as the non-pharmacological approach are reviewed in detail for each rat model. Results from experiments on these models indicate that classical factors contributing to the pathology of hypertension and diabetes combination—Including hypertension, hyperglycemia, hyperinsulinemia and hyperlipidemia—can now be treated, although these treatments do not completely prevent renal complications. Animal studies have focused on several mechanisms involved in hypertension/diabetes that remain to be translated into clinical medicine, including hypoxia, oxidative stress, and advanced glycation. Several target molecules have been identified that need to be incorporated into a treatment modality. The challenge continues to be the identification and interpretation of the clinical evidence from the animal models and their application to human treatment.

  3. Ranking candidate genes in rat models of type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Ståhl Fredrik

    2009-07-01

    Full Text Available Abstract Background Rat models are frequently used to find genomic regions that contribute to complex diseases, so called quantitative trait loci (QTLs. In general, the genomic regions found to be associated with a quantitative trait are rather large, covering hundreds of genes. To help selecting appropriate candidate genes from QTLs associated with type 2 diabetes models in rat, we have developed a web tool called Candidate Gene Capture (CGC, specifically adopted for this disorder. Methods CGC combines diabetes-related genomic regions in rat with rat/human homology data, textual descriptions of gene effects and an array of 789 keywords. Each keyword is assigned values that reflect its co-occurrence with 24 different reference terms describing sub-phenotypes of type 2 diabetes (for example "insulin resistance". The genes are then ranked based on the occurrences of keywords in the describing texts. Results CGC includes QTLs from type 2 diabetes models in rat. When comparing gene rankings from CGC based on one sub-phenotype, with manual gene ratings for four QTLs, very similar results were obtained. In total, 24 different sub-phenotypes are available as reference terms in the application and based on differences in gene ranking, they fall into separate clusters. Conclusion The very good agreement between the CGC gene ranking and the manual rating confirms that CGC is as a reliable tool for interpreting textual information. This, together with the possibility to select many different sub-phenotypes, makes CGC a versatile tool for finding candidate genes. CGC is publicly available at http://ratmap.org/CGC.

  4. Experimental crescentic glomerulonephritis: a new bicongenic rat model

    Directory of Open Access Journals (Sweden)

    Zelpha D’Souza

    2013-11-01

    Crescentic glomerulonephritis (CRGN is a major cause of human kidney failure, but the underlying mechanisms are not fully understood. Wistar Kyoto (WKY rats are uniquely susceptible to CRGN following injection of nephrotoxic serum, whereas Lewis (LEW rats are resistant. Our previous genetic studies of nephrotoxic nephritis (NTN, a form of CRGN induced by nephrotoxic serum, identified Fcgr3 and Jund as WKY genes underlying the two strongest quantitative trait loci for NTN phenotypes: Crgn1 and Crgn2, respectively. We also showed that introgression of WKY Crgn1 or Crgn2 individually into a LEW background did not lead to the formation of glomerular crescents. We have now generated a bicongenic strain, LEW.WCrgn1,2, in which WKY Crgn1 and Crgn2 are both introgressed into the LEW genetic background. These rats show development of NTN phenotypes, including glomerular crescents. Furthermore, we characterised macrophage function and glomerular cytokine profiles in this new strain. Additionally, we show that LEW.WCrgn1,2 rats are resistant to the development of glomerular crescents that is usually induced following immunisation with recombinant rat α3(IVNC1, the specific Goodpasture autoantigen located in the glomerular basement membrane against which the immune response is directed in experimental autoimmune glomerulonephritis. Our results show that the new bicongenic strain responds differently to two distinct experimental triggers of CRGN. This is the first time that CRGN has been induced on a normally resistant rat genetic background and identifies the LEW.WCrgn1,2 strain as a new, potentially valuable model of macrophage-dependent glomerulonephritis.

  5. Methodological characteristics in establishing rat models of poststroke depression

    Institute of Scientific and Technical Information of China (English)

    Fuyou Liu; Shi Yang; Weiyin Chen; Jinyu Wang; Yi Tang; Guanxiang Zhu

    2006-01-01

    BACKGROUND: Ideal model of poststroke depression (PSD) may be induced in rats guided by the theoretical evidence that "primary endogenous mechanism" and "reactivity mechanism" theories for PSD in human being.OBJECTIVE: To investigate the feasibility of comprehensive methods to induce PSD models in rats.DESrGN: A randomized controlled animal trial.SETTING: Department of Neurology, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine.MATERrALS: Male SD rats of SPF degree, weighing 350-500 g, were provided by the experimental animal center of Chengdu University of Traditional Chinese Medicine. The rats were raised for 1 week adaptively, then screened behaviorally by open-field test and passive avoidance test. Forty-five rats with close scores were randomly divided into normal control group (n =10), simple stroke group (n =10), stress group (n =10) and PSD group (n =15).METHODS: The experiments were carried out in the laboratory of Chengdu University of Traditional Chinese Medicine from July 2002 to February 2003. ① Rat models of focal cerebral ischemia were induced by thread embolization, then treated with separate raising and unpredictable stress to induce PSD models. ②The neurologic deficit was evaluated by Longa 5-grade standard (the higher the score, the severer the neurologic deficit) and horizontal round rod test (normal rat could stay on it for at least 3 minutes). ③ The behavioral changes of PSD rats were evaluated by the saccharin water test, open-field text and passive avoidance test,including the changes of interest, spontaneous and exploratory activities, etc. ④ The levels of monoamine neurotransmitters, including norepinephrine (NE), serotonin (5-HT) and dopamine, in brain were determined using fluorospectrophotometry.MAIN OUTCOME MEASURES: ① Score of Longa 5-grade standard; Stayed time in the horizontal round rod test;② Amount of saccharin water consumption; Open-field text: time stayed in the central square, times

  6. Subcellular redistribution of the synapse-associated proteins PSD-95 and SAP97 in animal models of Parkinson's disease and L-DOPA-induced dyskinesia.

    Science.gov (United States)

    Nash, J E; Johnston, T H; Collingridge, G L; Garner, C C; Brotchie, J M

    2005-04-01

    Abnormalities in subcellular localization and interaction between receptors and their signaling molecules occur within the striatum in Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID). Synapse-associated proteins (SAPs), for example, PSD-95 and SAP97 organize the molecular architecture of synapses and regulate interactions between receptors and downstream-signaling molecules. Here, we show that expression and subcellular distribution of PSD-95 and SAP97 are altered in the striatum of unilateral 6-OHDA-lesioned rats following repeated vehicle (a model of PD) or L-DOPA administration (a model of L-DOPA-induced dyskinesia). Furthermore, following dopamine-depletion and development of behavioral deficits in Rotorod performance, indicative of parkinsonism, we observed a dramatic decrease in total striatal levels of PSD-95 and SAP97 (to 25.6 +/- 9.9% and 19.0 +/- 5.0% of control, respectively). The remaining proteins were redistributed from the synapse into vesicular compartments. L-DOPA (6.5mg/kg twice a day, 21 days) induced a rotational response, which became markedly enhanced with repeated treatment (day 1: -15.8+/-7.3 rotations cf day 21: 758.2+/-114.0 rotations). Post L-DOPA treatment, PSD-95 and SAP97 levels increased (367.4 +/- 43.2% and 159.9 +/- 9.5% from control values, respectively), with both being redistributed toward synaptic membranes from vesicular compartments. In situ hybridization showed that changes in total levels of PSD-95, but not SAP97, were accompanied by qualitatively similar changes in mRNA. These data highlight the potential role of abnormalities in the subcellular distribution of SAPs in the pathophysiology of a neurological disease.

  7. Particulate matter inhalation exacerbates cardiopulmonary injury in a rat model of isoproterenol-induced cardiomyopathy

    Science.gov (United States)

    Ambient particulate matter (PM) exposure is linked to cardiovascular events and death, especially among individuals with heart disease. A model of toxic cardiomyopathy was developed in Spontaneously Hypertensive Heart Failure (SHHF) rats to explore potential mechanisms. Rats were...

  8. Establishment of reproducible osteosarcoma rat model using orthotopic implantation technique.

    Science.gov (United States)

    Yu, Zhe; Sun, Honghui; Fan, Qingyu; Long, Hua; Yang, Tongtao; Ma, Bao'an

    2009-05-01

    In experimental musculoskeletal oncology, there remains a need for animal models that can be used to assess the efficacy of new and innovative treatment methodologies for bone tumors. Rat plays a very important role in the bone field especially in the evaluation of metabolic bone diseases. The objective of this study was to develop a rat osteosarcoma model for evaluation of new surgical and molecular methods of treatment for extremity sarcoma. One hundred male SD rats weighing 125.45+/-8.19 g were divided into 5 groups and anesthetized intraperitoneally with 10% chloral hydrate. Orthotopic implantation models of rat osteosarcoma were performed by injecting directly into the SD rat femur with a needle for inoculation with SD tumor cells. In the first step of the experiment, 2x10(5) to 1x10(6) UMR106 cells in 50 microl were injected intraosseously into median or distal part of the femoral shaft and the tumor take rate was determined. The second stage consisted of determining tumor volume, correlating findings from ultrasound with findings from necropsia and determining time of survival. In the third stage, the orthotopically implanted tumors and lung nodules were resected entirely, sectioned, and then counter stained with hematoxylin and eosin for histopathologic evaluation. The tumor take rate was 100% for implants with 8x10(5) tumor cells or more, which was much less than the amount required for subcutaneous implantation, with a high lung metastasis rate of 93.0%. Ultrasound and necropsia findings matched closely (r=0.942; ptechnique for measuring cancer at any stage. Tumor growth curve showed that orthotopically implanted tumors expanded vigorously with time-lapse, especially in the first 3 weeks. The median time of survival was 38 days and surgical mortality was 0%. The UMR106 cell line has strong carcinogenic capability and high lung metastasis frequency. The present rat osteosarcoma model was shown to be feasible: the take rate was high, surgical mortality was

  9. Experimental model of arthritis induced by Paracoccidioides brasiliensis in rats.

    Science.gov (United States)

    Loth, Eduardo Alexandre; Biazin, Samia Khalil; Paula, Claudete Rodrigues; Simão, Rita de Cássia Garcia; de Franco, Marcello Fabiano; Puccia, Rosana; Gandra, Rinaldo Ferreira

    2012-09-01

    Paracoccidioidomycosis (PCM), a disease caused by the fungus Paracoccidioides brasiliensis (Pb), is highly prevalent in Brazil, where it is the principal cause of death by systemic mycoses. The disease primarily affects men aged 30-50 year old and usually starts as a pulmonary focus and then may spread to other organs and systems, including the joints. The present study aimed to develop an experimental model of paracoccidioidomycotic arthritis. Two-month-old male Wistar rats (n = 48) were used, divided in 6 groups: test groups EG/15 and EG/45 (received one dose of 100 μl of saline containing 10(5) Pb viable yeasts in the knee); heat killed Pb-group HK/15 and HK/45 (received a suspension of 10(5) Pb nonviable yeasts in the knee) and control groups CG/15 and CG/45 (received only sterile saline in the knee). The rats were killed 15 and 45 days postinoculation. In contrast with the control rats, the histopathology of the joints of rats of the test groups (EG/15 and EG/45) revealed a picture of well-established PCM arthritis characterized by extensive sclerosing granulomatous inflammation with numerous multiple budding fungal cells. The X-ray examination revealed joint alterations in these groups. Only metabolic active fungi evoked inflammation. The experimental model was able to induce fungal arthritis in the knees of the rats infected with metabolic active P. brasiliensis. The disease tended to be regressive and restrained by the immune system. No evidence of fungal dissemination to the lungs was observed.

  10. Chronic gastritis rat model and role of inducing factors

    Institute of Scientific and Technical Information of China (English)

    Zun Xiang; Jian-Min Si; Huai-De Huang

    2004-01-01

    AIM: To establish an experimental animal model of chronic gastritis in a short term and to investigate the effects of several potential inflammation-inducing factors on rat gastric mucosa.METHODS: Twenty-four healthy, male SD rats were treated with intragastric administration of 600 mL/L alcohol, 20mmol/L sodium deoxycholate and 0.5 g/L ammonia (factor A), forage containing low levels of vitamins (factor B), and/or indomethacin (factor C), according to an L8(27)orthogonal design. After 12 wk, gastric antral and body mucosae were pathologically examined.RESULTS: Chronic gastritis model was successfully induced in rats treated with factor A for 12 wk. After the treatment of animals, the gastric mucosal inflammation was significantly different from that in controls, and the number of pyloric glands at antrum and parietal cells at body were obviously reduced (P<0.01). Indomethacin induced gastritis but without atrophy, and short-term vitamin deficiency failed to induce chronic gastritis and gastric atrophy, In addition,indomethacin and vitamin deficiency had no synergistic effect in inducing gastritis with the factor A. No atypical hyperplasia and intestinal metaplasia in the gastric antrum and body were observed in all rats studied.CONCLUSION: Combined intragastric administration of 600 mL/L alcohol, 20 mmol/L sodium deoxycholate and 0.5 g/L ammonia induces chronic gastritis and gastric atrophy in rats. Indomethacin induces chronic gastritis only.The long-term roles of these factors in gastric inflammation and carcinogenesis need to be further elucidated.

  11. Creation of Consistent Burn Wounds: A Rat Model

    Directory of Open Access Journals (Sweden)

    Elijah Zhengyang Cai

    2014-07-01

    Full Text Available Background Burn infliction techniques are poorly described in rat models. An accurate study can only be achieved with wounds that are uniform in size and depth. We describe a simple reproducible method for creating consistent burn wounds in rats. Methods Ten male Sprague-Dawley rats were anesthetized and dorsum shaved. A 100 g cylindrical stainless-steel rod (1 cm diameter was heated to 100℃ in boiling water. Temperature was monitored using a thermocouple. We performed two consecutive toe-pinch tests on different limbs to assess the depth of sedation. Burn infliction was limited to the loin. The skin was pulled upwards, away from the underlying viscera, creating a flat surface. The rod rested on its own weight for 5, 10, and 20 seconds at three different sites on each rat. Wounds were evaluated for size, morphology and depth. Results Average wound size was 0.9957 cm2 (standard deviation [SD] 0.1845 (n=30. Wounds created with duration of 5 seconds were pale, with an indistinct margin of erythema. Wounds of 10 and 20 seconds were well-defined, uniformly brown with a rim of erythema. Average depths of tissue damage were 1.30 mm (SD 0.424, 2.35 mm (SD 0.071, and 2.60 mm (SD 0.283 for duration of 5, 10, 20 seconds respectively. Burn duration of 5 seconds resulted in full-thickness damage. Burn duration of 10 seconds and 20 seconds resulted in full-thickness damage, involving subjacent skeletal muscle. Conclusions This is a simple reproducible method for creating burn wounds consistent in size and depth in a rat burn model.

  12. A rat model for embolic encephalitis

    DEFF Research Database (Denmark)

    Astrup, Lærke Boye; Rasmussen, Rune Skovgaard; Aalbæk, Bent;

    2011-01-01

    -brain-barrier. This provides our model with several advantages: minimized surgical intervention, bacteria gain access to the brain by the circulation and, no foreign materials are implated in the brain. We thereby mirror the human scenario in several ways: 1: Cerebral infarction by thrombosis or disseminated intravascular...... have recently shown that sepsis is a common cause of microabscesses in the brain, and that S. aureus is one of the most common organisms isolated from these abscesses. This raises the question whether the blood-brain barrier truly makes the brain an immune-privileged organ or not. This makes the brain...... it is difficult to obtain tissue for further examination. This puts a hard demand on animal models of brain lesions in sepsis. We hereby present a novel animal model of embolic encephalitis. Our model introduces bacteria by an embolus to an area of brain necrosis and damage to the blood...

  13. The inhibition of nanog gene transfer on the inflammatory reaction induced by microglial cell in Parkinson disease rats%转nanog基因抑制帕金森病大鼠脑内小胶质细胞介导的炎性反应

    Institute of Scientific and Technical Information of China (English)

    陈施艳; 张志坚; 刘丽金; 林红; 吴秀丽; 王伟; 王志强

    2014-01-01

    目的 探讨转nanog基因对6-羟多巴胺(6-OHDA)诱导的帕金森病大鼠中脑黑质区小胶质细胞的激活及肿瘤坏死因子α(TNF-α)表达的影响.方法 将大鼠随机分为对照、6-OHDA+ PBS、6-OHDA+ PNL与6-OHDA+nanog组.模型组大鼠左侧纹状体内注射6-OHDA,再将PBS、慢病毒空载体PNL-IRES.EGFP (PNL)、转nanog基因载体分别注入6-OHDA+ PBS、6-OHDA+ PNL与6-OHDA+ nanog组大鼠左侧纹状体;14 d后,注射阿朴吗啡(APO),观察大鼠的旋转行为;免疫组织化学染色观察黑质多巴胺能神经元数量;免疫荧光观测黑质区小胶质细胞数量及TNF-α表达.结果 注射后14 d,6-OHDA+ nanog组大鼠APO诱发的旋转效应低于6-OHDA+ PNL与6-OHDA+PBS组(P<0.05);模型组注射侧黑质多巴胺能神经元数量较对照组明显减少(P<0.05),但6-OHDA+ nanog组存活的多巴胺能神经元数量多于6-OHDA+ PNL与6-OHDA+ PBS组(P<0.05).模型组大鼠注射侧黑质区小胶质细胞数量和TNF-α表达均较对照组增加(P<0.05),但6-OHDA+ nanog组小胶质细胞数目和TNF-α表达水平低于6-OHDA+ PNL与6-OHDA+ PBS组(P<0.05).结论 转nanog基因可抑制帕金森病大鼠脑内小胶质细胞活化介导的炎性反应,具有神经元保护作用.

  14. The differential effects of 5-HT(1A) receptor stimulation on dopamine receptor-mediated abnormal involuntary movements and rotations in the primed hemiparkinsonian rat.

    Science.gov (United States)

    Dupre, Kristin B; Eskow, Karen L; Negron, Giselle; Bishop, Christopher

    2007-07-16

    Serotonin 1A receptor (5-HT(1A)R) agonists have emerged as valuable supplements to l-DOPA therapy, demonstrating that they can decrease side effects and enhance motor function in animal models of Parkinson's disease (PD) and human PD patients. The precise mechanism by which these receptors act remains unknown and there is limited information on how 5-HT(1A)R stimulation impacts striatal dopamine (DA) D1 receptor (D1R) and D2 receptor (D2R) function. The current study examined the effects of 5-HT(1A)R stimulation on DA receptor-mediated behaviors. Male Sprague-Dawley rats were rendered hemiparkinsonian by unilateral 6-OHDA lesions and primed with the D1R agonist SKF81297 (0.8 mg/kg, i.p.) in order to sensitize DA receptors. Using a randomized within subjects design, rats received a first injection of: Vehicle (dH(2)O) or the 5-HT(1A)R agonist +/-8-OH-DPAT (0.1 or 1.0 mg/kg, i.p.), followed by a second injection of: Vehicle (dimethyl sulfoxide), the D1R agonist SKF81297 (0.8 mg/kg, i.p.), the D2R agonist quinpirole (0.2 mg/kg, i.p.), or l-DOPA (12 mg/kg+benserazide, 15 mg/kg, i.p.). On test days, rats were monitored over a 2-h period immediately following the second injection for abnormal involuntary movements (AIMs), analogous to dyskinesia observed in PD patients, and contralateral rotations. The present findings indicate that 5-HT(1A)R stimulation reduces AIMs induced by D1R, D2R and l-DOPA administration while its effects on DA agonist-induced rotations were receptor-dependent, suggesting that direct 5-HT(1A)R and DA receptor interactions may contribute to the unique profile of 5-HT(1A)R agonists for the improvement of PD treatment.

  15. Ventricular repolarization in a rat model of global heart failure.

    Science.gov (United States)

    Krandycheva, Valeria; Kharin, Sergey; Strelkova, Marina; Shumikhin, Konstantin; Sobolev, Aleksey; Shmakov, Dmitry

    2013-07-01

    Isoproterenol in high doses induces infarction-like myocardial damage and structural and functional remodelling of the ventricular myocardium. The purpose of the present study was to investigate ventricular repolarization in a rat model of isoproterenol-induced heart failure. Isoproterenol was administered twice to female Wistar rats (170 mg/kg, s.c., 24 h apart). Four weeks after the injections, cardiac output was measured and unipolar epicardial ventricular electrograms were recorded in situ. Activation-recovery intervals were calculated to assess repolarization. Histological examination of the heart ventricles was also performed. Heart failure in rats treated with isoproterenol was indicated by myocardial histopathological damage and reduced cardiac output. In rats with heart failure, the regional differences in activation-recovery interval prolongation over the ventricular epicardium resulted in increasing heterogeneity in the activation-recovery interval distribution and increasing repolarization heterogeneity of the ventricular subepicardium. Myocardial damage and haemodynamic changes in heart failure induced by isoproterenol were accompanied by significant changes in ventricular repolarization, which were not associated with myocardial hypertrophy.

  16. Innervation of ectopic endometrium in a rat model of endometriosis

    OpenAIRE

    Berkley, Karen J; Dmitrieva, Natalia; Curtis, Kathleen S.; Papka, Raymond E

    2004-01-01

    Endometriosis (ENDO) is a disorder in which vascularized growths of endometrial tissue occur outside the uterus. Its symptoms include reduced fertility and severe pelvic pain. Mechanisms that maintain the ectopic growths and evoke symptoms are poorly understood. One factor not yet considered is that the ectopic growths develop their own innervation. Here, we tested the hypothesis that the growths develop both an autonomic and a sensory innervation. We used a rat model of surgically induced EN...

  17. The Laboratory Rat as an Animal Model for Osteoporosis Research

    OpenAIRE

    Lelovas, Pavlos P; Xanthos, Theodoros T.; Thoma, Sofia E; Lyritis, George P; Dontas, Ismene A

    2008-01-01

    Osteoporosis is an important systemic disorder, affecting mainly Caucasian women, with a diverse and multifactorial etiology. A large variety of animal species, including rodents, rabbits, dogs, and primates, have been used as animal models in osteoporosis research. Among these, the laboratory rat is the preferred animal for most researchers. Its skeleton has been studied extensively, and although there are several limitations to its similarity to the human condition, these can be overcome th...

  18. Spatial memory impairments in a prediabetic rat model

    OpenAIRE

    Soares,E.; Prediger, R. D.; Nunes, S.; A.A. Castro; Viana, S .D.; Lemos, C.; C. M. Souza; Agostinho, P; Cunha, R. A.; E. Carvalho; Ribeiro, C. A. Fontes; Reis, F.; PEREIRA, F. C.

    2013-01-01

    Diabetes is associated with an increased risk for brain disorders, namely cognitive impairments associated with hippocampal dysfunction underlying diabetic encephalopathy. However, the impact of a prediabetic state on cognitive function is unknown. Therefore, we now investigated whether spatial learning and memory deficits and the underlying hippocampal dysfunction were already present in a prediabetic animal model. Adult Wistar rats drinking high-sucrose (HSu) diet (35% sucrose solution duri...

  19. An improved experimental model for peripheral neuropathy in rats

    Directory of Open Access Journals (Sweden)

    Q.M. Dias

    Full Text Available A modification of the Bennett and Xie chronic constriction injury model of peripheral painful neuropathy was developed in rats. Under tribromoethanol anesthesia, a single ligature with 100% cotton glace thread was placed around the right sciatic nerve proximal to its trifurcation. The change in the hind paw reflex threshold after mechanical stimulation observed with this modified model was compared to the change in threshold observed in rats subjected to the Bennett and Xie or the Kim and Chung spinal ligation models. The mechanical threshold was measured with an automated electronic von Frey apparatus 0, 2, 7, and 14 days after surgery, and this threshold was compared to that measured in sham rats. All injury models produced significant hyperalgesia in the operated hind limb. The modified model produced mean ± SD thresholds in g (19.98 ± 3.08, 14.98 ± 1.86, and 13.80 ± 1.00 at 2, 7, and 14 days after surgery, respectively similar to those obtained with the spinal ligation model (20.03 ± 1.99, 13.46 ± 2.55, and 12.46 ± 2.38 at 2, 7, and 14 days after surgery, respectively, but less variable when compared to the Bennett and Xie model (21.20 ± 8.06, 18.61 ± 7.69, and 18.76 ± 6.46 at 2, 7, and 14 days after surgery, respectively. The modified method required less surgical skill than the spinal nerve ligation model.

  20. An improved experimental model for peripheral neuropathy in rats

    Energy Technology Data Exchange (ETDEWEB)

    Dias, Q.M.; Rossaneis, A.C.; Fais, R.S.; Prado, W.A. [Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil)

    2013-03-15

    A modification of the Bennett and Xie chronic constriction injury model of peripheral painful neuropathy was developed in rats. Under tribromoethanol anesthesia, a single ligature with 100% cotton glace thread was placed around the right sciatic nerve proximal to its trifurcation. The change in the hind paw reflex threshold after mechanical stimulation observed with this modified model was compared to the change in threshold observed in rats subjected to the Bennett and Xie or the Kim and Chung spinal ligation models. The mechanical threshold was measured with an automated electronic von Frey apparatus 0, 2, 7, and 14 days after surgery, and this threshold was compared to that measured in sham rats. All injury models produced significant hyperalgesia in the operated hind limb. The modified model produced mean ± SD thresholds in g (19.98 ± 3.08, 14.98 ± 1.86, and 13.80 ± 1.00 at 2, 7, and 14 days after surgery, respectively) similar to those obtained with the spinal ligation model (20.03 ± 1.99, 13.46 ± 2.55, and 12.46 ± 2.38 at 2, 7, and 14 days after surgery, respectively), but less variable when compared to the Bennett and Xie model (21.20 ± 8.06, 18.61 ± 7.69, and 18.76 ± 6.46 at 2, 7, and 14 days after surgery, respectively). The modified method required less surgical skill than the spinal nerve ligation model.

  1. The Fischer 344 rat as a model of presbycusis.

    Science.gov (United States)

    Syka, Josef

    2010-06-01

    Due to the rising number of the aged human population all over the world, presbycusis is a phenomenon that deserves the increasing attention of the medical community as regards to prevention and treatment. This requires finding appropriate animal models for human presbycusis that will be useful in future experiments. Among the available rat strains, the Fischer 344 (F344) strain promises to serve as a model producing prompt and profound presbycusis. Hearing thresholds begin to increase in this strain during the first year of life; toward the end of the second year, the thresholds are very high. The threshold shifts progress independently in both ears. The rapid deterioration of distortion product otoacoustic emissions, with the majority of outer hair cells (OHC) being present and morphologically intact, is apparently produced by the disruption of prestin. The age-related changes within inner ear function are accompanied by deterioration of acoustical signal processing within central auditory system, mainly due to impaired GABA inhibition. The loss of GABA inhibition in old animals is expressed primarily in the inferior colliculus but is also present in the cochlear nuclei and the auditory cortex. Sound-evoked behavioral reactions are also impaired in old F344 rats. Taken together, the described characteristics of the aging F344 rat auditory system supports the idea that this strain may serve as a suitable model for studying the mechanisms of presbycusis, its prevention and treatment.

  2. Standardization of model to induce obesity in rats

    Directory of Open Access Journals (Sweden)

    Gipsis Suárez Román

    2013-10-01

    Full Text Available Background: Obesity is a risk factor for multiple diseases. There are various rat models to induce this condition. Genetic models and diet-induced obesity are expensive. Within the models of hypothalamic obesity, there is one achieved by the administration of monosodium glutamate during the neonatal period. This substance is not expensive and causes the major metabolic alterations observed in human obesity. Objective: to select an appropriate treatment scheme to induce obesity with monosodium glutamate during neonatal period. Methods: monosodium glutamate was administered to Wistar rats during the neonatal period, using three different treatment schemes (with five, seven and ten doses of 4mg/g/day through two routes of administration: subcutaneous and intraperitoneal routes. Controls were administered 0.9% sodium chloride. To establish the diagnosis of obesity, the following variables were measured at 90 days: weight, snout-anus length and Lee index. Results: with all treatment schemes tested, snout-anus length was statistically different between the group treated with monosodium glutamate and the controls group. 100% of the rats that reached adulthood injected with monosodium glutamate was obese. Conclusion: the scheme of five doses of monosodium glutamate, applied subcutaneously on alternate days, was selected as obesity is obtained with less handling and lower percentage of neonatal deaths.

  3. Aerosol Infection Model of Tuberculosis in Wistar Rats

    Directory of Open Access Journals (Sweden)

    Sheshagiri Gaonkar

    2010-01-01

    Full Text Available We explored suitability of a rat tuberculosis aerosol infection model for investigating the pharmacodynamics of new antimycobacterial agents. Infection of rats via the aerosol route led to a reproducible course of M. tuberculosis infection in the lungs. The pulmonary bacterial load increased logarithmically during the first six weeks, thereafter, the infection stabilized for the next 12 weeks. We observed macroscopically visible granulomas in the lungs with demonstrable acid-fast bacilli and associated histopathology. Rifampicin (RIF at a dose range of 30 to 270 mg/kg exhibited a sharp dose response while isoniazid (INH at a dose range of 10 to 90 mg/kg and ethambutol (EMB at 100 to 1000 mg/kg showed shallow dose responses. Pyrazinamide (PZA had no dose response between 300 and 1000 mg/kg dose range. In a separate time kill study at fixed drug doses (RIF 90 mg/kg, INH 30 mg/kg, EMB 300 mg/kg, and PZA 300 mg/kg the bactericidal effect of all the four drugs increased with longer duration of treatment from two weeks to four weeks. The observed infection profile and therapeutic outcomes in this rat model suggest that it can be used as an additional, pharmacologically relevant efficacy model to develop novel antitubercular compounds at the interface of discovery and development.

  4. Aerosol infection model of tuberculosis in wistar rats.

    Science.gov (United States)

    Gaonkar, Sheshagiri; Bharath, Sowmya; Kumar, Naveen; Balasubramanian, V; Shandil, Radha K

    2010-01-01

    We explored suitability of a rat tuberculosis aerosol infection model for investigating the pharmacodynamics of new antimycobacterial agents. Infection of rats via the aerosol route led to a reproducible course of M. tuberculosis infection in the lungs. The pulmonary bacterial load increased logarithmically during the first six weeks, thereafter, the infection stabilized for the next 12 weeks. We observed macroscopically visible granulomas in the lungs with demonstrable acid-fast bacilli and associated histopathology. Rifampicin (RIF) at a dose range of 30 to 270 mg/kg exhibited a sharp dose response while isoniazid (INH) at a dose range of 10 to 90 mg/kg and ethambutol (EMB) at 100 to 1000 mg/kg showed shallow dose responses. Pyrazinamide (PZA) had no dose response between 300 and 1000 mg/kg dose range. In a separate time kill study at fixed drug doses (RIF 90 mg/kg, INH 30 mg/kg, EMB 300 mg/kg, and PZA 300 mg/kg) the bactericidal effect of all the four drugs increased with longer duration of treatment from two weeks to four weeks. The observed infection profile and therapeutic outcomes in this rat model suggest that it can be used as an additional, pharmacologically relevant efficacy model to develop novel antitubercular compounds at the interface of discovery and development.

  5. Protein kinase C inhibitor improves motor complications in a rat model of Parkinson's disease%蛋白激酶C抑制剂改善帕金森病大鼠异动症的研究

    Institute of Scientific and Technical Information of China (English)

    孔敏; 宋璐; 巴茂文; 刘振国

    2010-01-01

    Objective To investigate the cytological and behavioral effects of protein kinase C (PKC) inhibitor tamoxifen on levodopa-induced motor complications of a rat model. Methods The hemi-parkinsonian rat model was produced by stereotaxically injecting 6-hydroxydopamine (6-OHDA) into right medial forebrain bundle (MFB). Two sets of experiments were performed. First, rats were intraperitoneally treated with 50 mg/kg levodopa plus 12.5 mg/kg henserazide, twice daily for 22 days. On day 23, the rats received either tamoxifen or vehicle before levodopa administration. Rotational duration and peak rotation were estimated. After being sacrificed, subcellular distribution and phosphorylation (S890 and S896) of N-methyl-D-aspartate receptor subunit 1 (NR1) were observed by Western blot. Results Our study showed that tamoxifen reduced peak rotation [(121.0±7.6) times vs. (161.55±22.1) times, t=2.6, P<0.05]. Moreover, tamoxifen could regulate subcellular distribution of NR1 which was closely associated with levodopa-induced motor complications, reduce the expression of NR1 in the membrane protein as compared with levodopa+ vehicle group [(82.4%±5.1%) vs. (103.0%±3.5%), t= 6.7, P<0.05], and reduce the phosphorylation of NR1S890 (77.2%±4.2%) and NR1S896 (98.4%±6. 4%), respectively (t= 5.9,3.6,both P<0.05). Conclusions These results indicate that chronic levodopa treatment activates serine kinase and leads to phosphorylation of glutamate receptors, and thus contributes to development of motor complications. Pharmaceuticals which inhibit serine kinase, such as PKC, may be useful in the treatment and prevention of motor complications in parkinsonian patients.%目的 探讨蛋白激酶C(PKC)抑制剂他莫昔芬对左旋多巴诱发异动症的细胞学与行为学效应. 方法将6-羟多巴胺立体定向注射于大鼠前脑内侧束建立帕金森病(PD)动物模型.模型成功的PD大鼠接受每天2次左旋多巴(50 mg/kg左旋多巴+12.5 mg

  6. Gastrodin inhibits neuroinflammation in rotenone-induced Parkinson's disease model rats

    Institute of Scientific and Technical Information of China (English)

    Chun Li; Xin Chen; Nan Zhang; Yangwen Song; Yang Mu

    2012-01-01

    The present study showed that the latency of rats moving on a vertical grid was significantly prolonged, and the number of rats sliding down from the declined plane was increased remarkably, in rotenone-induced Parkinson's disease model rats compared with control rats. The moving latency recovered to normal levels, but the number of slides was significantly increased at 28 days after model establishment. The slope test is a meaningful approach to evaluate the symptoms of Parkinson's disease model rats treated with rotenone. In addition, loss of substantia nigral dopaminergic neurons in model rats was observed at 1 day after the model was established, and continued gradually at 14 and 28 days. The expression of tyrosine hydroxylase-positive cells was significantly increased in gastrodin-treated rats at 14 days. Significant numbers of activated microglia cells were observed in model rats at 14 and 28 days; treatment of rats with Madopar at 28 days suppressed microglial activation. Treatment of rats with gastrodin or Madopar at 28 days significantly reduced interleukin-1β expression. The loss of substantia nigral dopaminergic neurons paralleled the microglial activation in Parkinson's disease model rats treated with rotenone. The inflammatory factors tumor necrosis factor-α and interleukin-1β are involved in the substantia nigral damage. Gastrodin could protect dopaminergic neurons via inhibition of interleukin-1β expression and neuroinflammation in the substantia nigra.

  7. The selective 5-HT1A receptor antagonist WAY-100635 inhibits neuronal activity of the ventromedial prefrontal cortex in a rodent model of Parkinson' s disease%选择性5-HT1A受体拮抗剂WAY-100635抑制帕金森病模型大鼠腹内侧前额叶皮质的神经活动

    Institute of Scientific and Technical Information of China (English)

    曹健; 刘健; 张巧俊; 王涛; 王爽; 韩玲娜; 李强

    2007-01-01

    目的 腹内侧前额叶皮质在随意运动的起始和控制、情感以及认知中具有重要作用.然而,黑质-纹状体通路变性后腹内侧前额叶皮质的神经活动和5-HT1A受体的作用仍不清楚.本研究观察了6-羟基多巴胺(6-hydroxydopamine,6-OHDA)损毁黑质致密部(substantia nigra pars compacta,SNc)后大鼠腹内侧前额叶皮质神经活动的变化和体循环给予选择性5-HT1A受体拮抗剂WAY-100635后神经元活动的改变.方法 采用在体玻璃微电极细胞外记录方法,记录正常大鼠和SNc单侧损毁大鼠的腹内侧前额叶皮质神经元的活动.结果 6-OHDA损毁SNc大鼠的腹内侧前额叶皮质神经元放电频率显著增加,放电形式没有明显改变.体循环给予WAY-100635(0.1 mg/kg,i.v.)不改变正常大鼠腹内侧前额叶皮质神经元的平均放电频率和放电形式,而显著降低了SNc损毁大鼠前额叶皮质神经元的平均放电频率.结论 黑质-纹状体通路的变性可导致腹内侧前额叶皮质神经活动增强,5-HT1A受体拮抗剂WAY-100635可以抑制这种活动增强,提示可能存在腹内侧前额叶皮质5-HT1A受体功能失调.%Objective The ventral part of the medial prefrontal cortex (mPFC) plays an important role in initiation and control of voluntary movement, mood and cognition. However, after the degeneration of the nigrostriatal pathway, the neuronal activity of the ventral mPFC and the role of serotonin1A (5-hydroxytryptamine, 5-HT1A) receptors in the firing of the neurons are still unknown. The present study is to investigate the change of neuronal activity in the ventral mPFC and the effect of systemic administration of the selective 5-HT1A receptor antagonist WAY- 100635 on the activity of the neurons in normal and 6-hydroxydopamine (6-OHDA)-lesioned rats. Methods Single unit responses were recorded extracellularly with glass microelectrodes from ventral mPFC neurons in normal rats and 6-OHDA unilaterally lesiond rats in vivo

  8. Rat models of asthma and chronic obstructive lung disease.

    Science.gov (United States)

    Martin, James G; Tamaoka, Meiyo

    2006-01-01

    The rat has been extensively used to model asthma and somewhat less extensively to model chronic obstructive pulmonary disease (COPD). The features of asthma that have been successfully modeled include allergen-induced airway constriction, eosinophilic inflammation and allergen-induced airway hyperresponsiveness. T-cell involvement has been directly demonstrated using adoptive transfer techniques. Both CD4+ and CD8+ T cells are activated in response to allergen challenge in the sensitized rat and express Thelper2 cytokines (IL-4, IL-5 and IL-13). Repeated allergen exposure causes airway remodeling. Dry gas hyperpnea challenge also evokes increases in lung resistance, allowing exercise-induced asthma to be modeled. COPD is modeled using elastase-induced parenchymal injury to mimic emphysema. Cigarette smoke-induced airspace enlargement occurs but requires months of cigarette exposure. Inflammation and fibrosis of peripheral airways is an important aspect of COPD that is less well modeled. Novel approaches to the treatment of COPD have been reported including treatments aimed at parenchymal regeneration.

  9. Use of surgical techniques in the rat pancreas transplantation model

    Institute of Scientific and Technical Information of China (English)

    Yi Ma; Zhi-Yong Guo

    2008-01-01

    BACKGROUND:Pancreas transplantation is currently considered to be the most reliable and effective treatment for insulin-dependent diabetes mellitus (also called type 1 diabetes). With the improvement of microsurgical techniques, pancreas transplantation in rats has been the major model for physiological and immunological experimental studies in the past 20 years. We investigated the surgical techniques of pancreas transplantation in rats by analysing the difference between cervical segmental pancreas transplantation and abdominal pancreaticoduodenal transplantation. METHODS:Two hundred and forty male adult Wistar rats weighing 200-300 g were used, 120 as donors and 120 as recipients. Sixty cervical segmental pancreas transplants and 60 abdominal pancreaticoduodenal transplants were carried out and vessel anastomoses were made with microsurgical techniques. RESULTS:The time of donor pancreas harvesting in the cervical and abdominal groups was 31±6 and 37.6±3.8 min, respectively, and the lengths of recipient operations were 49.2±5.6 and 60.6±7.8 min. The time for donor operation was not signiifcantly different (P>0.05), but the recipient operation time in the abdominal group was longer than that in the cervical group (P0.05). CONCLUSIONS:Both pancreas transplantation methods are stable models for immunological and physiological studies in pancreas transplantation. Since each has its own advantages and disadvantages, the designer can choose the appropriate method according to the requirements of the study.

  10. Research of combined liver-kidney transplantation model in rats

    Institute of Scientific and Technical Information of China (English)

    Jiageng Zhu; Jun Li; Ruipeng Jia; Jianghao Su; Mingshun Shen; Zhigang Cao

    2007-01-01

    Objective: To set up a simple and reliable rat model of combined liver-kidney transplantation. Methods: SD rats served as both donors and recipients. 4℃ sodium lactate Ringer's was infused from portal veins to donated livers,and from abdominal aorta to donated kidneys, respectively. Anastomosis of the portal vein and the inferior vena cava (IVC) inferior to the right kidney between the graft and the recipient was performed by a double cuff method, then the superior hepatic vena cava with suture. A patch of donated renal artery was anastomosed to the recipient abdominal aorta. The urethra and bile duct were reconstructed with a simple inside bracket. Results: Among 65 cases of combined liver-kidney transplantation, the success rate in the late 40 cases was 77.5%. The function of the grafted liver and kidney remained normal. Conclusion: This rat model of combined liver-kidney transplantation can be established in common laboratory conditions with high success rate and meet the needs of renal transplantation experiment.

  11. Achilles tendinosis: a morphometrical study in a rat model.

    Science.gov (United States)

    Silva, Rafael Duarte; Glazebrook, Mark Anthony; Campos, Vinicius Castro; Vasconcelos, Anilton Cesar

    2011-01-01

    This study addresses the morphopathogenesis of Achilles tendinosis, using a rat model and presenting quantitative analysis of time-dependent histological changes. Thirty Wistar rats were used, randomly split in experimental and control groups. Animals of the experimental group were submitted to a treadmill running scheme. Five animals of each group were euthanized at four, eight and sixteen weeks. Achilles tendons were collected and processed routinely for histopath sections. Slides were stained by Hematoxylin-Eosin, Picrosirius Red, Alcian Blue, AgNOR, TUNEL and evaluated morphometrically. Cellular density decreased slightly along the time and was higher in the experimental group than in controls at fourth, eighth and sixteenth weeks. Fiber microtearing, percentual of reticular fibers and glycosaminoglycans content increased along the time and were higher in experimental group than in controls at all-time intervals. AgNOR labeling here interpreted as a marker of transcription activity was higher in the experimental groups than in controls at all-time intervals. Apoptotic cells were more frequent and diffusely distributed in tendinosis samples than in control groups. These results suggest that as mechanical overload is becoming chronic, cellular turnover and matrix deposition increases leading to tendinosis. The combination of staining techniques and morphometry used here to describe the evolution of lesions occurring in a rat model system has proved to be suited for the study of induced Achilles tendinosis.

  12. Rodent models in neuroscience research: is it a rat race?

    Directory of Open Access Journals (Sweden)

    Bart Ellenbroek

    2016-10-01

    Full Text Available Rodents (especially Mus musculus and Rattus norvegicus have been the most widely used models in biomedical research for many years. A notable shift has taken place over the last two decades, with mice taking a more and more prominent role in biomedical science compared to rats. This shift was primarily instigated by the availability of a much larger genetic toolbox for mice, particularly embryonic-stem-cell-based targeting technology for gene disruption. With the recent emergence of tools for altering the rat genome, notably genome-editing technologies, the technological gap between the two organisms is closing, and it is becoming more important to consider the physiological, anatomical, biochemical and pharmacological differences between rats and mice when choosing the right model system for a specific biological question. The aim of this short review and accompanying poster is to highlight some of the most important differences, and to discuss their impact on studies of human diseases, with a special focus on neuropsychiatric disorders.

  13. A rat model for embolic encephalitis

    DEFF Research Database (Denmark)

    Astrup, Lærke Boye; Agerholm, Jørgen Steen; Aalbæk, Bent

    2011-01-01

    µl thrombin (2.5 IU/ml) in a catheter until coagulated. A sterile fibrin-clot of 5 mm was selected for embolization and injected via the ECA catheter. The common carotid artery was clamped during injection thereby directing the embolus via the internal carotid artery to the brain. The clot...... gain access to the brain by the circulation and, no foreign materials other than bacteria are implated in the brain. This ensures high face-validity and high construct-validity of the model for three reasons: 1) Cerebral infarction by thrombosis or disseminated intravascular coagulation is a key...

  14. Characterization of an animal model of postmenopausal hypertension in spontaneously hypertensive rats.

    Science.gov (United States)

    Fortepiani, Lourdes A; Zhang, Huimin; Racusen, Lorraine; Roberts, L Jackson; Reckelhoff, Jane F

    2003-03-01

    Blood pressure (BP) increases in postmenopausal women. The mechanisms responsible are unknown. The present study was performed to characterize a model of postmenopausal hypertension in the rat and to determine the role that oxidative stress may play in mediating the postmenopausal hypertension. Spontaneously hypertensive rats were ovariectomized (ovx) or left intact (PMR) at 8 months and were aged to 18 months. These animals were compared with young females (YF; 4 or 8 months of age) and old males (18 months) for some measurements. Estradiol levels were decreased in PMR rats to levels not different from YF rats in proestrous or from old males. BP increased progressively with age in PMR rats but not in ovx or male rats, such that the gender difference in hypertension disappeared by 18 months. Glomerular filtration rate was lower in ovx and PMR rats than in YF rats. Renal plasma flow and renal vascular resistance were similar between YF and ovx rats, but lower and higher, respectively, in PMR rats. Serum testosterone increased by 60% in ovx rats and 400% in PMR rats compared with YF rats. Plasma renin activity also increased in PMR rats but not in ovx rats. Chronic treatment (for 8 months beginning at 8 months of age) of PMR rats with vitamins E and C, but not tempol, resulted in a significant reduction in BP and excretion of F2-isoprostanes. In contrast, tempol, but not vitamins E and C, reduced BP in old males. These data suggest that the PMR rats, but not ovx rats, may be a suitable model for the study of postmenopausal hypertension, and that oxidative stress plays a role in the increased BP.

  15. A naturalistic glyceryl trinitrate infusion migraine model in the rat

    DEFF Research Database (Denmark)

    Ramachandran, Roshni; Bhatt, Deepak Kumar; Ploug, Kenneth Beri

    2012-01-01

    Glyceryl trinitrate (GTN) infusion is a reliable method to provoke migraine-like headaches in humans. Previous studies have simulated this human model in anaesthetized or in awake rodents using GTN doses 10,000 times higher than used in humans. The relevance of such toxicological doses to migraine...... is not certain. Anaesthesia and low blood pressure caused by high GTN doses both can affect the expression of nociceptive marker c-fos. Therefore, our aim was to simulate the human GTN migraine model in awake rats using a clinically relevant dose....

  16. Resibufogenin corrects hypertension in a rat model of human preeclampsia.

    Science.gov (United States)

    Vu, Hop; Ianosi-Irimie, Monica; Danchuk, Svitlana; Rabon, Edd; Nogawa, Toshihiko; Kamano, Yoshiaki; Pettit, G Robert; Wiese, Thomas; Puschett, Jules B

    2006-02-01

    The study of the pathogenesis of preeclampsia has been hampered by a relative dearth of animal models. We developed a rat model of preeclampsia in which the excretion of a circulating inhibitor of Na/K ATPase, marinobufagenin (MBG), is elevated. These animals develop hypertension, proteinuria, and intrauterine growth restriction. The administration of a congener of MBG, resibufogenin (RBG), reduces blood pressure to normal in these animals, as is the case when given to pregnant animals rendered hypertensive by the administration of MBG. Studies of Na/K ATPase inhibition by MBG and RBG reveal that these agents are equally effective as inhibitors of the enzyme.

  17. Sleep Changes in a Rat Prenatal Stress Model of Depression

    DEFF Research Database (Denmark)

    Skoven, Christian; Sickman, Helle M.; Bastlund, Jesper Frank

    Major depression is one of the most frequently occurring mental health disorders, but is characterized by diverse symptomatology. Sleep disturbances, however, are commonplace in depressive patients. These alterations include increased duration of Rapid Eye Movement Sleep (REMS) and increased sleep...... fragmentation. Stressful life events during the second trimester of human pregnancy increase the risk of depression in the offspring. Similarly, rodents exposed to prenatal stress (PNS) during gestation express depression- like behavioral changes. Accordingly, we investigated sleep changes in a rat PNS model...... of depression, to elucidate whether these are similar to those seen in clinical depression. Pregnant Sprague-Dawley rats were submitted to repeated variable stress during gestational days 13-21. The young adult offspring were surgically implanted with electrodes for subsequent electroencephalographic...

  18. In vivo photoacoustic imaging of osteosarcoma in a rat model

    Science.gov (United States)

    Hu, Jun; Yu, Menglei; Ye, Fei; Xing, Da

    2011-02-01

    Osteosarcoma is one of the most common primary malignant tumors of the bone and the second leading cause of cancer-related deaths in the pediatric age group. Confirmed diagnosis and prompt treatment of osteosarcoma are critical for effective prognosis. In this study, we investigate the application of photoacoustic imaging (PAI) for the detection of osteosarcoma in an animal model. Cross-section images of a normal rat leg and a tumorous rat leg were successfully reconstructed in vivo. Morphological changes and the development of the implanted osteosarcoma were accurately mapped with time-dependent photoacoustic images. Furthermore, we evaluate the use of gold nanorods as contrast agents for imaging osteosarcoma with PAI. This is the first study that uses PAI to detect osteosarcoma in vivo, and the results suggest that PAI has the potential clinical application for detecting osteosarcoma in the early stage.

  19. Efficacy of Female Rat Models in Translational Cardiovascular Aging Research

    Directory of Open Access Journals (Sweden)

    K. M. Rice

    2014-01-01

    Full Text Available Cardiovascular disease is the leading cause of death in women in the United States. Aging is a primary risk factor for the development of cardiovascular disease as well as cardiovascular-related morbidity and mortality. Aging is a universal process that all humans undergo; however, research in aging is limited by cost and time constraints. Therefore, most research in aging has been done in primates and rodents; however it is unknown how well the effects of aging in rat models translate into humans. To compound the complication of aging gender has also been indicated as a risk factor for various cardiovascular diseases. This review addresses the systemic pathophysiology of the cardiovascular system associated with aging and gender for aging research with regard to the applicability of rat derived data for translational application to human aging.

  20. A standardised and reproducible model of intra-abdominal infection and abscess formation in rats

    NARCIS (Netherlands)

    Bosscha, K; Nieuwenhuijs, VB; Gooszen, AW; van Duijvenbode-Beumer, H; Visser, MR; Verweij, Willem; Akkermans, LMA

    2000-01-01

    Objective: To develop a standardised and reproducible model of intra-abdominal infection and abscess formation in rats. Design: Experimental study. Setting: University hospital, The Netherlands. Subjects: 36 adult male Wistar rats. Interventions: In 32 rats, peritonitis was produced using two differ

  1. Azithromycin reduces inflammation in a rat model of acute conjunctivitis

    Science.gov (United States)

    Fernandez-Robredo, Patricia; Recalde, Sergio; Moreno-Orduña, Maite; García-García, Laura; Zarranz-Ventura, Javier; García-Layana, Alfredo

    2013-01-01

    Purpose Macrolide antibiotics are known to have various anti-inflammatory effects in addition to their antimicrobial activity, but the mechanisms are still unclear. The effect of azithromycin on inflammatory molecules in the lipopolysaccharide-induced rat conjunctivitis model was investigated. Methods Twenty-four Wistar rats were divided into two groups receiving topical ocular azithromycin (15 mg/g) or vehicle. In total, six doses (25 µl) were administered as one dose twice a day for three days before subconjunctival lipopolysaccharide injection (3 mg/ml). Before the rats were euthanized, mucus secretion, conjunctival and palpebral edema and redness were evaluated. Real-time polymerase chain reaction was used to determine gene expression for interleukin-6, cyclooxygenase-2, tumor necrosis factor-α, matrix metalloproteinase (MMP)-2, and MMP-9. Interleukin-6 was determined with enzyme-linked immunosorbent assay, nuclear factor-kappa B with western blot, and MMP-2 activity with gelatin zymogram. Four eyes per group were processed for histology and subsequent periodic acid-Schiff staining and CD68 for immunofluorescence. The Student t test or the Wilcoxon test for independent samples was applied (SPSS v.15.0). Results Azithromycin-treated animals showed a significant reduction in all clinical signs (p<0.05) compared to controls. Interleukin-6 (p<0.05), nuclear factor-kappa B protein expression (p<0.01), and MMP-2 activity (p<0.05) in conjunctival homogenates were significantly reduced compared with the control animals. MMP-2 gene expression showed a tendency to decrease in the azithromycin group (p=0.063). Mucus secretion by goblet cells and the macrophage count in conjunctival tissue were also decreased in the azithromycin group (p<0.05). Conclusions These results suggest that azithromycin administration ameliorates induced inflammation effects in a rat model of acute conjunctivitis. PMID:23378729

  2. A rat model for muscle regeneration in the soft palate.

    Directory of Open Access Journals (Sweden)

    Paola L Carvajal Monroy

    Full Text Available BACKGROUND: Children with a cleft in the soft palate have difficulties with speech, swallowing, and sucking. Despite successful surgical repositioning of the muscles, optimal function is often not achieved. Scar formation and defective regeneration may hamper the functional recovery of the muscles after cleft palate repair. Therefore, the aim of this study is to investigate the anatomy and histology of the soft palate in rats, and to establish an in vivo model for muscle regeneration after surgical injury. METHODS: Fourteen adult male Sprague Dawley rats were divided into four groups. Groups 1 (n = 4 and 2 (n = 2 were used to investigate the anatomy and histology of the soft palate, respectively. Group 3 (n = 6 was used for surgical wounding of the soft palate, and group 4 (n = 2 was used as unwounded control group. The wounds (1 mm were evaluated by (immunohistochemistry (AZAN staining, Pax7, MyoD, MyoG, MyHC, and ASMA after 7 days. RESULTS: The present study shows that the anatomy and histology of the soft palate muscles of the rat is largely comparable with that in humans. All wounds showed clinical evidence of healing after 7 days. AZAN staining demonstrated extensive collagen deposition in the wound area, and initial regeneration of muscle fibers and salivary glands. Proliferating and differentiating satellite cells were identified in the wound area by antibody staining. CONCLUSIONS: This model is the first, suitable for studying muscle regeneration in the rat soft palate, and allows the development of novel adjuvant strategies to promote muscle regeneration after cleft palate surgery.

  3. The elusive rat model of conditioned placebo analgesia.

    Science.gov (United States)

    McNabb, Christopher T; White, Michelle M; Harris, Amber L; Fuchs, Perry N

    2014-10-01

    Recent research on human placebo analgesia has suggested the need for rodent models to further elucidate the neural substrates of the placebo effect. This series of 3 experiments therefore was performed in an attempt to develop a model of placebo analgesia in rats. In each study, female Sprague-Dawley rats received an L5 spinal nerve ligation to induce a neuropathic pain condition. Each rat then underwent a 4-day conditioning procedure in which an active analgesic drug or its vehicle (unconditioned stimulus) was associated with the following cues (conditioned stimuli): novel testing room (environmental), vanilla scent cue (olfactory), dim incandescent lighting (visual), restraint procedure/injection (tactile), and time of day and injection-test latency (temporal). The analgesics for each experiment were as follows: Experiment 1 used 90 mg/kg gabapentin, experiment 2 used 3mg/kg loperamide hydrochloride, and experiment 3 used 6 mg/kg morphine sulfate. On the following test day, half of the animals received the opposite treatment, resulting in 4 conditioning manipulations: drug/drug, drug/vehicle, vehicle/drug, and vehicle/vehicle. Nociceptive thresholds were assessed with the mechanical paw withdrawal threshold test each day after the conditioning procedure. In all 3 experiments, no significant differences were detected on test day between control and placebo groups, indicating a lack of a conditioned placebo analgesic response. Our results contrast with prior research that implies the existence of a reliable and robust response to placebo treatment. We conclude that placebo analgesia in rats is not particularly robust and that it is difficult to achieve using conventional procedures and proper experimental design.

  4. Newly Developed Rat Model of Chronic Kidney Disease-Mineral Bone Disorder.

    Science.gov (United States)

    Watanabe, Kentaro; Fujii, Hideki; Goto, Shunsuke; Nakai, Kentaro; Kono, Keiji; Watanabe, Shuhei; Shinohara, Masami; Nishi, Shinichi

    2017-07-01

    Chronic kidney disease-mineral bone disorder (CKD-MBD) is associated with all-cause and cardiovascular morbidity and mortality in patients with CKD. Thus, elucidating its pathophysiological mechanisms is essential for improving the prognosis. We evaluated characteristics of CKD-MBD in a newly developed CKD rat model. We used male Sprague-Dawley (SD) rats and spontaneously diabetic Torii (SDT) rats, which are used as models for nonobese type 2 diabetes. CKD was induced by 5/6 nephrectomy (Nx). At 10 weeks, the rats were classified into six groups and administered with a vehicle or a low- or high-dose paricalcitol thrice a week. At 20 weeks, the rats were sacrificed; blood and urinary biochemical analyses and histological analysis of the aorta were performed. At 20 weeks, hemoglobin A1c (HbA1c) levels, blood pressure, and renal function were not significantly different among the six groups. Serum calcium and phosphate levels tended to be higher in SDT-Nx rats than in SD-Nx rats. The urinary excretion of calcium and phosphate was significantly greater in SDT-Nx rats than in SD-Nx rats. After administering paricalcitol, serum parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) levels were significantly higher in SDT-Nx rats than in SD-Nx rats. The degree of aortic calcification was significantly more severe and the aortic calcium content was significantly greater in SDT-Nx rats than in SD-Nx rats. We suggest that our new CKD rat model using SDT rats represents a useful CKD-MBD model, and this model was greatly influenced by paricalcitol administration. Further studies are needed to clarify the detailed mechanisms underlying this model.

  5. A series of rat segmental forelimb ectopic implantation models.

    Science.gov (United States)

    Zhou, Xianyu; Luo, Xusong; Gao, Bowen; Liu, Fei; Gu, Chuan; Yu, Qingxiong; Li, Qingfeng; Zhu, Hainan

    2017-05-09

    Temporary ectopic implantation has been performed in clinical practice to salvage devascularized amputated tissues for delayed replantation purpose. In this study, we established a series of segmental forelimb ectopic implantation models in rats, including forelimb, forearm, forepaw, digit, and double forelimbs, to mimic the clinical context. Time of amputated limbs harvesting in donors and ectopic implantation process in recipients were recorded. Survival time and mortalities of recipients were also recorded. Sixty days after ectopic implantation, a full-field laser perfusion imager (FLPI) was used to detect the blood flow of amputated limbs and micro-CT imaging was used to examine bone morphological changes. Histological sections of amputated limbs were stained with hematoxylin and eosin to evaluate pathological changes. Implanted amputated limbs in all models achieved long term survival and there were no obvious morphological and histological changes were found according to results of micro-CT and histology study. Thus, a series of rat segmental forelimb temporary ectopic implantation models have been well established. To our knowledge, this is the first rodent animal model related to forelimb temporary ectopic implantation. These models might facilitate further research related to salvage, reconstruction and better aesthetic and functional outcome of upper extremity/digit in temporary ectopic implantation scenario.

  6. The utility of Apc-mutant rats in modeling human colon cancer

    Directory of Open Access Journals (Sweden)

    Amy A. Irving

    2014-11-01

    Full Text Available Prior to the advent of genetic engineering in the mouse, the rat was the model of choice for investigating the etiology of cancer. Now, recent advances in the manipulation of the rat genome, combined with a growing recognition of the physiological differences between mice and rats, have reignited interest in the rat as a model of human cancer. Two recently developed rat models, the polyposis in the rat colon (Pirc and Kyoto Apc Delta (KAD strains, each carry mutations in the intestinal-cancer-associated adenomatous polyposis coli (Apc gene. In contrast to mouse models carrying Apc mutations, in which cancers develop mainly in the small intestine rather than in the colon and there is no gender bias, these rat models exhibit colonic predisposition and gender-specific susceptibility, as seen in human colon cancer. The rat also provides other experimental resources as a model organism that are not provided by the mouse: the structure of its chromosomes facilitates the analysis of genomic events, the size of its colon permits longitudinal analysis of tumor growth, and the size of biological samples from the animal facilitates multiplexed molecular analyses of the tumor and its host. Thus, the underlying biology and experimental resources of these rat models provide important avenues for investigation. We anticipate that advances in disease modeling in the rat will synergize with resources that are being developed in the mouse to provide a deeper understanding of human colon cancer.

  7. The utility of Apc-mutant rats in modeling human colon cancer

    Science.gov (United States)

    Irving, Amy A.; Yoshimi, Kazuto; Hart, Marcia L.; Parker, Taybor; Clipson, Linda; Ford, Madeline R.; Kuramoto, Takashi; Dove, William F.; Amos-Landgraf, James M.

    2014-01-01

    Prior to the advent of genetic engineering in the mouse, the rat was the model of choice for investigating the etiology of cancer. Now, recent advances in the manipulation of the rat genome, combined with a growing recognition of the physiological differences between mice and rats, have reignited interest in the rat as a model of human cancer. Two recently developed rat models, the polyposis in the rat colon (Pirc) and Kyoto Apc Delta (KAD) strains, each carry mutations in the intestinal-cancer-associated adenomatous polyposis coli (Apc) gene. In contrast to mouse models carrying Apc mutations, in which cancers develop mainly in the small intestine rather than in the colon and there is no gender bias, these rat models exhibit colonic predisposition and gender-specific susceptibility, as seen in human colon cancer. The rat also provides other experimental resources as a model organism that are not provided by the mouse: the structure of its chromosomes facilitates the analysis of genomic events, the size of its colon permits longitudinal analysis of tumor growth, and the size of biological samples from the animal facilitates multiplexed molecular analyses of the tumor and its host. Thus, the underlying biology and experimental resources of these rat models provide important avenues for investigation. We anticipate that advances in disease modeling in the rat will synergize with resources that are being developed in the mouse to provide a deeper understanding of human colon cancer. PMID:25288683

  8. Arterial hypoxemia and intrapulmonary vasodilatation in rat models of portal hypertension.

    Science.gov (United States)

    Katsuta, Yasumi; Zhang, Xue-Jun; Ohsuga, Masaru; Akimoto, Toshio; Komeichi, Hirokazu; Shimizu, Shuji; Kato, Yoshihito; Miyamoto, Akiko; Satomura, Katsuaki; Takano, Teruo

    2005-08-01

    Rats with chronic bile duct ligation (CBDL) and portal vein ligation (PVL) are used as models of portal hypertension. CBDL rats show hypoxemia with intrapulmonary vasodilatation (IPVD), and are recognized as a model of hepatopulmonary syndrome (HPS), while PVL rats are normoxemic. We investigated the differences in arterial oxygenation between these models, and the key factors leading to HPS. Forty-eight Sprague-Dawley rats were prepared as CBDL or PVL models, or as Sham rats. Arterial oxygenation, hemodynamics (reference sample method), and IPVD were simultaneously evaluated in conscious and unrestrained animals, using (141)Ce- or (113)Sn-labeled microspheres (15 microm in diameter), respectively. Endothelin-1 (ET-1) and nitrate/nitrite (end products of nitric oxide; NOx) production by the lung tissue (increment across the lungs) was also determined. The extent of IPVD was similar in both models, but hypoxemia was only observed in CBDL rats. The ET-1 level and the increment in NOx were significantly increased in CBDL rats, and the increment was directly correlated with impairment of oxygenation. Blood flow through the bronchial arteries (anatomical shunting) was increased in CBDL rats, reaching more than three times the level in PVL rats or Sham rats. These results support the hypothesis that NO derived from the lung tissues contributes to hypoxemia, and IPVD appears to be a prerequisite for impaired oxygenation. The considerable increase of anatomical shunting may potentially contribute to impaired oxygenation in CBDL rats.

  9. Surgery results in exaggerated and persistent cognitive decline in a rat model of the Metabolic Syndrome.

    Science.gov (United States)

    Feng, Xiaomei; Degos, Vincent; Koch, Lauren G; Britton, Steven L; Zhu, Yinggang; Vacas, Susana; Terrando, Niccolò; Nelson, Jeffrey; Su, Xiao; Maze, Mervyn

    2013-05-01

    Postoperative cognitive decline can be reproduced in animal models. In a well-validated rat model of the Metabolic Syndrome, we sought to investigate whether surgery induced a more severe and persistent form of cognitive decline similar to that noted in preliminary clinical studies. In rats that had been selectively bred for low and high exercise endurance, the low capacity runners (LCR) exhibited features of Metabolic Syndrome (obesity, dyslipidemia, insulin resistance, and hypertension). Tibial fracture surgery was performed under isoflurane anesthesia in LCR and high capacity runner (HCR) rats and cognitive function was assessed postoperatively in a trace-fear conditioning paradigm and Morris Water Maze; non-operated rats were exposed to anesthesia and analgesia (sham). Group sizes were n = 6. On postoperative D7, LCR rats had shorter freezing times than postoperative HCR rats. Five months postoperatively, LCR rats had a flatter learning trajectory and took longer to locate the submerged platform than postoperative HCR rats; dwell-time in the target quadrant in a probe trial was shorter in the postoperative LCR compared to HCR rats. LCR and HCR sham rats did not differ in any test. Postoperatively, LCR rats diverged from HCR rats exhibiting a greater decline in memory, acutely, with persistent learning and memory decline, remotely; this could not be attributed to changes in locomotor or swimming performance. This Metabolic Syndrome animal model of surgery-induced cognitive decline corroborates, with high fidelity, preliminary findings of postoperative cognitive dysfunction in Metabolic Syndrome patients.

  10. Establishment of animal model of dual liver transplantation in rat.

    Directory of Open Access Journals (Sweden)

    Ying Zhang

    Full Text Available The animal model of the whole-size and reduced-size liver transplantation in both rat and mouse has been successfully established. Because of the difficulties and complexities in microsurgical technology, the animal model of dual liver transplantation was still not established for twelve years since the first human dual liver transplantation has been made a success. There is an essential need to establish this animal model to lay a basic foundation for clinical practice. To study the physiological and histopathological changes of dual liver transplantation, "Y" type vein from the cross part between vena cava and two iliac of donor and "Y' type prosthesis were employed to recanalize portal vein and the bile duct between dual liver grafts and recipient. The dual right upper lobes about 45-50% of the recipient liver volume were taken as donor, one was orthotopically implanted at its original position, the other was rotated 180° sagitally and heterotopically positioned in the left upper quadrant. Microcirculation parameters, liver function, immunohistochemistry and survival were analyzed to evaluate the function of dual liver grafts. No significant difference in the hepatic microcirculatory flow was found between two grafts in the first 90 minutes after reperfusion. Light and electronic microscope showed the liver architecture was maintained without obvious features of cellular destruction and the continuity of the endothelium was preserved. Only 3 heterotopically positioned graft appeared patchy desquamation of endothelial cell, mitochondrial swelling and hepatocytes cytoplasmic vacuolization. Immunohistochemistry revealed there is no difference in hepatocyte activity and the ability of endothelia to contract and relax after reperfusion between dual grafts. Dual grafts made a rapid amelioration of liver function after reperfusion. 7 rats survived more than 7 days with survival rate of 58.3.%. Using "Y" type vein and bile duct prosthesis, we

  11. Antifibrotic effect of heparin on liver fibrosis model in rats

    Institute of Scientific and Technical Information of China (English)

    Binita; Shah; Gaurang; Shah

    2012-01-01

    AIM: To evaluate the effect of chronic thrombin inhibition by heparin on experimentally induced chronic liver injury (liver fibrosis) in rats. METHODS: Chronic liver injury (liver fibrosis) was induced in Wistar rats by oral administration of carbon tetrachloride (CCl 4 ) for 7 wk, an animal model with persistent severe hepatic fibrosis. Intravenous administration of the thrombin antagonist (heparin) started 1 wk after the start of CCl 4 intoxication for 6 wk. After completion of treatment (7 wk), markers of hepatic dysfunction were measured and changes evaluated histopathologically. RESULTS: Higher serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), total, direct and indirect bilirubin levels, as well as lower fibrinogen levels, were found in CCl 4 intoxicated rats. Heparin, silymarin and combination of drug (heparin and silymarin) treatment for 6 wk prevented a rise in SGOT, SGPT, ALP, total, direct and indirect bilirubin levels and improved fibrinogen levels. Deterioration in hepatic function determined by the fibrosis area was retarded, as evident from hepatic histopathology. Total protein levels were not changed in all groups.CONCLUSION: Heparin, a thrombin antagonist, preserved hepatic function and reduced severity of hepatic dysfunction/fibrogenesis. Combination of heparin and silymarin produced additional benefits on liver fibrosis.

  12. Innervation of ectopic endometrium in a rat model of endometriosis.

    Science.gov (United States)

    Berkley, Karen J; Dmitrieva, Natalia; Curtis, Kathleen S; Papka, Raymond E

    2004-07-27

    Endometriosis (ENDO) is a disorder in which vascularized growths of endometrial tissue occur outside the uterus. Its symptoms include reduced fertility and severe pelvic pain. Mechanisms that maintain the ectopic growths and evoke symptoms are poorly understood. One factor not yet considered is that the ectopic growths develop their own innervation. Here, we tested the hypothesis that the growths develop both an autonomic and a sensory innervation. We used a rat model of surgically induced ENDO whose growths mimic those in women. Furthermore, similar to women with ENDO, such rats exhibit reduced fertility and increased pelvic nociception. The ENDO was induced by autotransplanting, on mesenteric cascade arteries, small pieces of uterus that formed vascularized cysts. The cysts and healthy uterus were harvested from proestrous rats and immunostained using the pan-neuronal marker PGP9.5 and specific markers for calcitonin gene-related peptide (CGRP) (sensory C and A delta fibers), substance P (SP) (sensory C and A delta fibers) and vesicular monoamine transporter (sympathetic fibers). Cysts (like the uterus) were robustly innervated, with many PGP9.5-stained neurites accompanying blood vessels and extending into nearby luminal epithelial layers. CGRP-, SP-, and vesicular monoamine transporter-immunostained neurites also were observed, with CGRP and SP neurites extending the furthest into the cyst lining. These results demonstrate that ectopic endometrial growths develop an autonomic and sensory innervation. This innervation could contribute not only to symptoms associated with ENDO but also to maintenance of the ectopic growths.

  13. Opposite effect of mast cell stabilizers ketotifen and tranilast on the vasoconstrictor response to electrical field stimulation in rat mesenteric artery.

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    Esther Sastre

    Full Text Available OBJECTIVES: We analyzed whether mast cell stabilization by either ketotifen or tranilast could alter either sympathetic or nitrergic innervation function in rat mesenteric arteries. METHODS: Electrical field stimulation (EFS-induced contraction was analyzed in mesenteric segments from 6-month-old Wistar rats in three experimental groups: control, 3-hour ketotifen incubated (0.1 αmol/L, and 3-hour tranilast incubated (0.1 mmol/L. To assess the possible participation of nitrergic or sympathetic innervation, EFS contraction was analyzed in the presence of non-selective nitric oxide synthase (NOS inhibitor L-NAME (0.1 mmol/L, α-adrenergic receptor antagonist phentolamine (0.1 µmol/L, or the neurotoxin 6-hydroxydopamine (6-OHDA, 1.46 mmol/L. Nitric oxide (NO and superoxide anion (O2.(- levels were measured, as were vasomotor responses to noradrenaline (NA and to NO donor DEA-NO, in the presence and absence of 0.1 mmol/L tempol. Phosphorylated neuronal NOS (P-nNOS expression was also analyzed. RESULTS: EFS-induced contraction was increased by ketotifen and decreased by tranilast. L-NAME increased the vasoconstrictor response to EFS only in control segments. The vasodilator response to DEA-NO was higher in ketotifen- and tranilast-incubated segments, while tempol increased vasodilator response to DEA-NO only in control segments. Both NO and O2(- release, and P-nNOS expression were diminished by ketotifen and by tranilast treatment. The decrease in EFS-induced contraction produced by phentolamine was lower in tranilast-incubated segments. NA vasomotor response was decreased only by tranilast. The remnant vasoconstriction observed in control and ketotifen-incubated segments was abolished by 6-OHDA. CONCLUSION: While both ketotifen and tranilast diminish nitrergic innervation function, only tranilast diminishes sympathetic innnervation function, thus they alter the vasoconstrictor response to EFS in opposing manners.

  14. A modified rat model of isolated bilateral pulmonary contusion.

    Science.gov (United States)

    Wang, Shaohua; Ruan, Zheng; Zhang, Jie; Zheng, Jin

    2012-09-01

    The aim of the present study was to create a feasible specific rat model of isolated bilateral pulmonary contusion (PC) and to evaluate the relationship between severity of hypoxemia and quantity of contusion lesions. Anesthetized rats were placed in a prone position. Injury energy ranging from 2.1 to 3.0 J was produced by a falling weight passed through a specially designed arched shield to the bilateral chest wall of rats. After injury (4 h), the contusion volume was measured using computer-generated three-dimensional reconstruction from a chest computed tomographic scan and expressed as a percentage of total lung volume. Arterial partial pressure of oxygen (PaO(2)) in blood gas analysis and contusion volume percentage were used to assess the severity of contusion. Heart and lung biopsy was used to confirm the diagnosis and rule out the existence of myocardial contusion. There were 3 cases of death and 1 case of death in the 3.0 J and the 2.4 J group, respectively. PaO(2) in the 2.7 J group was significantly lower than that in the lower energy groups (Ppulmonary contusion in the 2.7 J group was significantly higher compared to that of the lower energy groups (Pcontusion percentage (R(2)=0.76). Hemorrhage, edema and neutrophil infiltration were determined by lung biopsy. No evidence of myocardial contusion was documented in multiple heart biopsies. The method illustrated in this research effectively duplicates isolated bilateral pulmonary contusion in rats, the severity of which is highly correlated with the contusion size. Thus, 2.7 J can be regarded as the maximal energy for sublethal injury.

  15. Transplanted Neural Stem Cells: Playing a Neuroprotective Role by Ceruloplasmin in the Substantia Nigra of PD Model Rats?

    Science.gov (United States)

    Xiao, Jia-Jia; Yin, Ming; Wang, Ze-Jian; Wang, Xiao-Ping

    2015-01-01

    Although mounting evidence suggests that ceruloplasmin (CP) deficiency and iron deposition are pivotal factors responsible for exacerbating demise of dopaminergic neurons in the substantia nigra (SN) of the Parkinsonism and neural stem cells (NSCs) are believed to be excellent candidates for compensating the lost dopaminergic neurons, there are few researches to explore the change of CP expression and of iron deposition in the pathological microenvironment of SN after NSCs transplantation and the ability of grafted NSCs to differentiate directionally into dopaminergic neurons under the changed homeostasis. With substantia nigral stereotaxic technique and NSCs transplantation, we found that tyrosine hydroxylase and CP expression decreased and iron deposition increased in the lesioned SN after 6-OHDA administration compared with control, while tyrosine hydroxylase and CP expression increased and iron deposition decreased after NSCs transplantation compared to 6-OHDA administration alone. Only a small number of embedding NSCs are able to differentiate into dopaminergic neurons. These results suggest that grafted NSCs have an influence on improving the content of CP expression, which may play a neuroprotective role by decreasing iron deposition and ameliorating damage of dopaminergic neurons and possibly underline the iron-related common mechanism of Parkinson's disease and Wilson's disease.

  16. Mechanism of auditory hypersensitivity in human autism using autism model rats.

    Science.gov (United States)

    Ida-Eto, Michiru; Hara, Nao; Ohkawara, Takeshi; Narita, Masaaki

    2017-04-01

    Auditory hypersensitivity is one of the major complications in autism spectrum disorder. The aim of this study was to investigate whether the auditory brain center is affected in autism model rats. Autism model rats were prepared by prenatal exposure to thalidomide on embryonic day 9 and 10 in pregnant rats. The superior olivary complex (SOC), a complex of auditory nuclei, was immunostained with anti-calbindin d28k antibody at postnatal day 50. In autism model rats, SOC immunoreactivity was markedly decreased. Strength of immunostaining of SOC auditory fibers was also weak in autism model rats. Surprisingly, the size of the medial nucleus of trapezoid body, a nucleus exerting inhibitory function in SOC, was significantly decreased in autism model rats. Auditory hypersensitivity may be, in part, due to impairment of inhibitory processing by the auditory brain center. © 2016 Japan Pediatric Society.

  17. ideal hepatotoxicity model in rats using carbon tetrachloride (ccl4)

    African Journals Online (AJOL)

    DR. AMINU

    twenty five (25) rats each; rats in group I are negative control, were not induced with lipid peroxidation. Rats in ... MDA after 96 hours of CCl4 treatment compared with control group. However, rats treated ... EXPERIMENTAL DESIGN. Experimental ... Biochemical Analysis ... these parameters was shown to be proportional to.

  18. Animal models of schizophrenia: developmental preparation in rats.

    Science.gov (United States)

    Ratajczak, Piotr; Wozniak, Anna; Nowakowska, Elzbieta

    2013-01-01

    Schizophrenia manifests itself primarily with positive symptoms, negative symptoms and cognitive disorders. Animal models of mental diseases seem to be an important tool in understanding key theories related with pathophysiology of the disorder and are used to assess efficacy of new drugs. References describe four basic groups of animal models of schizophrenia, such as: models created by pharmacological intervention, genetic models, lesion models and models of developmental disorders of primary brain structures. Of the models referred to above, the group of developmental disorder models is particularly noteworthy, as they are primarily easy to use, and the methods are highly sensitive. High scientific value of these models is associated with the neurodevelopmental theory which stipulates that at an early stage of body development, a number of interactions between genetic and environmental factors may affect the development of neurons which may cause disorders of brain cytoarchitecture development. We review six developmental models of schizophrenia in rats (MAM--methylooxymethanol acetate, prenatal stress, maternal deprivation, isolation rearing, prenatal immune challenge and maternal malnutrition) that are all validated by disruption in PPI.

  19. Novel rat tail discitis model using bioluminescent Staphylococcus aureus.

    Science.gov (United States)

    Bostian, Phillip A; Karnes, Jonathan M; Cui, Shari; Robinson, Lisa J; Daffner, Scott D; Witt, Michelle R; Emery, Sanford E

    2017-09-01

    Management of spondylodiscitis is a challenging clinical problem requiring medical and surgical treatment strategies. The purpose of this study was to establish a rat model of spondylodiscitis that utilizes bioluminescent Staphylococcus aureus (S. aureus), thus permitting in vivo surveillance of infection intensity. Inocula of the bioluminescent S. aureus strain XEN36 were created in concentrations of 10(2) CFU/0.1 ml, 10(4)  CFU/0.1 ml, and 10(6)  CFU/0.1 ml. Three groups of rats were injected with the bacteria in the most proximal intervertebral tail segment. The third most proximal tail segment was injected with saline as a control. Bioluminescence was measured at baseline, 3 days, and weekly for a total of 6 weeks. Detected bioluminescence for each group peaked at day 3 and returned to baseline in 21 days. The average intensity was highest for the experimental group injected with the most concentrated bacterial solution (10(6)  CFU/0.1 ml). Radiographic analysis revealed loss of intervertebral disc space and evidence of osseous bridging. Saline-injected spaces exhibited no decrease in intervertebral spacing as compared to distal sites. Histologic analysis revealed neutrophilic infiltrates, destruction of the annulus fibrosus and nucleus pulposus, destruction of vertebral endplates, and osseous bridging. Saline-injected discs exhibited preserved annulus fibrosus and nucleus pulposus on histology. This study demonstrates that injection of bioluminescent S. aureus into the intervertebral disc of a rat tail is a viable animal model for spondylodiscitis research. This model allows for real-time, in vivo quantification of infection intensity, which may decrease the number of animals required for infection studies of the intervertebral disc. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2075-2081, 2017. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  20. [Histological study of a model of keratoepithelioplasty in the rat].

    Science.gov (United States)

    Amano, S; Sawa, M; Ishii, Y

    1992-11-01

    A model for keratoepithelioplasty (KEP) was developed using the Lewis rat, and histological studies were performed using the model. The entire corneal epithelium was removed using a spatula and a 1.5-mm-width of the conjunctiva including the limbus was excised. An oval corneal lamellar graft (3 x 1.5 mm) with an intact epithelium taken from another Lewis rat was transplanted on the denuded limbus. Biomicroscopic observation showed significantly less vascular invasion in the part of the cornea adjacent to the lenticule than in other part of cornea, and clear cornea was maintained in the cornea adjacent to the lenticule. Histologically only few vessels were recognized in the lenticule, and the epithelial cells on the lenticule showed histological characteristics of corneal epithelium. These results indicate that surgical function of KEP can be obtained because the lenticules keep distance between corneal epithelium and conjunctival vessels. And it is also confirmed that this model is useful in research on the pathophysiological mechanism of KEP.

  1. Keratoepithelioplasty in rat: development of a model and histological study.

    Science.gov (United States)

    Amano, S; Sawa, M; Ishii, Y

    1992-01-01

    A model for keratoepithelioplasty (KEP) was developed using the Lewis rat, and histological studies were performed using this model. The entire corneal epithelium was removed mechanically and a 1.5-mm width of the conjunctiva including the limbus was excised. An oval corneal lamellar graft (3 x 1.5 mm) with an intact epithelium taken from another Lewis rat was transplanted on the denuded limbus. Biomicroscopic observations showed much less vascular invasion in the part of the cornea adjacent to the lenticule than in other parts of the cornea, and the cornea remained clear adjacent to the lenticule. Histologically, a few vessels were observed in the corneal stroma under the lenticule. Epithelial cells on the lenticule specimens showed histological characteristics of the corneal epithelium. These findings indicate that one of the functions of KEP is to block neovascularization in the newly developing corneal epithelium by transplanting the lenticule between the corneal epithelium and conjunctival vessels. The present study also confirmed that this model is useful in the research of the pathophysiological mechanism of KEP.

  2. The Dimethylnitrosamine Induced Liver Fibrosis Model in the Rat.

    Science.gov (United States)

    Chooi, Kum Fai; Kuppan Rajendran, Dinesh Babu; Phang, Siew Siang Gary; Toh, Han Hui Alden

    2016-06-17

    Four to six week old, male Wistar rats were used to produce animal models of liver fibrosis. The process requires four weeks of administration of 10 mg/kg dimethylnitrosamine (DMN), given intraperitoneally for three consecutive days per week. Intraperitoneal injections were performed in the fume hood as DMN is a known hepatoxin and carcinogen. The model has several advantages. Firstly, liver changes can be studied sequentially or at particular stages of interest. Secondly, the stage of liver disease can be monitored by measurement of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes. Thirdly, the severity of liver damage at different stages can be confirmed by sacrifice of animals at designated time points, followed by histological examination of Masson's Trichome stained liver tissues. After four weeks of DMN dosing, the typical fibrosis score is 5 to 6 on the Ishak scale. The model can be reproduced consistently and has been widely used to assess the efficacy of potential anti-fibrotic agents.

  3. In vivo bioluminescence imaging of neurogenesis - the role of the blood brain barrier in an experimental model of Parkinson's disease.

    Science.gov (United States)

    Fricke, Inga B; Schelhaas, Sonja; Zinnhardt, Bastian; Viel, Thomas; Hermann, Sven; Couillard-Després, Sébastien; Jacobs, Andreas H

    2017-02-13

    Bioluminescence imaging in transgenic mice expressing firefly luciferase in Doublecortin(+) (Dcx) neuroblasts might serve as a powerful tool to study the role of neurogenesis in models of brain injury and neurodegeneration using non-invasive, longitudinal in vivo imaging. Therefore, we aimed to use BLI in B6(Cg)-Tyrc-2J/J Dcx-Luc (Doublecortin-Luciferase, Dcx-Luc) mice to investigate its suitability to assess neurogenesis in a unilateral injection model of Parkinson's disease. We further aimed to assess the blood brain barrier leakage associated with the intranigral 6-OHDA injection to evaluate its impact on substrate delivery and bioluminescence signal intensity. Two weeks after lesion, we observed an increase in bioluminescence signal in the ipsilateral hippocampal region in both, 6-OHDA and vehicle injected Dcx-Luc mice. At the same time, no corresponding increase in Dcx(+) neuroblast numbers could be observed in the dentate gyrus of C57Bl6 mice. Blood brain barrier leakage was observed in the hippocampal region and in the degenerating substantia nigra of C57Bl6 mice in vivo using T1 weighted Magnetic Resonance Imaging with Gadovist(®) and ex vivo using Evans Blue Fluorescence Reflectance Imaging and mouse Immunoglobulin G staining. Our data suggests a BLI signal dependency on blood brain barrier permeability, underlining a major pitfall of substrate/tracer dependent imaging in invasive disease models.

  4. Specificity of Metabolic Syndrome Model Reproduction at Pubertal and Adult Male Rats

    Directory of Open Access Journals (Sweden)

    Bondarenko Larysa Borysivna

    2015-09-01

    Full Text Available Background and Aims: Comparative estimation of metabolic syndrome (MS mediated changes of blood, cardio-vascular system, liver, pancreas and kidneys morphologic structure in adult and pubertal rats. Materials and Methods: Wistar albino male rats of two age categories (young animals of 21 days age (50-70g and adults (160-180g were divided into 4 groups (8 animals in each: 1 - Control 1 (intact young rats; 2 - Control 2 (intact adult rats; 3 - MS3 (young rats with MS and 4 - MS4 (adult rats with MS. The metabolic syndrome model was induced by full replacement of drinking water with 20% fructose solution (200g/l. After 60 days of MS modeling, determination of rat hematological and serum biochemical parameters, glucose tolerance, blood pressure, liver rates of lipid peroxydation and chromatin DNA fragmentation, as well as morphological macroscopic and microscopic studies were carried out. Results: In pubertal rats, glucose tolerance, hypertension, blood clotting disturbances, DNAfragmentation and lipid peroxydation rates were affected more profoundly, while mature rats showed greater Pseudo Pelger-Huet anomaly development, serum cholesterol and lipoproteins increases, liver and kidney morphology changes. Conclusions: Our current data combined with previous results of other authors allow us to conclude that an animal model (Wistar rats of MS is quite easily obtained in a full age range, from juvenile to mature rats.

  5. The MAM-E17 schizophrenia rat model: Comprehensive behavioral analysis of pre-pubertal, pubertal and adult rats.

    Science.gov (United States)

    Kállai, Veronika; Tóth, Attila; Gálosi, Rita; Péczely, László; Ollmann, Tamás; Petykó, Zoltán; László, Kristóf; Kállai, János; Szabó, Imre; Karádi, Zoltán; Lénárd, László

    2017-08-14

    The MAM-E17 model is one of the most accepted schizophrenia rat models, which follows the neurodevelopmental theory of the disease. While symptoms of MAM-E17 rats were studied extensively, their examinations were usually restricted to adulthood and in a few cases to prepuberty. It is well known, however, that schizophrenia symptoms often start at puberty or early adulthood. Therefore the purpose of this study was to investigate the behavioral characteristics of MAM-E17 rats in various tests throughout three different age-periods, namely in prepuberty, late puberty and adulthood. In open field test, MAM-E17 rats displayed increased locomotor activity, elevated sniffing frequency and, as tendency, enhanced rearing activity. The elevated activity turned up in late puberty and remained there in adulthood, too. There was also a deficient prepulse inhibition (PPI) of startle response in late puberty and adulthood, but not before puberty. In rotarod task, MAM-treated rats performed better than control rats. The enhanced performance on rotarod was only present in late puberty and adulthood. In elevated plus maze test MAM-treated rats displayed diminished anxiety mostly in prepuberty. Histological analysis revealed reduced volume and cell disarray in the dorsal hippocampus. This is the first comprehensive study about symptoms of MAM-E17 rats manifested in behavioral tests carried out in prepuberty, late puberty and adulthood. Results display the age-dependent appearance of schizophrenia symptoms in the same rats. The present findings provide basic information to accomplish the schizophrenia related animal research, as well as can also confer further data to develop preventive treatment for human patients. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. A SIMPLE EXPERIMENTAL MODEL OF HEAT SHOCK RESPONSE IN RATS

    Directory of Open Access Journals (Sweden)

    Tufi Neder Meyer

    1998-10-01

    Full Text Available Objective: To obtain a simple model for the elicitation of the heat shock response in rats. Design: Laboratory study. Setting: University research laboratories. Sample: Seventy-nine adult male albino rats (weight range 200 g to 570 g. Procedures: Exposure to heat stress by heating animals in a warm bath for 5 min after their rectal temperatures reached 107.60 F (420 C. Liver and lung samples were collected for heat-shock protein 70 (HSP70 detection (Western analysis. Results: Western analysis was positive for HSP70 in the liver and in the lungs of heated animals. There was a temporal correlation between heating and HSP70 detection: it was strongest 1 day after heating and reduced afterwards. No heated animals died. Conclusion: These data show that heating rats in a warm (45o C bath, according to parameters set in this model, elicits efficiently the heat shock response.OBJETIVO: Obter um modelo simples para tentar esclarecer a resposta ao choque térmico em ratos. LOCAL: Laboratório de pesquisa da Universidade. MÉTODO: Amostra: 79 ratos albinos, adultos, entre 200g a 570g. Procedimentos: Exposição ao calor, em banho quente, por 5 minutos, após a temperatura retal chegar a 42 graus centigrados. Biópsias de fígado e pulmão foram obtidas para detectar a proteina 70 (HSP 70, pelo "Western blot". RESULTADOS: As análises foram positivas nos animais aquecidos, com uma correlação entre aquecimento e constatação da HSP 70. Foi mais elevada no primeiro dia e não houve óbitos nos animais aquecidos. CONCLUSÃO: Os ratos aquecidos a 45 graus centígrados respondem eficientemente ao choque térmico.

  7. Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

    OpenAIRE

    Zhang, Jing; Li, Pei; Guo, Hai-fang; Liu, Li; Liu, Xiao-dong

    2012-01-01

    Aim: To characterize pharmacokinetic-pharmacodynamic modeling of diclofenac in Freund's complete adjuvant (FCA)-induced arthritic rats using prostaglandin E2 (PGE2) as a biomarker. Methods: The pharmacokinetics of diclofenac was investigated using 20-day-old arthritic rats. PGE2 level in the rats was measured using an enzyme immunoassay. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to illustrate the relationship between the plasma concentration of diclofenac and the inhibitio...

  8. Neurophysiological modeling of bladder afferent activity in the rat overactive bladder model

    NARCIS (Netherlands)

    Choudhary, M. (Mahipal); E. van Asselt (Els); R. van Mastrigt (Ron); F. Clavica (Francesco)

    2015-01-01

    textabstractThe overactive bladder (OAB) is a syndrome-based urinary dysfunction characterized by “urgency, with or without urge incontinence, usually with frequency and nocturia”. Earlier we developed a mathematical model of bladder nerve activity during voiding in anesthetized rats and found that

  9. Relationship between Immunological Abnormalities in Rat Models of Diabetes Mellitus and the Amplification Circuits for Diabetes

    Science.gov (United States)

    Shimomura, Tomoko; Asao, Hironobu; Wakabayashi, Ichiro

    2017-01-01

    A better understanding of pathogenic mechanisms is required in order to treat diseases. However, the mechanisms of diabetes mellitus and diabetic complications are extremely complex. Immune reactions are involved in the pathogenesis of diabetes and its complications, while diabetes influences immune reactions. Furthermore, both diabetes and immune reactions are influenced by genetic and environmental factors. To address these issues, animal models are useful tools. So far, various animal models of diabetes have been developed in rats, which have advantages over mice models in terms of the larger volume of tissue samples and the variety of type 2 diabetes models. In this review, we introduce rat models of diabetes and summarize the immune reactions in diabetic rat models. Finally, we speculate on the relationship between immune reactions and diabetic episodes. For example, diabetes-prone Biobreeding rats, type 1 diabetes model rats, exhibit increased autoreactive cellular and inflammatory immune reactions, while Goto-Kakizaki rats, type 2 diabetes model rats, exhibit increased Th2 reactions and attenuation of phagocytic activity. Investigation of immunological abnormalities in various diabetic rat models is useful for elucidating complicated mechanisms in the pathophysiology of diabetes. Studying immunological alterations, such as predominance of Th1/17 or Th2 cells, humoral immunity, and innate immune reactions, may improve understanding the structure of amplification circuits for diabetes in future studies.

  10. The Effect of Opsteoporotic Model Rats Induced by Retinoic Acid

    Institute of Scientific and Technical Information of China (English)

    Xu Peng; Yao Jianfeng; Jin Weizhang; Cai Qiankun; Guo Xiong

    2005-01-01

    Objective: To study the effect of retinoic acid on inducing osteoporosis in female rat. Methods: 48SD female rats were divided randomly into experiment group and control group. Retinoic acid was administered orally to experiment group with 80mg.kg-1d-1 for 15 days. Then the rats were sacrificed on the 0th, 30th, 60th days after last administration. The serum concentration of Ca, P, BGP, E2, AKP and TRAP were detected. Components of collagen and proteoglycan in the bones and BMD were also assayed .The femoral morphometric change and epiphyseal plate cartilage histological changes were observed. Results: After a 15-day period treatment with retinoic acid, charateristics of experiment group were compared with control, it is shown that the concentration of serum E2 and BGP declined, the activity of AKP and TRAP increased while BMP decreased, the bone mass of both spongy bone and cortical bone reduced, the number of spongy bone osteoclasts and their activity increased, number of epiphyseal plate chondrocyte reduced, cartilage hypertrophic zone displayed dyscalcification, and no difference of other markers was found in the two groups. On the 30th day after the last administration, the experiment group appeared a declined number of cancellous bone osteoclast and level of serum AKP yet they were still higher than control. Number of epiphyseal chondrocyte, serum BGP and tibial BMD, though higher than before, were still lower than control. Other markers were no difference. On the 60th day after treatment, although the femoral cancellous bone mass was still less and cancellous osteoblast was more than control, the cortical bone mass, cancellous osteoclast number and level of serum Ca and P were all remained no different between two groups.Conclusion: Retinoic acid possessed a better short-term effect than long-term effect. Cancellous bone loss lasted much longer than cortical bone and more obviously; the bone matrix in this osteoporosis model was able to repair itself

  11. The isolated perfused rat liver : standardization of a time-honoured model

    NARCIS (Netherlands)

    Bessems, M.; t'Hart, N. A.; Tolba, R.; Doorschodt, B. M.; D Leuvenink, H. G.; Ploeg, R. J.; Minor, T.; van Gulik, T. M.

    For many years, the isolated perfused rat liver (IPRL) model has been used to investigate the physiology and pathophysiology of the rat liver. This in vitro model provides the opportunity to assess cellular injury and liver function in an isolated setting. This review offers an update of recent

  12. Validation of infrared thermography in serotonin-induced itch model in rats

    DEFF Research Database (Denmark)

    Dagnæs-Hansen, Frederik; Jasemian, Yousef; Gazerani, Parisa

    The number of scratching bouts is generally used as a standard method in animal models of itch. The aim of the present study was to validate the application of infrared thermography (IR-Th) in a serotonin-induced itch model in rats. Adult Sprague-Dawley male rats (n = 24) were used in 3 consecutive...

  13. Effects of Ginkgo biloba leaf extract on Alzheimer' s Disease Model of Rats

    Institute of Scientific and Technical Information of China (English)

    GONGQi-Hai; WUQin; HUANGXie-Nan; SUNAn-Sheng; SHIJing-Shan

    2004-01-01

    AIM: To examine the protective effects of Ginkgo biloba extract (GbE) on the learning and memory in the Alzheimer disease (AD) model induced by aluminum salt in rats, and to examine the potential mechanisms. METHODS. The AD model of rats was induced by administration and drinking of aluminum chloride solution. The abilities of spatial leafing and

  14. Metformin and atorvastatin reduce adhesion formation in a rat uterine horn model.

    Science.gov (United States)

    Yilmaz, Bulent; Aksakal, Orhan; Gungor, Tayfun; Sirvan, Levent; Sut, Necdet; Kelekci, Sefa; Soysal, Sunullah; Mollamahmutoglu, Leyla

    2009-03-01

    The aim of the present study was to determine whether atorvastatin and metformin are effective in preventing adhesions in a rat uterine horn model. A total of 40 non-pregnant, female Wistar albino rats, weighing 180-210 g, were used as a model for post-operative adhesion formation. The rats were randomized into four groups after seven standard lesions were inflicted in each uterine horn and lower abdominal sidewall using bipolar cauterization. The rats were given atorvastatin 2.5 mg/kg/day, p.o. (10 rats), atorvastatin 30 mg/kg/day, p.o. (10 rats), metformin 50 mg/kg/day, p.o. (10 rats) and no treatment was applied in the control group (10 rats). The animals were killed 2 weeks later and adhesions were scored both clinically and pathologically by authors blinded to groups. One rat in the control group died before the end of the 2 week period. Total clinical adhesion scores regarding extent, severity and degree of adhesions and histopathological findings including inflammation and fibrosis were significantly lower in the metformin (P Metformin and atorvastatin are both effective for prevention of adhesion formation in a rat uterine horn model.

  15. Respiratory Tract Lung Geometry and Dosimetry Model for Male Sprague-Dawley Rats

    Energy Technology Data Exchange (ETDEWEB)

    Miller, Frederick J.; Asgharian, Bahman; Schroeter, Jeffry D.; Price, Owen; Corley, Richard A.; Einstein, Daniel R.; Jacob, Rick E.; Cox, Timothy C.; Kabilan, Senthil; Bentley, Timothy

    2015-07-24

    While inhalation toxicological studies of various compounds have been conducted using a number of different strains of rats, mechanistic dosimetry models have only had tracheobronchial (TB) structural data for Long-Evans rats, detailed morphometric data on the alveolar region of Sprague-Dawley rats and limited alveolar data on other strains. Based upon CT imaging data for two male Sprague-Dawley rats, a 15-generation, symmetric typical path model was developed for the TB region. Literature data for the alveolar region of Sprague-Dawley rats were analyzed to develop an eight-generation model, and the two regions were joined to provide a complete lower respiratory tract model for Sprague-Dawley rats. The resulting lung model was used to examine particle deposition in Sprague-Dawley rats and to compare these results with predicted deposition in Long-Evans rats. Relationships of various physiologic variables and lung volumes were either developed in this study or extracted from the literature to provide the necessary input data for examining particle deposition. While the lengths, diameters and branching angles of the TB airways differed between the two Sprague-Dawley rats, the predicted deposition patterns in the three major respiratory tract regions were very similar. Between Sprague-Dawley and Long-Evans rats, significant differences in TB and alveolar predicted deposition fractions were observed over a wide range of particle sizes, with TB deposition fractions being up to 3- to 4-fold greater in Sprague-Dawley rats and alveolar deposition being significantly greater in Long-Evans rats. Thus, strain-specific lung geometry models should be used for particle deposition calculations and interspecies dose comparisons.

  16. Description of “Tail Suspension” as a Model of ‹mmobilization in Rats

    Directory of Open Access Journals (Sweden)

    Ayçe Atalay

    2002-09-01

    Full Text Available Since human beings have included outer space to their living places, effects of gravity on bone has been extensively studied. Authors claim that basic biologic mechanisms are similar in rats and human so rats should serve as a useful model for studying osteoporosis. Models for simulating microgravity conditions can be grouped into two as local and systemic models. We aimed to summarize models for immobilization as well as detailed description of tail suspension model.

  17. Modeling the Nonlinear Motion of the Rat Central Airways.

    Science.gov (United States)

    Ibrahim, G; Rona, A; Hainsworth, S V

    2016-01-01

    Advances in volumetric medical imaging techniques all