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Sample records for asphyxia induced brain

  1. Fatal mechanical asphyxia induces changes in energy utilization in the rat brain: An (18)F-FDG-PET study.

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    Ma, Suhua; You, Shengzhong; Hao, Li; Zhang, Dongchuan; Quan, Li

    2015-07-01

    This study was designed to evaluate changes in brain glucose metabolism in rats following ligature strangulation. Thirteen male Wistar rats were used in the present study, divided into control (n=7) and asphyxia groups (n=6, ligature strangulation). Positron emission tomography (PET) with 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) was used to evaluate brain glucose metabolism. Rats were scanned for PET-CT, and image data co-registered with a T2WI MRI template using SPM8 software. Image J was employed to draw regions of interest (ROIs) from the MRI template and acquire ROI activity information from the PET images. In the asphyxia group vs. controls, (18)F-FDG uptake (FU) was decreased in the substantia nigra (25.26%, pglucose metabolism distribution map in the asphyxiated rat brains were substantially changed versus controls. PET with (18)F-FDG can demonstrate excitement and inhibition of different brain areas even in cases of ligature strangulation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. Phospholipid alterations in the brain and heart in a rat model of asphyxia-induced cardiac arrest and cardiopulmonary bypass resuscitation.

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    Kim, Junhwan; Lampe, Joshua W; Yin, Tai; Shinozaki, Koichiro; Becker, Lance B

    2015-10-01

    Cardiac arrest (CA) induces whole-body ischemia, causing damage to multiple organs. Ischemic damage to the brain is mainly responsible for patient mortality. However, the molecular mechanism responsible for brain damage is not understood. Prior studies have provided evidence that degradation of membrane phospholipids plays key roles in ischemia/reperfusion injury. The aim of this study is to correlate organ damage to phospholipid alterations following 30 min asphyxia-induced CA or CA followed by cardiopulmonary bypass (CPB) resuscitation using a rat model. Following 30 min CA and CPB resuscitation, rats showed no brain function, moderately compromised heart function, and died within a few hours; typical outcomes of severe CA. However, we did not find any significant change in the content or composition of phospholipids in either tissue following 30 min CA or CA followed by CPB resuscitation. We found a substantial increase in lysophosphatidylinositol in both tissues, and a small increase in lysophosphatidylethanolamine and lysophosphatidylcholine only in brain tissue following CA. CPB resuscitation significantly decreased lysophosphatidylinositol but did not alter the other lyso species. These results indicate that a decrease in phospholipids is not a cause of brain damage in CA or a characteristic of brain ischemia. However, a significant increase in lysophosphatidylcholine and lysophosphatidylethanolamine found only in the brain with more damage suggests that impaired phospholipid metabolism may be correlated with the severity of ischemia in CA. In addition, the unique response of lysophosphatidylinositol suggests that phosphatidylinositol metabolism is highly sensitive to cellular conditions altered by ischemia and resuscitation.

  3. Neuropathology and brain weight in traumatic-crush asphyxia.

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    Al-Sarraj, Safa; Laxton, Ross; Swift, Ben; Kolar, Alexander J; Chapman, Rob C; Fegan-Earl, Ashley W; Cary, Nat R B

    2017-11-01

    Traumatic (crush) asphyxia is a rare condition caused by severe compression of the chest and trunk leading to often extreme so-called asphyxial signs, including cyanosis in head and neck regions, multiple petechiae, and subconjunctival haemorrhage as well as neurological manifestations. To investigate the neuropathology and brain weight in traumatic asphyxia caused by different accidents such as industrial accidents and road traffic collision. Post mortem records of 20 cases of traumatic asphyxia (TA) resulting from different causes of which four brains are available for comprehensive neuropathological examination. The expected brain weights for given body height and associated 95% confidence range were calculated according to the following formula: baseline brain weight (BBW) + body height x rate (g/cm). The 95% confidence range was calculated by adding and subtracting the standard error (SE) x 1.96 (7-8). There was a trend for higher brain weight in the TA cohort but it was not significant (1494 g vs 1404 g, p = 0.1). The upper limits of the brain weight of 95% confidence was 1680 g vs 1660 g, p = 0.9. The neuropathological examination of four available brains from the TA cohort showed severe congestion of blood vessels, perivascular haemorrhages and occasional βAPP deposits consistent with early axonal disruption. Brain examination is informative as part of investigation of TA. Developing ischaemic changes and an increase in brain weight are the most likely indicators of a prolonged period of patient's survival. Copyright © 2017 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

  4. Differential involvement of the brain in neonatal asphyxia: a pathogenic explanation.

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    Sheth, R D; Bodensteiner, J B; Riggs, J E; Schochet, S S

    1995-11-01

    Multiple cystic lesions in brain parenchyma supplied by the anterior cerebral circulation is a recognized pattern of cerebral injury associated with hypoxic-ischemic encephalopathy in the term infant. This report presents a series of seven infants (gestational age, 39.3 +/- 2.8 weeks; range, 36 to 44 weeks) who developed multicystic encephalomalacia in the distribution of the anterior cerebral circulation after severe neonatal asphyxia. Cerebral imaging and pathologic studies demonstrate relative preservation of the cerebellum, brain stem, and cerebral structures supplied by the vertebrobasilar circulation. Compared to the vertebrobasilar vasculature, the anterior cerebral vessels in the term infant have dense sympathetic innervation. Asphyxia, a potent sympathetic stimulator, may induce vasoconstriction in the anterior circulation and differentially accentuate the effects of hypoxia/ischemia on cerebral tissue.

  5. Imaging patterns of brain injury in term-birth asphyxia

    NARCIS (Netherlands)

    Swarte, Renate; Lequin, Maarten; Cherian, Perumpillichira; Zecic, Alexandra; van Goudoever, Johannes; Govaert, Paul

    2009-01-01

    To develop an extended asphyxia-score based on cerebral ultrasound (US) and MRI in order to gain further insight into the pathophysiology of asphyxia. First week cerebral US and MRI of 80 asphyxiated term infants were scored according to a new scoring system based on separate grading of injury to

  6. Experimental modelling of the consequences of brief late gestation asphyxia on newborn lamb behaviour and brain structure.

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    Margie Castillo-Melendez

    Full Text Available Brief but severe asphyxia in late gestation or at the time of birth may lead to neonatal hypoxic ischemic encephalopathy and is associated with long-term neurodevelopmental impairment. We undertook this study to examine the consequences of transient in utero asphyxia in late gestation fetal sheep, on the newborn lamb after birth. Surgery was undertaken at 125 days gestation for implantation of fetal catheters and placement of a silastic cuff around the umbilical cord. At 132 days gestation (0.89 term, the cuff was inflated to induce umbilical cord occlusion (UCO, or sham (control. Fetal arterial blood samples were collected for assessment of fetal wellbeing and the pregnancy continued until birth. At birth, behavioral milestones for newborn lambs were recorded over 24 h, after which the lambs were euthanased for brain collection and histopathology assessments. After birth, UCO lambs displayed significant latencies to (i use all four legs, (ii attain a standing position, (iii find the udder, and (iv successfully suckle--compared to control lambs. Brains of UCO lambs showed widespread pathologies including cell death, white matter disruption, intra-parenchymal hemorrhage and inflammation, which were not observed in full term control brains. UCO resulted in some preterm births, but comparison with age-matched preterm non-UCO control lambs showed that prematurity per se was not responsible for the behavioral delays and brain structural abnormalities resulting from the in utero asphyxia. These results demonstrate that a single, brief fetal asphyxic episode in late gestation results in significant grey and white matter disruption in the developing brain, and causes significant behavioral delay in newborn lambs. These data are consistent with clinical observations that antenatal asphyxia is causal in the development of neonatal encephalopathy and provide an experimental model to advance our understanding of neuroprotective therapies.

  7. TIME COURSE MODIFICATIONS INDUCED BY PERINATAL ASPHYXIA IN RAT CNS

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    Francisco Capani

    2015-04-01

    Full Text Available Perinatal asphyxia (PA induced short and long term biochemical, synaptic, cytoskeletal and astrocytes alterations that has been associated with neuronal cell death following hypoxia . The lack of knowledge about the mechanisms underlying this dysfunction prompted us to investigate the changes in the synapse and neuronal cytoskeleton and related structures. For this study we used a well established murine model of PA. Full-term pregnant rats were rapidly decapitated and the uterus horns were placed in a water bath at 37 °C for different time of asphyxia. When their physiological conditions improved, they were given to surrogate mothers. One month, four month, 6 month and 18 month after PA rats were included in this study. Modifications were analyzed using photooxidation with phalloidin-eosin, conventional electron microscopy (EM, inmunocytochemistry and ethanolic phosphotungstic acid (E-PTA staining combining with electron tomography and 3-D reconstruction techniques and molecular biology studies. After one month of the PA insult, an increase in the F-actin staining in neostriatum and hippocampus synapses was observed using correlative fluorescent electron microscopy for phalloidin-eosin. Mushroom-shaped spines showed the most consistent staining. Strong alterations in the dendrite and astroglial cytoskeleton were found at four months of PA (1. After six months of PA, postsynaptic densities (PSDs of the rat neostriatum are highly modified . We observed an increment of PSDs thickness related with the duration and severity of the hypoxic insult. In addition, PSDs showed and increase in the ubiquitination level. Using 3-d reconstruction and electron tomography we observed showed clear signs of damage in the asphyctic PSDs. These changes are correlated with intense staining for ubiquitin (2. Finally, in 18 months old rat was observed a reduction in the number of synapses in the PA animals related with a decrease in BDNF staining.(3 Using protocols

  8. Environmental Enrichment Decreases Asphyxia-Induced Neurobehavioral Developmental Delay in Neonatal Rats

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    Peter Kiss

    2013-11-01

    Full Text Available Perinatal asphyxia during delivery produces long-term disability and represents a major problem in neonatal and pediatric care. Numerous neuroprotective approaches have been described to decrease the effects of perinatal asphyxia. Enriched environment is a popular strategy to counteract nervous system injuries. The aim of the present study was to investigate whether enriched environment is able to decrease the asphyxia-induced neurobehavioral developmental delay in neonatal rats. Asphyxia was induced in ready-to-deliver mothers by removing the pups by caesarian section after 15 min of asphyxia. Somatic and neurobehavioral development was tested daily and motor coordination weekly. Our results show that rats undergoing perinatal asphyxia had a marked developmental delay and worse performance in motor coordination tests. However, pups kept in enriched environment showed a decrease in the developmental delay observed in control asphyctic pups. Rats growing up in enriched environment did not show decrease in weight gain after the first week and the delay in reflex appearance was not as marked as in control rats. In addition, the development of motor coordination was not as strikingly delayed as in the control group. Short-term neurofunctional outcome are known to correlate with long-term deficits. Our results thus show that enriched environment could be a powerful strategy to decrease the deleterious developmental effects of perinatal asphyxia.

  9. Hippocampal Dendritic Spines Modifications Induced by Perinatal Asphyxia

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    G. E. Saraceno

    2012-01-01

    Full Text Available Perinatal asphyxia (PA affects the synaptic function and morphological organization. In previous works, we have shown neuronal and synaptic changes in rat neostriatum subjected to hypoxia leading to long-term ubi-protein accumulation. Since F-actin is highly concentrated in dendritic spines, modifications in its organization could be related with alterations induced by hypoxia in the central nervous system (CNS. In the present study, we investigate the effects of PA on the actin cytoskeleton of hippocampal postsynaptic densities (PSD in 4-month-old rats. PSD showed an increment in their thickness and in the level of ubiquitination. Correlative fluorescence-electron microscopy photooxidation showed a decrease in the number of F-actin-stained spines in hippocampal excitatory synapses subjected to PA. Although Western Blot analysis also showed a slight decrease in β-actin in PSD in PA animals, the difference was not significant. Taken together, this data suggests that long-term actin cytoskeleton might have role in PSD alterations which would be a spread phenomenon induced by PA.

  10. Asphyxia screening kit.

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    Zabidi, A; Khuan, L Y; Mansor, W

    2012-01-01

    Infant asphyxia is a condition due to insufficient oxygen intake suffered by newborn babies. A 4 to 9 million occurrences of infant asphyxia are reported each year by WHO. Early diagnosis of asphyxia is important to avoid complications such as damage to the brain, organ and tissue that could lead to fatality. This is possible with the automation of screening of infant asphyxia. Here, a non-invasive Asphyxia Screening Kit is developed. It is a Graphical User Interface that automatically detects asphyxia in infants from early birth to 6 months from their cries and displays the outcome of analysis. It is built with Matlab GUI underlied with signal processing algorithms, capable of achieving a classification accuracy of 96.03%. Successful implementation of ASK will assist to screen infant asphyxia for reference to clinicians for early diagnosis. In addition, ASK also provides an interface to enter patient information and images to be integrated with existing Hospital Information Management System.

  11. Cerebellar cytokine expression in a rat model for fetal asphyctic preconditioning and perinatal asphyxia

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    Vlassaks, Evi; Brudek, Tomasz; Pakkenberg, Bente

    2014-01-01

    Asphyctic brain injury is a major cause of neuronal inflammation in the perinatal period. Fetal asphyctic preconditioning has been shown to modulate the cerebral inflammatory cytokine response, hereby protecting the brain against asphyctic injury at birth. This study was designated to examine...... the effects of perinatal asphyxia and fetal asphyctic preconditioning on the inflammatory cytokine response in the cerebellum. Fetal asphyxia was induced at embryonic day 17 by clamping the uterine vasculature for 30 min. At term birth, global perinatal asphyxia was induced by placing the uterine horns...... was decreased 96 h postfetal asphyxia. When applied as preconditioning stimulus, fetal asphyxia attenuates the cerebellar cytokine response. These results indicate that sublethal fetal asphyxia may protect the cerebellum from perinatal asphyxia-induced damage via inhibition of inflammation....

  12. Brain caspase-3 and intestinal FABP responses in preterm and term rats submitted to birth asphyxia

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    R.L. Figueira

    2016-01-01

    Full Text Available Neonatal asphyxia can cause irreversible injury of multiple organs resulting in hypoxic-ischemic encephalopathy and necrotizing enterocolitis (NEC. This injury is dependent on time, severity, and gestational age, once the preterm babies need ventilator support. Our aim was to assess the different brain and intestinal effects of ischemia and reperfusion in neonate rats after birth anoxia and mechanical ventilation. Preterm and term neonates were divided into 8 subgroups (n=12/group: 1 preterm control (PTC, 2 preterm ventilated (PTV, 3 preterm asphyxiated (PTA, 4 preterm asphyxiated and ventilated (PTAV, 5 term control (TC, 6 term ventilated (TV, 7 term asphyxiated (TA, and 8 term asphyxiated and ventilated (TAV. We measured body, brain, and intestine weights and respective ratios [(BW, (BrW, (IW, (BrW/BW and (IW/BW]. Histology analysis and damage grading were performed in the brain (cortex/hippocampus and intestine (jejunum/ileum tissues, as well as immunohistochemistry analysis for caspase-3 and intestinal fatty acid-binding protein (I-FABP. IW was lower in the TA than in the other terms (P<0.05, and the IW/BW ratio was lower in the TA than in the TAV (P<0.005. PTA, PTAV and TA presented high levels of brain damage. In histological intestinal analysis, PTAV and TAV had higher scores than the other groups. Caspase-3 was higher in PTAV (cortex and TA (cortex/hippocampus (P<0.005. I-FABP was higher in PTAV (P<0.005 and TA (ileum (P<0.05. I-FABP expression was increased in PTAV subgroup (P<0.0001. Brain and intestinal responses in neonatal rats caused by neonatal asphyxia, with or without mechanical ventilation, varied with gestational age, with increased expression of caspase-3 and I-FABP biomarkers.

  13. ASPHYXIA, INTRACRANIAL HEMORRHAGES AND BRAIN EDEMA OF RISK CHILDREN IN THE ADVISORY INSTITUTE IN BITOLA FROM 1989-1994

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    M. ILIEVSKA,

    1997-09-01

    Full Text Available 3986 files have been examined in the Advisory Institute for a five year period in relation to the present risk factors in the pre, peri and postnatal period, the occurrence of asphyxia, I.H. (intracranial hemorrhages and brain edema and their outcome for the children. There were 958 or 32% risk children, out of them 206 or 22% were with asphyxia, 25 or 3% were with brain edema and 14 or 1,5% were with intracranial hemorrhages.The analysis for the risk factors shows that 119 of them were abortive , and from them 15% were born with asphyxia; 124 were SFD and 21% of them with asphyxia; 272 children weighed over 4500 gr., 7% of them with asphyxia and 0.4% with I.H., there were 68 twins, 12% of them with asphyxia. Out of the children with no risk registered, 6 were born with I.H., or 0,2%.Mothers under the age of 18 gave birth to 13% children with asphyxia; treated for sterility and anemia during pregnancy 15%; with increased blood pressure 14%; and 5% with maintained pregnancy.The highest delivery risk is present with children born with vacuum extraction (30% or every third child is with asphyxia and 3% with I.H. and with children delivered by caesarean section (14% with asphyxia.As for the position of the fetus-Citus pedalicus gave 55% children with asphyxia, and Situs pelvicus 12%.The worst damage is suffered by infants with premature amnion disruption (62% are with asphyxia; with the umbilical cord round the neck-56% with asphyxia and 6% with I.H.; and with muddled amniotic fluid and placenta pelvia-50%.The order of risk factors related to asphyxia, I.H. and brain edema is as follows: the first is premature amnion disruption, then follows the umbilical cord round the neck, the muddled amniotic fluid, and placenta previa and Citus pedalicus-which are obstetric problems. The next are the vacuum extraction and S.C. As for the gestatory period the order is as follows: first the abortive, then the twins and hypertrofic infants. The outcome of the

  14. Pathophysiology of Birth Asphyxia.

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    Rainaldi, Matthew A; Perlman, Jeffrey M

    2016-09-01

    The pathophysiology of asphyxia generally results from interruption of placental blood flow with resultant fetal hypoxia, hypercarbia, and acidosis. Circulatory and noncirculatory adaptive mechanisms exist that allow the fetus to cope with asphyxia and preserve vital organ function. With severe and/or prolonged insults, these compensatory mechanisms fail, resulting in hypoxic ischemic injury, leading to cell death via necrosis and apoptosis. Permanent brain injury is the most severe long-term consequence of perinatal asphyxia. The severity and location of injury is influenced by the mechanisms of injury, including degree and duration, as well as the developmental maturity of the brain. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Connexin Hemichannel Blockade Is Neuroprotective after Asphyxia in Preterm Fetal Sheep

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    Davidson, Joanne O; Paul P Drury; Green, Colin R.; Nicholson, Louise F.; Laura Bennet; Alistair J. Gunn

    2014-01-01

    Asphyxia around the time of preterm birth is associated with neurodevelopmental disability. In this study, we tested the hypothesis that blockade of connexin hemichannels would improve recovery of brain activity and reduce cell loss after asphyxia in preterm fetal sheep. Asphyxia was induced by 25 min of complete umbilical cord occlusion in preterm fetal sheep (103-104 d gestational age). Connexin hemichannels were blocked by intracerebroventricular infusion of mimetic peptide starting 90 min...

  16. DHA-supplemented diet increases the survival of rats following asphyxia-induced cardiac arrest and cardiopulmonary bypass resuscitation.

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    Kim, Junhwan; Yin, Tai; Shinozaki, Koichiro; Lampe, Joshua W; Becker, Lance B

    2016-11-04

    Accumulating evidence illustrates the beneficial effects of dietary docosahexaenoic acid (DHA) on cardiovascular diseases. However, its effects on cardiac arrest (CA) remain controversial in epidemiological studies and have not been reported in controlled animal studies. Here, we examined whether dietary DHA can improve survival, the most important endpoint in CA. Male Sprague-Dawley rats were randomized into two groups and received either a control diet or a DHA-supplemented diet for 7-8 weeks. Rats were then subjected to 20 min asphyxia-induced cardiac arrest followed by 30 min cardiopulmonary bypass resuscitation. Rat survival was monitored for additional 3.5 h following resuscitation. In the control group, 1 of 9 rats survived for 4 h, whereas 6 of 9 rats survived in the DHA-treated group. Surviving rats in the DHA-treated group displayed moderately improved hemodynamics compared to rats in the control group 1 h after the start of resuscitation. Rats in the control group showed no sign of brain function whereas rats in the DHA-treated group had recurrent seizures and spontaneous respiration, suggesting dietary DHA also protects the brain. Overall, our study shows that dietary DHA significantly improves rat survival following 20 min of severe CA.

  17. Pressure passive cerebral blood flow and breakdown of the blood-brain barrier in experimental fetal asphyxia

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    Lou, H C; Lassen, N A; Tweed, W A

    1979-01-01

    reaching CBF values up to 6 times normal at normal MABP of about 60 to 70 mmHg, and severe ischemia reaching CBF values close to zero in large cortical areas at MABP of 30 mmHg. CVP remained essentially unchanged at 10--15 mmHg. The severe and prolonged asphyxia rendered the blood-brain barrier leaky...... to the albumin tracer Evans blue. In four other fetuses umbilical cord clamping was omitted. However, only in one of these cases was acidosis completely avoided, and CBF autoregulation maintained. The three other fetuses were acidotic at the end of the surgical procedure and had impaired autoregulation....

  18. Examination of physiological function and biochemical disorders in a rat model of prolonged asphyxia-induced cardiac arrest followed by cardio pulmonary bypass resuscitation.

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    Kim, Junhwan; Yin, Tai; Yin, Ming; Zhang, Wei; Shinozaki, Koichiro; Selak, Mary A; Pappan, Kirk L; Lampe, Joshua W; Becker, Lance B

    2014-01-01

    Cardiac arrest induces whole body ischemia, which causes damage to multiple organs particularly the heart and the brain. There is clinical and preclinical evidence that neurological injury is responsible for high mortality and morbidity of patients even after successful cardiopulmonary resuscitation. A better understanding of the metabolic alterations in the brain during ischemia will enable the development of better targeted resuscitation protocols that repair the ischemic damage and minimize the additional damage caused by reperfusion. A validated whole body model of rodent arrest followed by resuscitation was utilized; animals were randomized into three groups: control, 30 minute asphyxial arrest, or 30 minutes asphyxial arrest followed by 60 min cardiopulmonary bypass (CPB) resuscitation. Blood gases and hemodynamics were monitored during the procedures. An untargeted metabolic survey of heart and brain tissues following cardiac arrest and after CPB resuscitation was conducted to better define the alterations associated with each condition. After 30 min cardiac arrest and 60 min CPB, the rats exhibited no observable brain function and weakened heart function in a physiological assessment. Heart and brain tissues harvested following 30 min ischemia had significant changes in the concentration of metabolites in lipid and carbohydrate metabolism. In addition, the brain had increased lysophospholipid content. CPB resuscitation significantly normalized metabolite concentrations in the heart tissue, but not in the brain tissue. The observation that metabolic alterations are seen primarily during cardiac arrest suggests that the events of ischemia are the major cause of neurological damage in our rat model of asphyxia-CPB resuscitation. Impaired glycolysis and increased lysophospholipids observed only in the brain suggest that altered energy metabolism and phospholipid degradation may be a central mechanism in unresuscitatable brain damage.

  19. Perinatal asphyxia: CNS development and deficits with delayed onset

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    Mario eHerrera-Marschitz

    2014-03-01

    Full Text Available Perinatal asphyxia constitutes a prototype of obstetric complications occurring when pulmonary oxygenation is delayed or interrupted. The primary insult relates to the duration of the period lacking oxygenation, leading to death if not re-established. Re-oxygenation leads to a secondary insult, related to a cascade of biochemical events required for restoring proper function. Perinatal asphyxia interferes with neonatal development, resulting in long-term deficits associated to mental and neurological diseases with delayed clinical onset, by mechanisms not yet clarified.In the experimental scenario, the effects observed long after perinatal asphyxia have been explained by over expression of sentinel proteins, such as poly(ADP-ribose polymerase-1 (PARP-1, competing for NAD+ during re-oxygenation, leading to the idea that sentinel protein inhibition constitutes a suitable therapeutic strategy. Asphyxia induces transcriptional activation of pro-inflammatory factors, in tandem with PARP-1 overactivation, and pharmacologically induced PARP-1 inhibition also down-regulates the expression of proinflammatory cytokines. Nicotinamide has been proposed as a suitable PARP-1 inhibitor. Its effect has been studied in an experimental model of global hypoxia in rats. In that model, the insult is induced by immersing rat foetuses into a water bath for various periods of time. Following asphyxia, the pups are delivered, treated, and nursed by surrogate dams, pending further experiments. Nicotinamide rapidly distributes into the brain following systemic administration, reaching steady state concentrations sufficient to inhibit PARP-1 activity for several hours, preventing several of the long-term consequences of perinatal asphyxia, supporting the idea that it constitutes a lead for exploring compounds with similar or better pharmacological profiles.

  20. Perinatal asphyxia: CNS development and deficits with delayed onset.

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    Herrera-Marschitz, Mario; Neira-Pena, Tanya; Rojas-Mancilla, Edgardo; Espina-Marchant, Pablo; Esmar, Daniela; Perez, Ronald; Muñoz, Valentina; Gutierrez-Hernandez, Manuel; Rivera, Benjamin; Simola, Nicola; Bustamante, Diego; Morales, Paola; Gebicke-Haerter, Peter J

    2014-01-01

    Perinatal asphyxia constitutes a prototype of obstetric complications occurring when pulmonary oxygenation is delayed or interrupted. The primary insult relates to the duration of the period lacking oxygenation, leading to death if not re-established. Re-oxygenation leads to a secondary insult, related to a cascade of biochemical events required for restoring proper function. Perinatal asphyxia interferes with neonatal development, resulting in long-term deficits associated to mental and neurological diseases with delayed clinical onset, by mechanisms not yet clarified. In the experimental scenario, the effects observed long after perinatal asphyxia have been explained by overexpression of sentinel proteins, such as poly(ADP-ribose) polymerase-1 (PARP-1), competing for NAD(+) during re-oxygenation, leading to the idea that sentinel protein inhibition constitutes a suitable therapeutic strategy. Asphyxia induces transcriptional activation of pro-inflammatory factors, in tandem with PARP-1 overactivation, and pharmacologically induced PARP-1 inhibition also down-regulates the expression of proinflammatory cytokines. Nicotinamide has been proposed as a suitable PARP-1 inhibitor. Its effect has been studied in an experimental model of global hypoxia in rats. In that model, the insult is induced by immersing rat fetus into a water bath for various periods of time. Following asphyxia, the pups are delivered, treated, and nursed by surrogate dams, pending further experiments. Nicotinamide rapidly distributes into the brain following systemic administration, reaching steady state concentrations sufficient to inhibit PARP-1 activity for several hours, preventing several of the long-term consequences of perinatal asphyxia, supporting the idea that nicotinamide constitutes a lead for exploring compounds with similar or better pharmacological profiles.

  1. Atrial fibrillation in rats induced by rapid transesophageal atrial pacing during brief episodes of asphyxia: A new in vivo model

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    Haugan, K.; Lam, Henrik Rye; Knudsen, C. B.

    2004-01-01

    in anesthetized male Sprague-Dawley rats. AF was reproducibly induced in 81% of the rats. The presence of AF was associated with an increased heart rate, and a decreased blood pressure. Treatment with amiodarone, D,L-sotalol, flecainide, and propranolol all reduced duration of AF, whereas verapamil treatment...... of verapamil. Relative to existing models of AF in larger animals, this model offers rapid, predictive, and inexpensive testing of antiarrhythmic/profibrillatory effects of new drugs.......Non-pharmacological in vivo models of atrial fibrillation (AF) have been developed in large animals only. We aimed to develop and characterize a new small animal non-pharmacological in vivo model of AF. AF was induced by transesophageal atrial burst pacing during 35 seconds periods of asphyxia...

  2. The prognostic value of multivoxel magnetic resonance spectroscopy determined metabolite levels in white and grey matter brain tissue for adverse outcome in term newborns following perinatal asphyxia

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    Doormaal, Pieter Jan van [University Medical Center Groningen and University of Groningen, Department of Pediatrics, Division of Neonatology, Groningen (Netherlands); Meander Medical Center Amersfoort, Department of Radiology, PO Box 1502, Amersfoort (Netherlands); Meiners, Linda C.; Sijens, Paul E. [University Medical Center Groningen and University of Groningen, Department of Radiology, Groningen (Netherlands); Horst, Hendrik J. ter; Veere, Christa N. van der [University Medical Center Groningen and University of Groningen, Department of Pediatrics, Division of Neonatology, Groningen (Netherlands)

    2012-04-15

    Magnetic resonance spectroscopy can identify brain metabolic changes in perinatal asphyxia by providing ratios of metabolites, such as choline (Cho), creatine (Cr), N-acetyl aspartate (NAA) and lactate (Lact) [Cho/Cr, Lact/NAA, etc.]. The purpose of this study was to quantify the separate white and grey matter metabolites in a slab cranial to the ventricles and relate these to the outcome. A standard 2D-chemical shift imaging protocol was used for measuring a transverse volume of interest located cranial to the ventricles allowing for direct comparison of the metabolites in white and grey matter brain tissue in 24 term asphyxiated newborns aged 3 to 16 days. Cho, NAA and Lact showed significant differences between four subgroups of asphyxiated infants with more and less favourable outcomes. High levels of Cho and Lact in the grey matter differentiated non-survivors from survivors (P = 0.003 and P = 0.017, respectively). In perinatal asphyxia the levels of Cho, NAA and Lact in both white and grey matter brain tissue are affected. The levels of Cho and Lact measured in the grey matter are the most indicative of survival. It is therefore advised to include grey matter brain tissue in the region of interest examined by multivoxel MR spectroscopy. (orig.)

  3. Perinatal asphyxia as the leading cause of death and brain injury of newborns: prognosis and neuroprotection of long-term outcomes [

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    Herrera-Marschitz, Mario

    2007-11-01

    Full Text Available [english] Interruption of oxygen availability and re-oxygenation at birth implies a severe metabolic insult, affecting the development of the central nervous system (CNS, increasing its vulnerability to challenges occurring at adult stages. It has been reported that perinatal asphyxia produces regionally specific neuronal decrease and neurite atrophy in basal ganglia, and hippocampus. In hippocampus, a concomitant increase of neurogenesis and neurite hypertrophy has also been observed. The potential neuroprotection of nicotinamide, a non-selective inhibitor of poly (ADP-ribose polymerase (PARP-1, has been investigated, finding functional and morphological improvements when administered 24h after the insult (0.8 mmol/kg, i.p., 24, 48 and 72 h after birth.. The main effect of nicotinamide has been seen in neostriatum, preventing an asphyxia-induced decrease of the number of nNOS cells, and nNOS- and dopamine-like neurite atrophy. The present results support the idea that nicotinamide can prevent the effects elicited by a sustained energy-failure condition, as occurring during perinatal asphyxia, enlightening the enzyme PARP-1 as a novel target for neuronal protection. The support by FONDECYT, ICBM-Enlace, DAAD-CONICYT Programme-2007 grants is acknowledged.

  4. Connexin hemichannel blockade is neuroprotective after asphyxia in preterm fetal sheep.

    Directory of Open Access Journals (Sweden)

    Joanne O Davidson

    Full Text Available Asphyxia around the time of preterm birth is associated with neurodevelopmental disability. In this study, we tested the hypothesis that blockade of connexin hemichannels would improve recovery of brain activity and reduce cell loss after asphyxia in preterm fetal sheep. Asphyxia was induced by 25 min of complete umbilical cord occlusion in preterm fetal sheep (103-104 d gestational age. Connexin hemichannels were blocked by intracerebroventricular infusion of mimetic peptide starting 90 min after asphyxia at a concentration of 50 µM/h for one hour followed by 50 µM/24 hour for 24 hours (occlusion-peptide group, n = 6 or vehicle infusion for controls (occlusion-vehicle group, n = 7. Peptide infusion was associated with earlier recovery of electroencephalographic power after asphyxia compared to occlusion-vehicle (p<0.05, with reduced neuronal loss in the caudate and putamen (p<0.05, but not in the hippocampus. In the intragyral and periventricular white matter, peptide administration was associated with an increase in total oligodendrocyte numbers (p<0.05 and immature/mature oligodendrocytes compared to occlusion-vehicle (p<0.05, with a significant increase in proliferation (p<0.05. Connexin hemichannel blockade was neuroprotective and reduced oligodendrocyte death and improved recovery of oligodendrocyte maturation in preterm fetuses after asphyxia.

  5. Connexin Hemichannel Blockade Is Neuroprotective after Asphyxia in Preterm Fetal Sheep

    Science.gov (United States)

    Davidson, Joanne O.; Drury, Paul P.; Green, Colin R.; Nicholson, Louise F.; Bennet, Laura; Gunn, Alistair J.

    2014-01-01

    Asphyxia around the time of preterm birth is associated with neurodevelopmental disability. In this study, we tested the hypothesis that blockade of connexin hemichannels would improve recovery of brain activity and reduce cell loss after asphyxia in preterm fetal sheep. Asphyxia was induced by 25 min of complete umbilical cord occlusion in preterm fetal sheep (103–104 d gestational age). Connexin hemichannels were blocked by intracerebroventricular infusion of mimetic peptide starting 90 min after asphyxia at a concentration of 50 µM/h for one hour followed by 50 µM/24 hour for 24 hours (occlusion-peptide group, n = 6) or vehicle infusion for controls (occlusion-vehicle group, n = 7). Peptide infusion was associated with earlier recovery of electroencephalographic power after asphyxia compared to occlusion-vehicle (p<0.05), with reduced neuronal loss in the caudate and putamen (p<0.05), but not in the hippocampus. In the intragyral and periventricular white matter, peptide administration was associated with an increase in total oligodendrocyte numbers (p<0.05) and immature/mature oligodendrocytes compared to occlusion-vehicle (p<0.05), with a significant increase in proliferation (p<0.05). Connexin hemichannel blockade was neuroprotective and reduced oligodendrocyte death and improved recovery of oligodendrocyte maturation in preterm fetuses after asphyxia. PMID:24865217

  6. Neuronal Damage Induced by Perinatal Asphyxia Is Attenuated by Postinjury Glutaredoxin-2 Administration

    Science.gov (United States)

    Holubiec, Mariana Inés; Tornatore, Tamara Logica; Rivière, Stéphanie; Kölliker-Frers, Rodolfo Alberto; Tau, Julia; Blanco, Eduardo; Galeano, Pablo; Lillig, Christopher Horst

    2017-01-01

    The general disruption of redox signaling following an ischemia-reperfusion episode has been proposed as a crucial component in neuronal death and consequently brain damage. Thioredoxin (Trx) family proteins control redox reactions and ensure protein regulation via specific, oxidative posttranslational modifications as part of cellular signaling processes. Trx proteins function in the manifestation, progression, and recovery following hypoxic/ischemic damage. Here, we analyzed the neuroprotective effects of postinjury, exogenous administration of Grx2 and Trx1 in a neonatal hypoxia/ischemia model. P7 Sprague-Dawley rats were subjected to right common carotid ligation or sham surgery, followed by an exposure to nitrogen. 1 h later, animals were injected i.p. with saline solution, 10 mg/kg recombinant Grx2 or Trx1, and euthanized 72 h postinjury. Results showed that Grx2 administration, and to some extent Trx1, attenuated part of the neuronal damage associated with a perinatal hypoxic/ischemic damage, such as glutamate excitotoxicity, axonal integrity, and astrogliosis. Moreover, these treatments also prevented some of the consequences of the induced neural injury, such as the delay of neurobehavioral development. To our knowledge, this is the first study demonstrating neuroprotective effects of recombinant Trx proteins on the outcome of neonatal hypoxia/ischemia, implying clinical potential as neuroprotective agents that might counteract neonatal hypoxia/ischemia injury. PMID:28706574

  7. Neuronal Damage Induced by Perinatal Asphyxia Is Attenuated by Postinjury Glutaredoxin-2 Administration

    Directory of Open Access Journals (Sweden)

    Juan Ignacio Romero

    2017-01-01

    Full Text Available The general disruption of redox signaling following an ischemia-reperfusion episode has been proposed as a crucial component in neuronal death and consequently brain damage. Thioredoxin (Trx family proteins control redox reactions and ensure protein regulation via specific, oxidative posttranslational modifications as part of cellular signaling processes. Trx proteins function in the manifestation, progression, and recovery following hypoxic/ischemic damage. Here, we analyzed the neuroprotective effects of postinjury, exogenous administration of Grx2 and Trx1 in a neonatal hypoxia/ischemia model. P7 Sprague-Dawley rats were subjected to right common carotid ligation or sham surgery, followed by an exposure to nitrogen. 1 h later, animals were injected i.p. with saline solution, 10 mg/kg recombinant Grx2 or Trx1, and euthanized 72 h postinjury. Results showed that Grx2 administration, and to some extent Trx1, attenuated part of the neuronal damage associated with a perinatal hypoxic/ischemic damage, such as glutamate excitotoxicity, axonal integrity, and astrogliosis. Moreover, these treatments also prevented some of the consequences of the induced neural injury, such as the delay of neurobehavioral development. To our knowledge, this is the first study demonstrating neuroprotective effects of recombinant Trx proteins on the outcome of neonatal hypoxia/ischemia, implying clinical potential as neuroprotective agents that might counteract neonatal hypoxia/ischemia injury.

  8. Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia : follow-up of two randomised controlled trials

    NARCIS (Netherlands)

    Kaandorp, Joepe J.; van Bel, Frank; Veen, Sylvia; Derks, Jan B.; Groenendaal, Floris; Rijken, Monique; Roze, Elise; Venema, Monica M. A. Uniken; Rademaker, Carin M. A.; Bos, Arend F.; Benders, Manon J. N. L.

    Objective Free-radical-induced reperfusion injury has been recognised as an important cause of brain tissue damage after birth asphyxia. Allopurinol reduces the formation of free radicals, thereby potentially limiting the amount of hypoxia-reperfusion damage. In this study the long-term outcome of

  9. Central cortico-subcortical involvement: a distinct pattern of brain damage caused by perinatal and postnatal asphyxia in term infants

    NARCIS (Netherlands)

    Rademakers, R. P.; van der Knaap, M. S.; Verbeeten, B.; Barth, P. G.; Valk, J.

    1995-01-01

    The MR findings in a characteristic pattern of hypoxic-ischemic brain damage in term infants are described. The MR images of seven patients with cerebral palsy and a specific pattern of central cortico-subcortical cerebral damage were studied retrospectively and correlated with clinical findings.

  10. Maternal creatine supplementation during pregnancy prevents acute and long-term deficits in skeletal muscle after birth asphyxia: a study of structure and function of hind limb muscle in the spiny mouse.

    Science.gov (United States)

    LaRosa, Domenic A; Ellery, Stacey J; Snow, Rod J; Walker, David W; Dickinson, Hayley

    2016-12-01

    Maternal antenatal creatine supplementation protects the brain, kidney, and diaphragm against the effects of birth asphyxia in the spiny mouse. In this study, we examined creatine's potential to prevent damage to axial skeletal muscles. Pregnant spiny mice were fed a control or creatine-supplemented diet from mid-pregnancy, and 1 d before term (39 d), fetuses were delivered by c-section with or without 7.5 min of birth asphyxia. At 24 h or 33 ± 2 d after birth, gastrocnemius muscles were obtained for ex-vivo study of twitch-tension, muscle fatigue, and structural and histochemical analysis. Birth asphyxia significantly reduced cross-sectional area of all muscle fiber types (P birth protects the muscle from asphyxia-induced damage at birth.

  11. ASPHYXIA AND DEVELOPMENTAL OUTCOME IN HIGH RISK INFANTS

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    Valentina DUKOVSKA

    2010-04-01

    Full Text Available Asphyxia is a risk factor that is very often related to neuro-developmental issues in high risk infants and equally affects preterm and term infants, however its outcome on the developed brain differs from the outcome on the preterm brain.In preterm infants, asphyxia usually exerts a hemorrhagic or ischaemic event and periventricular leukomalacia.In term infants, asphyxia leads to cerebral edema and atrophy of the brain, which may later lead to hypoxic ischaemic encephalopathy (HIE.The number of term infants with HIE who have survived is lower than those of preterm infants, while the percentage of term infants with HIE who have neuro-developmental issues is higher. Preemies face more problems in their motor development as a result of the brain damage, while term infants suffer from encephalopathy and their cognitive abilities are more affected.We have conducted a study about the effects that asphyxia has on the developmental outcomes in high risk infants. In our study, we did a longitudinal developmental follow-up of 30 high risk infants and an evaluation of their developmental outcome using the Griffiths Mental Development Scales, from the 4th month of life until the end of the 36th month. First, we found that high risk infants had a much lower developmental outcome than the control group during the trial. Finally, we found that asphyxia makes a difference in the developmental outcome of preterm infants without asphyxia who have a very low birth weight, the preterm infants with asphyxia, and the term infants with HIE-II.

  12. Radio-induced brain lesions

    Directory of Open Access Journals (Sweden)

    Gorgan Mircea Radu

    2014-03-01

    Full Text Available Introduction : Radiotherapy, an important tool in multimodal oncologic treatment, can cause radio-induced brain lesion development after a long period of time following irradiation.

  13. Asphyxia-activated corticocardiac signaling accelerates onset of cardiac arrest

    Science.gov (United States)

    Li, Duan; Mabrouk, Omar S.; Liu, Tiecheng; Tian, Fangyun; Xu, Gang; Rengifo, Santiago; Choi, Sarah J.; Mathur, Abhay; Crooks, Charles P.; Kennedy, Robert T.; Wang, Michael M.; Ghanbari, Hamid; Borjigin, Jimo

    2015-01-01

    The mechanism by which the healthy heart and brain die rapidly in the absence of oxygen is not well understood. We performed continuous electrocardiography and electroencephalography in rats undergoing experimental asphyxia and analyzed cortical release of core neurotransmitters, changes in brain and heart electrical activity, and brain–heart connectivity. Asphyxia stimulates a robust and sustained increase of functional and effective cortical connectivity, an immediate increase in cortical release of a large set of neurotransmitters, and a delayed activation of corticocardiac functional and effective connectivity that persists until the onset of ventricular fibrillation. Blocking the brain’s autonomic outflow significantly delayed terminal ventricular fibrillation and lengthened the duration of detectable cortical activities despite the continued absence of oxygen. These results demonstrate that asphyxia activates a brainstorm, which accelerates premature death of the heart and the brain. PMID:25848007

  14. Neonatal jaundice and birth asphyxia as major causes of cerebral ...

    African Journals Online (AJOL)

    Background: Cerebral Palsy is permanent sequela of severe nonprogressive insult to the immature brain of children. In Nigeria, kernicterus from neonatal jaundice and hypoxic ischaemic encephalopathy form severe birth asphyxia have been identified as among the leading causes of this scourge. Poor management of ...

  15. Neonatal jaundice and birth asphyxia as major causes of cerebral ...

    African Journals Online (AJOL)

    McRoy

    Background: Cerebral Palsy is permanent sequela of severe non- progressive insult to the immature brain of children. In Nigeria, kernicterus from neonatal jaundice and hypoxic ischaemic encephalopathy form severe birth asphyxia have been identified as among the leading causes of this scourge. Poor management of ...

  16. Antenatal dexamethasone after asphyxia increases neural injury in preterm fetal sheep.

    Directory of Open Access Journals (Sweden)

    Miriam E Koome

    Full Text Available BACKGROUND AND PURPOSE: Maternal glucocorticoid treatment for threatened premature delivery dramatically improves neonatal survival and short-term morbidity; however, its effects on neurodevelopmental outcome are variable. We investigated the effect of maternal glucocorticoid exposure after acute asphyxia on injury in the preterm brain. METHODS: Chronically instrumented singleton fetal sheep at 0.7 of gestation received asphyxia induced by complete umbilical cord occlusion for 25 minutes. 15 minutes after release of occlusion, ewes received a 3 ml i.m. injection of either dexamethasone (12 mg, n = 10 or saline (n = 10. Sheep were killed after 7 days recovery; survival of neurons in the hippocampus and basal ganglia, and oligodendrocytes in periventricular white matter were assessed using an unbiased stereological approach. RESULTS: Maternal dexamethasone after asphyxia was associated with more severe loss of neurons in the hippocampus (CA3 regions, 290 ± 76 vs 484 ± 98 neurons/mm(2, mean ± SEM, P<0.05 and basal ganglia (putamen, 538 ± 112 vs 814 ± 34 neurons/mm(2, P<0.05 compared to asphyxia-saline, and with greater loss of both total (913 ± 77 vs 1201 ± 75/mm(2, P<0.05 and immature/mature myelinating oligodendrocytes in periventricular white matter (66 ± 8 vs 114 ± 12/mm(2, P<0.05, vs sham controls 165 ± 10/mm(2, P<0.001. This was associated with transient hyperglycemia (peak 3.5 ± 0.2 vs. 1.4 ± 0.2 mmol/L at 6 h, P<0.05 and reduced suppression of EEG power in the first 24 h after occlusion (maximum -1.5 ± 1.2 dB vs. -5.0 ± 1.4 dB in saline controls, P<0.01, but later onset and fewer overt seizures. CONCLUSIONS: In preterm fetal sheep, exposure to maternal dexamethasone during recovery from asphyxia exacerbated brain damage.

  17. Life-long environmental enrichment counteracts spatial learning, reference and working memory deficits in middle-aged rats subjected to perinatal asphyxia

    Directory of Open Access Journals (Sweden)

    Pablo eGaleano

    2015-01-01

    Full Text Available Continuous environmental stimulation induced by exposure to enriched environment (EE has yielded cognitive benefits in different models of brain injury. Perinatal asphyxia results from a lack of oxygen supply to the fetus and is associated with long-lasting neurological deficits. However, the effects of EE in middle-aged rats suffering perinatal asphyxia are unknown. Therefore, the aim of the present study was to assess whether life-long exposure to EE could counteract the cognitive and behavioral alterations in middle-aged asphyctic rats. Experimental groups consisted of rats born vaginally (CTL, by cesarean section (C+, or by C+ following 19 min of asphyxia at birth (PA. At weaning, rats were assigned to standard (SE or enriched environment (EE for 18 months. During the last month of housing, animals were submitted to a behavioral test battery including Elevated Plus Maze, Open Field, Novel Object Recognition and Morris water maze (MWM. Results showed that middle-aged asphyctic rats, reared in SE, exhibited an impaired performance in the spatial reference and working memory versions of the MWM. EE was able to counteract these cognitive impairments. Moreover, EE improved the spatial learning performance of middle-aged CTL and C+ rats. On the other hand, all groups reared in SE did not differ in locomotor activity and anxiety levels, while EE reduced locomotion and anxiety, regardless of birth condition. Recognition memory was altered neither by birth condition nor by housing environment. These results support the importance of environmental stimulation across the lifespan to prevent cognitive deficits induced by perinatal asphyxia.

  18. Life-long environmental enrichment counteracts spatial learning, reference and working memory deficits in middle-aged rats subjected to perinatal asphyxia

    Science.gov (United States)

    Galeano, Pablo; Blanco, Eduardo; Logica Tornatore, Tamara M. A.; Romero, Juan I.; Holubiec, Mariana I.; Rodríguez de Fonseca, Fernando; Capani, Francisco

    2015-01-01

    Continuous environmental stimulation induced by exposure to enriched environment (EE) has yielded cognitive benefits in different models of brain injury. Perinatal asphyxia results from a lack of oxygen supply to the fetus and is associated with long-lasting neurological deficits. However, the effects of EE in middle-aged rats suffering perinatal asphyxia are unknown. Therefore, the aim of the present study was to assess whether life-long exposure to EE could counteract the cognitive and behavioral alterations in middle-aged asphyctic rats. Experimental groups consisted of rats born vaginally (CTL), by cesarean section (C+), or by C+ following 19 min of asphyxia at birth (PA). At weaning, rats were assigned to standard (SE) or enriched environment (EE) for 18 months. During the last month of housing, animals were submitted to a behavioral test battery including Elevated Plus Maze, Open Field, Novel Object Recognition and Morris water maze (MWM). Results showed that middle-aged asphyctic rats, reared in SE, exhibited an impaired performance in the spatial reference and working memory versions of the MWM. EE was able to counteract these cognitive impairments. Moreover, EE improved the spatial learning performance of middle-aged CTL and C+ rats. On the other hand, all groups reared in SE did not differ in locomotor activity and anxiety levels, while EE reduced locomotion and anxiety, regardless of birth condition. Recognition memory was altered neither by birth condition nor by housing environment. These results support the importance of environmental stimulation across the lifespan to prevent cognitive deficits induced by perinatal asphyxia. PMID:25601829

  19. Dexmedetomidine Postconditioning Reduces Brain Injury after Brain Hypoxia-Ischemia in Neonatal Rats.

    Science.gov (United States)

    Ren, Xiaoyan; Ma, Hong; Zuo, Zhiyi

    2016-06-01

    Perinatal asphyxia can lead to death and severe disability. Brain hypoxia-ischemia (HI) injury is the major pathophysiology contributing to death and severe disability after perinatal asphyxia. Here, seven-day old Sprague-Dawley rats were subjected to left brain HI. Dexmedetomidine was given intraperitoneally after the brain HI. Yohimbine or atipamezole, two α2 adrenergic receptor antagonists, were given 10 min before the dexmedetomidine injection. Neurological outcome was evaluated 7 or 28 days after the brain HI. Frontal cerebral cortex was harvested 6 h after the brain HI. Left brain HI reduced the left cerebral hemisphere weight assessed 7 days after the brain HI. This brain tissue loss was dose-dependently attenuated by dexmedetomidine. Dexmedetomidine applied within 1 h after the brain HI produced this effect. Dexmedetomidine attenuated the brain HI-induced brain tissue and cell loss as well as neurological and cognitive dysfunction assessed from 28 days after the brain HI. Dexmedetomidine postconditioning-induced neuroprotection was abolished by yohimbine or atipamezole. Brain HI increased tumor necrosis factor α and interleukin 1β in the brain tissues. This increase was attenuated by dexmedetomidine. Atipamezole inhibited this dexmedetomidine effect. Our results suggest that dexmedetomidine postconditioning reduces HI-induced brain injury in the neonatal rats. This effect may be mediated by α2 adrenergic receptor activation that inhibits inflammation in the ischemic brain tissues.

  20. Nondrowning Asphyxia in Veterinary Forensic Pathology: Suffocation, Strangulation, and Mechanical Asphyxia.

    Science.gov (United States)

    McEwen, B J

    2016-09-01

    Asphyxia in a forensic context refers to death by rapid cerebral anoxia or hypoxia due to accidental or nonaccidental injury. Death due to nondrowning asphyxia can occur with strangulation, suffocation, and mechanical asphyxia, each of which is categorized based on the mechanism of injury. Individuals dying due to various types of asphyxia may or may not have lesions, and even those lesions that are present may be due to other causes. The interpretation or opinion that death was due to asphyxia requires definitive and compelling evidence from the postmortem examination, death scene, and/or history. Beyond the postmortem examination, pathologists may be faced with questions of forensic importance that revolve around the behavioral and physiological responses in animals subjected to strangulation, suffocation, or mechanical asphyxia to determine if the animal suffered. While there is no prescriptive answer to these questions, it is apparent that, because of physiological and anatomical differences between humans and animals, for some mechanisms of asphyxia, consciousness is maintained for longer periods and the onset of death is later in animals than that described for people. Veterinary pathologists must be cognizant that direct extrapolation from the medical forensic literature to animals may be incorrect. This article reviews the terminology, classification, mechanisms, and lesions associated with asphyxial deaths in companion animals and highlights significant comparative differences of the response to various types of asphyxia in animals and people. © The Author(s) 2016.

  1. Minocycline Attenuates Iron-Induced Brain Injury.

    Science.gov (United States)

    Zhao, Fan; Xi, Guohua; Liu, Wenqaun; Keep, Richard F; Hua, Ya

    2016-01-01

    Iron plays an important role in brain injury after intracerebral hemorrhage (ICH). Our previous study found minocycline reduces iron overload after ICH. The present study examined the effects of minocycline on the subacute brain injury induced by iron. Rats had an intracaudate injection of 50 μl of saline, iron, or iron + minocycline. All the animals were euthanized at day 3. Rat brains were used for immunohistochemistry (n = 5-6 per each group) and Western blotting assay (n = 4). Brain swelling, blood-brain barrier (BBB) disruption, and iron-handling proteins were measured. We found that intracerebral injection of iron resulted in brain swelling, BBB disruption, and brain iron-handling protein upregulation (p minocycline with iron significantly reduced iron-induced brain swelling (n = 5, p Minocycline significantly decreased albumin protein levels in the ipsilateral basal ganglia (p minocycline co-injected animals. In conclusion, the present study suggests that minocycline attenuates brain swelling and BBB disruption via an iron-chelation mechanism.

  2. neonatal asphyxia and its manager

    African Journals Online (AJOL)

    others, so as to increase blood flow to 'priority' organs such as the brain, and the heart. ... disseminated intravascular, necrotizing enterocolitis and brain damage. When the brain is deprived of oxygen a series of biochemical and mechanical events occur. .... breath sounds are audible on auscultation and the skin is pink.

  3. Asphyxia from the eyes of the obstetrician

    Directory of Open Access Journals (Sweden)

    Alessandra Meloni

    2014-06-01

    Full Text Available Nowadays it is well recognized that there are multiple potential pathways causing hypoxic-ischemic events that may lead to cerebral palsy in term infants. The signs and symptoms of neonatal encephalopathy may range from mild to severe, depending on nature and timing of brain injury. The incidence of cerebral palsy has not changed over the last 30 years and one of the obstetricians’challenge is how to recognize babies at intrapartum risk both before and during labour. A detailed description of prepartum and intrapartum risk factors is available. A close surveillance of labour and intrapartum time should be mandatory as the valuation of all available data from obstetrical examination, cardiotocography, ultrasound and labour progression to reach the correct diagnosis with the lowest possible rate of error. The close monitoring should not exclude a humanized and compliant attitude versus labouring women and their families. We analysed the Cagliari Neonatal Intensive Care Unit (NICU activity during the last four years considering 22 asphyxiated babies (coming from 9 different hospitals who underwent hypothermia treatment. The main result was that the need to resuscitation procedures at birth correlates with adverse outcomes. Asphyxia still remains a matter of great concern also as medico legal claims. Considering that neonatal encephalopathy is a heterogeneous condition, it is unlikely that it will be eradicated. However, a comprehensive evaluation of all risk factors and of intrapartum surveillance available tools may reduce as much as possible adverse events.Proceedings of the 10th International Workshop on Neonatology · Cagliari (Italy · October 22nd-25th, 2014 · The last ten years, the next ten years in Neonatology Guest Editors: Vassilios Fanos, Michele Mussap, Gavino Faa, Apostolos Papageorgiou

  4. Radiation-induced brain injury: A review

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    Michael eRobbins

    2012-07-01

    Full Text Available Approximately 100,000 primary and metastatic brain tumor patients/year in the US survive long enough (> 6 months to experience radiation-induced brain injury. Prior to 1970, the human brain was thought to be highly radioresistant; the acute CNS syndrome occurs after single doses > 30 Gy; white matter necrosis occurs at fractionated doses > 60 Gy. Although white matter necrosis is uncommon with modern techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become important, because they have profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenesis of radiation-induced cognitive impairment. Given its central role in memory and neurogenesis, the majority of these studies have focused on the hippocampus. Irradiating pediatric and young adult rodent brains leads to several hippocampal changes including neuroinflammation and a marked reduction in neurogenesis. These data have been interpreted to suggest that shielding the hippocampus will prevent clinical radiation-induced cognitive impairment. However, this interpretation may be overly simplistic. Studies using older rodents, that more closely match the adult human brain tumor population, indicate that, unlike pediatric and young adult rats, older rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons. Nevertheless, older rats still exhibit cognitive impairment. This occurs in the absence of demyelination and/or white matter necrosis similar to what is observed clinically, suggesting that more subtle molecular, cellular and/or microanatomic modifications are involved in this radiation-induced brain injury. Given that radiation-induced cognitive impairment likely reflects damage to both hippocampal- and non-hippocampal-dependent domains, there is a critical need to investigate the microanatomic and functional effects of radiation in various brain

  5. Comparison of Umbilical Serum Copeptin Relative to Erythropoietin and S100B as Asphyxia Biomarkers at Birth.

    Science.gov (United States)

    Summanen, Milla; Seikku, Laura; Rahkonen, Petri; Stefanovic, Vedran; Teramo, Kari; Andersson, Sture; Kaila, Kai; Rahkonen, Leena

    2017-01-01

    Birth asphyxia, estimated to account for a million neonatal deaths annually, can cause a wide variety of neurodevelopmental impairments. There is a need to develop new, swift methods to identify those neonates who would benefit from neuroprotective treatments such as hypothermia. To examine the utility of cord serum copeptin, a stable byproduct of arginine vasopressin release, as a biomarker of birth asphyxia based on a comparison with 2 biomarkers of hypoxia and brain trauma: erythropoietin and S100B. The study population consisted of 140 singleton, term neonates: 113 controls and 27 with birth asphyxia (2/3 criteria met: umbilical artery pH Copeptin, S100B, and erythropoietin levels in umbilical artery samples were measured by immunoassays. Copeptin correlated in the entire study population more strongly with umbilical artery base excess than S100B and erythropoietin, and only copeptin correlated with arterial pH. Furthermore, only copeptin levels were significantly higher in cases of birth asphyxia, and in vaginally born neonates they were found to increase as a function of labor duration. Copeptin was elevated in neonates born via vacuum extraction, whereas erythropoietin levels showed a slight increase after emergency cesarean section. In this study population, S100B and erythropoietin were not valid biomarkers of birth asphyxia. In contrast, our work suggests that copeptin has high potential to become a routinely used biomarker for acute birth asphyxia and neonatal distress. © 2017 S. Karger AG, Basel.

  6. [Oxidative stress in perinatal asphyxia and hypoxic-ischaemic encephalopathy].

    Science.gov (United States)

    Nuñez, Antonio; Benavente, Isabel; Blanco, Dorotea; Boix, Héctor; Cabañas, Fernando; Chaffanel, Mercedes; Fernández-Colomer, Belén; Fernández-Lorenzo, José Ramón; Loureiro, Begoña; Moral, María Teresa; Pavón, Antonio; Tofé, Inés; Valverde, Eva; Vento, Máximo

    2017-06-23

    Birth asphyxia is one of the principal causes of early neonatal death. In survivors it may evolve to hypoxic-ischaemic encephalopathy and major long-term neurological morbidity. Prolonged and intense asphyxia will lead to energy exhaustion in tissues exclusively dependent on aerobic metabolism, such as the central nervous system. Energy deficit leads to ATP-dependent pumps blockage, with the subsequent loss of neuronal transmembrane potential. The most sensitive areas of the brain will die due to necrosis. In more resistant areas, neuronal hyper-excitability, massive entrance of ionic calcium, activation of NO-synthase, free radical generation, and alteration in mitochondrial metabolism will lead to a secondary energy failure and programmed neuronal death by means of the activation of the caspase pathways. A third phase has recently been described that includes persistent inflammation and epigenetic changes that would lead to a blockage of oligodendrocyte maturation, alteration of neurogenesis, axonal maturation, and synaptogenesis. In this scenario, oxidative stress plays a critical role causing direct damage to the central nervous system and activating metabolic cascades leading to apoptosis and inflammation. Moderate whole body hypothermia to preserve energy stores and to reduce the formation of oxygen reactive species attenuates the mechanisms that lead to the amplification of cerebral damage upon resuscitation. The combination of hypothermia with coadjuvant therapies may contribute to improve the prognosis. Copyright © 2017 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  7. Trans-resveratrol enriched maternal diet protects the immature hippocampus from perinatal asphyxia in rats.

    Science.gov (United States)

    Isac, Sebastian; Panaitescu, Anca Maria; Spataru, Ana; Iesanu, Mara; Totan, Alexandra; Udriste, Amalia; Cucu, Natalia; Peltecu, Gheorghe; Zagrean, Leon; Zagrean, Ana-Maria

    2017-07-13

    Trans-resveratrol (tRESV), a polyphenol with antioxidant properties, is common in many food sources, hence easily accessible for study as a maternal dietary supplement in perinatal asphyxia (PA). Hypoxic-ischemic encephalopathy secondary to PA affects especially vulnerable brain areas such as hippocampus and is a leading cause of neonatal morbidity. The purpose of this study is to identify new epigenetic mechanisms of brain inflammation and injury related to PA and to explore the benefit of tRESV enriched maternal diet. The hippocampal interleukin 1 beta (IL-1b), tumour necrosis factor alpha (TNFα) and S-100B protein, at 24-48h after 90min of asphyxia were assessed in postnatal day 6 rats whose mothers received either standard or tRESV enriched diet. The expression of non-coding microRNAs miR124, miR132, miR134, miR146 and miR15a as epigenetic markers of hippocampus response to PA was determined 24h post-asphyxia. Our results indicate that neural response to PA could be epigenetically controlled and that tRESV reduces asphyxia-related neuroinflammation and neural injury. Moreover, tRESV could increase, through epigenetic mechanisms, the tolerance to asphyxia, with possible impact on the neuronal maturation. Our data support the neuroprotective quality of tRESV when used as a supplement in the maternal diet on the offspring's outcome in PA. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Effect of neonatal asphyxia on the impairment of the auditory pathway by recording auditory brainstem responses in newborn piglets: a new experimentation model to study the perinatal hypoxic-ischemic damage on the auditory system.

    Directory of Open Access Journals (Sweden)

    Francisco Jose Alvarez

    Full Text Available Hypoxia-ischemia (HI is a major perinatal problem that results in severe damage to the brain impairing the normal development of the auditory system. The purpose of the present study is to study the effect of perinatal asphyxia on the auditory pathway by recording auditory brain responses in a novel animal experimentation model in newborn piglets.Hypoxia-ischemia was induced to 1.3 day-old piglets by clamping 30 minutes both carotid arteries by vascular occluders and lowering the fraction of inspired oxygen. We compared the Auditory Brain Responses (ABRs of newborn piglets exposed to acute hypoxia/ischemia (n = 6 and a control group with no such exposure (n = 10. ABRs were recorded for both ears before the start of the experiment (baseline, after 30 minutes of HI injury, and every 30 minutes during 6 h after the HI injury.Auditory brain responses were altered during the hypoxic-ischemic insult but recovered 30-60 minutes later. Hypoxia/ischemia seemed to induce auditory functional damage by increasing I-V latencies and decreasing wave I, III and V amplitudes, although differences were not significant.The described experimental model of hypoxia-ischemia in newborn piglets may be useful for studying the effect of perinatal asphyxia on the impairment of the auditory pathway.

  9. Effect of neonatal asphyxia on the impairment of the auditory pathway by recording auditory brainstem responses in newborn piglets: a new experimentation model to study the perinatal hypoxic-ischemic damage on the auditory system.

    Science.gov (United States)

    Alvarez, Francisco Jose; Revuelta, Miren; Santaolalla, Francisco; Alvarez, Antonia; Lafuente, Hector; Arteaga, Olatz; Alonso-Alconada, Daniel; Sanchez-del-Rey, Ana; Hilario, Enrique; Martinez-Ibargüen, Agustin

    2015-01-01

    Hypoxia-ischemia (HI) is a major perinatal problem that results in severe damage to the brain impairing the normal development of the auditory system. The purpose of the present study is to study the effect of perinatal asphyxia on the auditory pathway by recording auditory brain responses in a novel animal experimentation model in newborn piglets. Hypoxia-ischemia was induced to 1.3 day-old piglets by clamping 30 minutes both carotid arteries by vascular occluders and lowering the fraction of inspired oxygen. We compared the Auditory Brain Responses (ABRs) of newborn piglets exposed to acute hypoxia/ischemia (n = 6) and a control group with no such exposure (n = 10). ABRs were recorded for both ears before the start of the experiment (baseline), after 30 minutes of HI injury, and every 30 minutes during 6 h after the HI injury. Auditory brain responses were altered during the hypoxic-ischemic insult but recovered 30-60 minutes later. Hypoxia/ischemia seemed to induce auditory functional damage by increasing I-V latencies and decreasing wave I, III and V amplitudes, although differences were not significant. The described experimental model of hypoxia-ischemia in newborn piglets may be useful for studying the effect of perinatal asphyxia on the impairment of the auditory pathway.

  10. Long-term sequelae of perinatal asphyxia in the aging rat

    DEFF Research Database (Denmark)

    Weitzdoerfer, R; Gerstl, N; Hoeger, H

    2002-01-01

    Information on the consequences of perinatal asphyxia (PA) on brain morphology and function in the aging rat is missing although several groups have hypothesized that PA may be responsible for neurological and psychiatric deficits in the adult. We therefore decided to study the effects of PA on t...... for understanding CNS pathology in the aging subject, animal or human.......Information on the consequences of perinatal asphyxia (PA) on brain morphology and function in the aging rat is missing although several groups have hypothesized that PA may be responsible for neurological and psychiatric deficits in the adult. We therefore decided to study the effects of PA...... on the central nervous system (CNS) in terms of morphology, immunohistochemistry, neurology and behavior in the aging animal. Hippocampus and cerebellum were evaluated morphologically by histological, immunohistochemical and magnetic resonance imaging and cerebellum also by stereological tests. Neurological...

  11. Obesity-Induced Hypertension: Brain Signaling Pathways

    Science.gov (United States)

    da Silva, Alexandre A.; Wang, Zhen; Fang, Taolin; Aberdein, Nicola; de Lara Rodriguez, Cecilia E. P.; Hall, John E.

    2017-01-01

    Obesity greatly increases the risk for cardiovascular, metabolic, and renal diseases and is one of the most significant and preventable causes of increased blood pressure (BP) in patients with essential hypertension. This review high-lights recent advances in our understanding of central nervous system (CNS) signaling pathways that contribute to the etiology and pathogenesis of obesity-induced hypertension. We discuss the role of excess adiposity and activation of the brain leptin-melanocortin system in causing increased sympathetic activity in obesity. In addition, we highlight other potential brain mechanisms by which increased weight gain modulates metabolic and cardiovascular functions. Unraveling the CNS mechanisms responsible for increased sympathetic activation and hypertension and how circulating hormones activate brain signaling pathways to control BP offer potentially important therapeutic targets for obesity and hypertension. PMID:27262997

  12. Obesity-Induced Hypertension: Brain Signaling Pathways.

    Science.gov (United States)

    do Carmo, Jussara M; da Silva, Alexandre A; Wang, Zhen; Fang, Taolin; Aberdein, Nicola; de Lara Rodriguez, Cecilia E P; Hall, John E

    2016-07-01

    Obesity greatly increases the risk for cardiovascular, metabolic, and renal diseases and is one of the most significant and preventable causes of increased blood pressure (BP) in patients with essential hypertension. This review highlights recent advances in our understanding of central nervous system (CNS) signaling pathways that contribute to the etiology and pathogenesis of obesity-induced hypertension. We discuss the role of excess adiposity and activation of the brain leptin-melanocortin system in causing increased sympathetic activity in obesity. In addition, we highlight other potential brain mechanisms by which increased weight gain modulates metabolic and cardiovascular functions. Unraveling the CNS mechanisms responsible for increased sympathetic activation and hypertension and how circulating hormones activate brain signaling pathways to control BP offer potentially important therapeutic targets for obesity and hypertension.

  13. A case report of Traumatic Asphyxia

    Directory of Open Access Journals (Sweden)

    B Sah

    2015-06-01

    Full Text Available Traumatic asphyxia is a condition presenting with cervicofacial cyanosis and edema, subconjunctival hemorrhage, and petechial hemorrhages of the face, neck, and upper chest that occurs due to a compressive force to the thoracoabdominal region.In this case report a 52 years old lady who was brought to the mortuary because of death due to traumatic asphyxia as a result of being stampeded by her own cows upon her chest was discussed. Congestion on both the conjunctiva, cyanosis on chin and adjacent upper left side of neck found with a well demarcated area observed between the cyanosed area over face and the normal area of neck. Hematoma was present in the chin and the adjacent neck region.Apart from quickly eliminating organ pathologies and initiation of supportive therapy in a case of traumatic asphyxia, possibility of formation of hematoma in neck after few hours of getting injured should also be considered, as this type of hematoma may contribute to the cause of death.DOI: http://dx.doi.org/10.3126/jcmsn.v10i3.12777 Journal of College of Medical Sciences-Nepal, 2014, Vol-10, No-3, 51-55

  14. Obesity-Induced Hypertension: Brain Signaling Pathways

    OpenAIRE

    do Carmo, Jussara M.; da Silva, Alexandre A.; Wang, Zhen; Fang, Taolin; Aberdein, Nicola; de Lara Rodriguez, Cecilia E. P.; Hall, John E.

    2016-01-01

    Obesity greatly increases the risk for cardiovascular, metabolic, and renal diseases and is one of the most significant and preventable causes of increased blood pressure (BP) in patients with essential hypertension. This review high-lights recent advances in our understanding of central nervous system (CNS) signaling pathways that contribute to the etiology and pathogenesis of obesity-induced hypertension. We discuss the role of excess adiposity and activation of the brain leptin-melanocorti...

  15. Renal dysfunction in early adulthood following birth asphyxia in male spiny mice, and its amelioration by maternal creatine supplementation during pregnancy.

    Science.gov (United States)

    Ellery, Stacey J; LaRosa, Domenic A; Cullen-McEwen, Luise A; Brown, Russell D; Snow, Rod J; Walker, David W; Kett, Michelle M; Dickinson, Hayley

    2017-04-01

    Acute kidney injury affects ~70% of asphyxiated newborns, and increases their risk of developing chronic kidney disease later in life. Acute kidney injury is driven by renal oxygen deprivation during asphyxia, thus we hypothesized that creatine administered antenatally would protect the kidney from the long-term effects of birth asphyxia. Pregnant spiny mice were fed standard chow or chow supplemented with 5% creatine from 20-d gestation (midgestation). One day prior to term (37-d gestation), pups were delivered by caesarean or subjected to intrauterine asphyxia. Litters were allocated to one of two time-points. Kidneys were collected at 1 mo of age to estimate nephron number (stereology). Renal function (excretory profile and glomerular filtration rate) was measured at 3 mo of age, and kidneys then collected for assessment of glomerulosclerosis. Compared with controls, at 1 mo of age male (but not female) birth-asphyxia offspring had 20% fewer nephrons (P birth-asphyxia offspring had 31% lower glomerular filtration rate (P birth asphyxia. Maternal creatine supplementation during pregnancy may be an effective prophylactic to prevent birth asphyxia induced acute kidney injury and the emergence of chronic kidney disease.

  16. Assessing birth asphyxia using strictly observational signs, the ARC ...

    African Journals Online (AJOL)

    The Apgar Scoring system is the sole assessment tool for newborn asphyxia,but the Apgar scoring system has many limitations as it does not assess conditions before and after delivery, that might trigger asphyxia. Moreover, the score combine subjective and objective signs as well as observations and measurements which ...

  17. Mothers' knowledge about birth asphyxia: The need to do more!

    African Journals Online (AJOL)

    2012-07-19

    Jul 19, 2012 ... to facilitate voluntary adaptation of behavior that promote health.[1] From the aforementioned, health ... of such complications of labor and childbirth is perinatal asphyxia. Birth asphyxia is defined as the ... to children from within and outside Ogun State of Nigeria, the hospital also offers primary care within a ...

  18. Severe Birth Asphyxia in Wesley Guild Hospital, lesa: A persistent ...

    African Journals Online (AJOL)

    To compare the incidence and the mortality associated with severe birth asphyxia over the 1994 to 1998 and 1999 to 2003 periods in a Nigerian Teaching Hospital. These periods were characterized by different social orders and health financing in the country. The babies admitted with the diagnosis of severe birth asphyxia ...

  19. Does perinatal asphyxia contribute to neurological dysfunction in preterm infants?

    NARCIS (Netherlands)

    van Iersel, Patricia A. M.; Bakker, Saskia C. M.; Jonker, Arnold J. H.; Hadders-Algra, Mijna

    Background: Children born preterm are known to be at risk for neurodevelopmental disorders. The role of perinatal asphyxia in this increased risk is still a matter of debate. Aim: To analyze the contribution of perinatal asphyxia in a population of preterm infants admitted to a secondary paediatric

  20. Perinatal asphyxia in a specialist hospital in Port Harcourt, Nigeria ...

    African Journals Online (AJOL)

    Perinatal asphyxia in a specialist hospital in Port Harcourt, Nigeria. BA West, PI Opara. Abstract. Objectives: To find the prevalence, and identify risk factors and outcome in neonates who were admitted into the Braithewaite Memorial Specialist Hospital (BMSH) for perinatal asphyxia. Method: This was a descriptive cross ...

  1. Boosting Focally-Induced Brain Plasticity by Dopamine

    National Research Council Canada - National Science Library

    Kuo, Min-Fang; Paulus, Walter; Nitsche, Michael A

    2008-01-01

    .... Transcranial direct current stimulation (tDCS) induces cortical excitability enhancement by anodal and depression by cathodal brain polarization, which is not restricted to specific subgroups of synapses...

  2. [Neurological consequences following perinatal asphyxia in preschool age children].

    Science.gov (United States)

    Nabieva, T N

    2009-01-01

    Various groups have been addressing the question of whether perinatal asphyxia (PA) affects on newborn health and nervous system. It is widely accepted that severe PA causes motor and cognitive alterations and leads to a variety of brain disorders: cerebral palsy, epilepsy, mental retardation as well as psychiatric deficits. At the same time it was established, that large percentage of children, surviving PA didn't demonstrate apparent sequelae, but mild physical and mental delay in future. With the purpose of disclose further consequences of PA on child development, we examine 20 children (6 years old) surviving mild or moderate PA without severe neurological pathology. In most cases we revealed muscle tone disturbances, physical development and growth retardation, speech pathology in the form of dyslaliya and speech delay. Intact cognitive capacities in these children combine with limited information content. Our investigation discovered, that the presence of certain psychoneurological characteristics such as hyperexcitability, irritability, timidity, aggressiveness; reduced activity, concentration and motivation -- are the consequences of survived birth trauma. These characteristics producing undue fatiguability, inattention, restlessness and diminished working-capacity, can pose additional problems in education process. In the absence of individual approach without taking into account emotional and motivational peculiarities, this category of children could not completely realize their intact cognitive capacities and represent risk group for further mild retardation.

  3. Cerebral blood flow and oxygenation in infants after birth asphyxia. Clinically useful information?

    DEFF Research Database (Denmark)

    Greisen, Gorm

    2014-01-01

    of cellular energy charge during the hours following severe birth asphyxia was observed twenty years later by sequential cranial magnetic resonance spectroscopy. This led to the concept of delayed energy failure that is linked to mitochondrial dysfunction and apoptotic cell death. Abnormally increased...... perfusion and lack of normal cerebral blood flow regulation are also typically present, but whether the perfusion abnormalities at this secondary stage are detrimental, beneficial, or a mere epiphenomenon remains elusive. In contrast, incomplete reoxygenation of the brain during and following resuscitation...

  4. Effect of Marine Collagen Peptides on Physiological and Neurobehavioral Development of Male Rats with Perinatal Asphyxia

    Directory of Open Access Journals (Sweden)

    Linlin Xu

    2015-06-01

    Full Text Available Asphyxia during delivery produces long-term deficits in brain development. We investigated the neuroprotective effects of marine collagen peptides (MCPs, isolated from Chum Salmon skin by enzymatic hydrolysis, on male rats with perinatal asphyxia (PA. PA was performed by immersing rat fetuses with uterine horns removed from ready-to-deliver rats into a water bath for 15 min. Caesarean-delivered pups were used as controls. PA rats were intragastrically administered with 0.33 g/kg, 1.0 g/kg and 3.0 g/kg body weight MCPs from postnatal day 0 (PND 0 till the age of 90-days. Behavioral tests were carried out at PND21, PND 28 and PND 90. The results indicated that MCPs facilitated early body weight gain of the PA pups, however had little effects on early physiological development. Behavioral tests revealed that MCPs facilitated long-term learning and memory of the pups with PA through reducing oxidative damage and acetylcholinesterase (AChE activity in the brain, and increasing hippocampus phosphorylated cAMP-response element binding protein (p-CREB and brain derived neurotrophic factor (BDNF expression.

  5. Propofol administration to the maternal-fetal unit improved fetal EEG and influenced cerebral apoptotic pathway in preterm lambs suffering from severe asphyxia

    NARCIS (Netherlands)

    Seehase, M.; Jennekens, W.; Zwanenburg, A.; Andriessen, P.; Collins, J.J.; Kuypers, E.; Zimmermann, L.J.; Vles, J.; Gavilanes, A.W.; Kramer, B.W.

    2015-01-01

    BACKGROUND: Term and near-term infants are at high risk of developing brain injury and life-long disability if they have suffered from severe perinatal asphyxia. We hypothesized that propofol administration to the maternal-fetal unit can diminish cerebral injury in term and near-term infant fetuses

  6. Traumatic brain injury-induced sleep disorders

    Directory of Open Access Journals (Sweden)

    Viola-Saltzman M

    2016-02-01

    Full Text Available Mari Viola-Saltzman, Camelia Musleh Department of Neurology, NorthShore University HealthSystem, Evanston, IL, USA Abstract: Sleep disturbances are frequently identified following traumatic brain injury, affecting 30%–70% of persons, and often occur after mild head injury. Insomnia, fatigue, and sleepiness are the most frequent sleep complaints after traumatic brain injury. Sleep apnea, narcolepsy, periodic limb movement disorder, and parasomnias may also occur after a head injury. In addition, depression, anxiety, and pain are common brain injury comorbidities with significant influence on sleep quality. Two types of traumatic brain injury that may negatively impact sleep are acceleration/deceleration injuries causing generalized brain damage and contact injuries causing focal brain damage. Polysomnography, multiple sleep latency testing, and/or actigraphy may be utilized to diagnose sleep disorders after a head injury. Depending on the disorder, treatment may include the use of medications, positive airway pressure, and/or behavioral modifications. Unfortunately, the treatment of sleep disorders associated with traumatic brain injury may not improve neuropsychological function or sleepiness. Keywords: traumatic brain injury, insomnia, hypersomnia, sleep apnea, periodic limb movement disorder, fatigue

  7. From "apparent death" to "birth asphyxia": a history of blame.

    Science.gov (United States)

    Obladen, Michael

    2017-11-08

    Since the sixteenth century, competition between midwives and surgeons has created a culture of blame around the difficult delivery. In the late seventeenth century, 100 years before oxygen was discovered, researchers associated "apparent death of the newborn" with impaired respiratory function of the placenta. The diagnosis "birth asphyxia" replaced the term "apparent death of the newborn" during the mass phobia of being buried alive in the eighteenth century. This shifted the interpretation from unavoidable fate to a preventable condition. Although the semantic inaccuracy ("pulselessness") was debated, "asphyxia" was not scientifically defined until 1992. From 1792 the diagnosis was based on a lack of oxygen. "Blue" and "white" asphyxia were perceived as different disorders in the eighteenth, and as different grades of the same disorder in the nineteenth century. In 1862, William Little linked birth asphyxia with cerebral palsy, and although never confirmed, his hypothesis was accepted by scientists and the public. Fetal well-being was assessed by auscultating heart beats since 1822, and continuous electronic fetal monitoring was introduced in the 1960s without scientific assessment. It neither diminished the incidence of birth asphyxia nor of cerebral palsy, but rather raised the rate of cesarean sections and litigation against obstetricians and midwives.Pediatric Research advance online publication, 8 November 2017; doi:10.1038/pr.2017.238.

  8. PERINATAL ASPHYXIA AS POTENTIAL SOURCE OF CHILDREN WITH DEVELOPMENTAL PSYCHO-MOTOR DIFFICULTIES

    Directory of Open Access Journals (Sweden)

    Elizabeta ZISOVSKA

    1997-09-01

    Full Text Available Besides the great improvement of aostetrics and neanatal intensive care, certain percentage of new born children suffer from perinatal asphyxia (PA and that is one of the first reasons for hypoxic and ischemic brain damage which leads to neuro-developing handicap. In order to show how strong is the correaltion between PA and permanent sequele, an early, precise and prompt diagnosis of asphyxia and its influence on neonatal brain is neccessary.This study presents answers to the following issues.1.Which parameters define precisely the perinatal asphyxia?2.How great is the PA incidence on our material?3.What is the percentage of postasphyxic encephalopathy (PAE in the group of asphyxic new born children?4.Which of these children bear high risk for developmental psycho-motor difficulties?MaterialThe new born children delivered on time in the Clinic of Gynecology and Obstetrics.Methods1.Early diagnosis of PA according to the score consisted of high specific, sensitivity and positive and predictive value2.Consequent neurological check-ups and PAE cathegori-zation for seven days3.Ultrasound examination of CNS through big fontanelle4.Lab analysesResults5.639 successive new born children delivered on time were examined. The included scouring system covers APGAR score at the 5th minute, cardiotocographic record, base deficit in ABS, meconium around the amniotic water. According to this system, 81 child passed the PA , i.e., 14,3/ 1.000 new born children delivered on time. Out of them, 54 have signs of PAE (9,5/1000 new born children delivered on time, i.e., 66,6% of all asphyxia new born children. Classification has been made according to the PAE grade: 34 children survived the first grade (62,9%, 11 children survived the second grade (20,4% and 9 new born children survived the third grade (16,7%. According to data in literature and long year studies of this issue, the children from the group who passed the second and the third grade of PAE have the risk

  9. Asphyxia from the eyes of the neonatologist

    Directory of Open Access Journals (Sweden)

    Paolo Gancia

    2014-06-01

    Full Text Available The perinatal asphyxia occurs at a frequency of 4-6‰ in developed countries The hypoxic-ischemic encephalopathy (HIE has an incidence of 0.5-2‰, and is a frequent cause of death and severe disability. Cerebral hypothermia is a well-established therapy of HIE, and its benefits have been described by systematic reviews and meta-analyses of numerous controlled clinical trials. Authors describe their experience in implementation of cerebral hypotermia in a Neonatal Intensive Care Unit, the creation of a network to perform neurophysiologic study of asphyxiated infants ≥ 35 weeks gestation, potential hypothermia candidates. Neurodevelopmental prognosis of HIE infants is of paramount importance for parents. To improve the quality of prognosis and communication with the parents, two studies have been undertaken. First, EEG and magnetic resonance imaging (MRI relationships analysis showed that the severity of the background EEG is associated with the severity and location of MRI lesion patterns in infants treated with hypothermia because of HIE. The second study aims to elucidate the relationships between MRI patterns and neurodevelopmental assessment by Griffiths scales. We found that neuroimaging findings correlate significantly with overall neurodevelopmental assessment at 12 and 24 months of life; in particular, this correlation is significant for the loco-motor and psycho-social sides. These instrumental data, with the EEG evaluation and clinical data, allow the neonatologist to predict quite precisely the neurological outcome of an infant. Proceedings of the 10th International Workshop on Neonatology · Cagliari (Italy · October 22nd-25th, 2014 · The last ten years, the next ten years in Neonatology Guest Editors: Vassilios Fanos, Michele Mussap, Gavino Faa, Apostolos Papageorgiou

  10. Circulatory responses to asphyxia differ if the asphyxia occurs in utero or ex utero in near-term lambs.

    Directory of Open Access Journals (Sweden)

    Kristina S Sobotka

    Full Text Available A cornerstone of neonatal resuscitation teaching suggests that a rapid vagal-mediated bradycardia is one of the first signs of perinatal compromise. As this understanding is based primarily on fetal studies, we investigated whether the heart rate and blood pressure response to total asphyxia is influenced by whether the animal is in utero or ex utero.Fetal sheep were instrumented at ∼ 139 days of gestation and then asphyxiated by umbilical cord occlusion until mean arterial blood pressure decreased to ∼ 20 mmHg. Lambs were either completely submerged in amniotic fluid (in utero; n = 8 throughout the asphyxia or were delivered and then remained ex utero (ex utero; n = 8 throughout the asphyxia. Heart rate and arterial blood pressure were continuously recorded.Heart rate was higher in ex utero lambs than in utero lambs. Heart rates in in utero lambs rapidly decreased, while heart rates in ex utero lambs initially increased following cord occlusion (for ∼ 1.5 min before they started to decrease. Mean arterial pressure initially increased then decreased in both groups.Heart rate response to asphyxia was markedly different depending upon whether the lamb was in utero or ex utero. This indicates that the cardiovascular responses to perinatal asphyxia are significantly influenced by the newborn's local environment. As such, based solely on heart rate, the stage and severity of a perinatal asphyxic event may not be as accurate as previously assumed.

  11. Correlation between echocardiographic superior vena cava flow and short-term outcome in infants with asphyxia.

    Science.gov (United States)

    Kumagai, Takeshi; Higuchi, Ryuzo; Higa, Asumi; Tsuno, Yoshinobu; Hiramatsu, Chisako; Sugimoto, Takuya; Booka, Mina; Okutani, Takahiro; Yoshikawa, Norishige

    2013-05-01

    To assess the relationship between superior vena cava (SVC) flow and short-term outcome in infants with perinatal asphyxia. Infants in sequence born after more than 35 weeks of gestation who had been hospitalized at the NICU and normal neonatal wards of Wakayama Medical University between May 2005 and September 2010 were recruited for this observational cohort study. The study eligibility criterion was the presence of perinatal asphyxia, as evidenced by abnormal fetal heart rate monitoring and an Apgar score of 7 or less at 1 min or need for resuscitation using positive pressure ventilation. SVC flow was measured in the first three days of life by Doppler echocardiography as described by Kluckow and Evans. Short-term outcome was defined as poor if MRI demonstrated bilateral lesions of the basal ganglia and thalamus and/or multicystic encephalomalacia due to hypoxic ischemia. In the head cooling group, SVC flow in infants with a good outcome was lower than that in infants with a poor outcome at 12h (36.9±7.7 vs. 113.4±42.4 ml/kg/min (p=0.01)), 24h (75.2±25.3 vs. 155.6±45.7 ml/kg/min (p=0.03)), and 48 h (92.5±34.2 vs. 161.1±46.7 ml/kg/min (p=0.04)) after birth. SVC flow decreased promptly after introduction of head cooling in infants who had a good outcome, whereas it increased gradually after head cooling in those who had a poor outcome. We speculate that regulation of brain circulation is disrupted in infants with asphyxia who show a poor outcome. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. Traumatic brain injury and obesity induce persistent central insulin resistance.

    Science.gov (United States)

    Karelina, Kate; Sarac, Benjamin; Freeman, Lindsey M; Gaier, Kristopher R; Weil, Zachary M

    2016-04-01

    Traumatic brain injury (TBI)-induced impairments in cerebral energy metabolism impede tissue repair and contribute to delayed functional recovery. Moreover, the transient alteration in brain glucose utilization corresponds to a period of increased vulnerability to the negative effects of a subsequent TBI. In order to better understand the factors contributing to TBI-induced central metabolic dysfunction, we examined the effect of single and repeated TBIs on brain insulin signalling. Here we show that TBI induced acute brain insulin resistance, which resolved within 7 days following a single injury but persisted until 28 days following repeated injuries. Obesity, which causes brain insulin resistance and neuroinflammation, exacerbated the consequences of TBI. Obese mice that underwent a TBI exhibited a prolonged reduction of Akt (also known as protein kinase B) signalling, exacerbated neuroinflammation (microglial activation), learning and memory deficits, and anxiety-like behaviours. Taken together, the transient changes in brain insulin sensitivity following TBI suggest a reduced capacity of the injured brain to respond to the neuroprotective and anti-inflammatory actions of insulin and Akt signalling, and thus may be a contributing factor for the damaging neuroinflammation and long-lasting deficits that occur following TBI. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  13. D-galactose-induced brain ageing model

    DEFF Research Database (Denmark)

    Sadigh-Eteghad, Saeed; Majdi, Alireza; McCann, Sarah K.

    2017-01-01

    Animal models are commonly used in brain ageing research. Amongst these, models where rodents are exposed to d-galactose are held to recapitulate a number of features of ageing including neurobehavioral and neurochemical changes. However, results from animal studies are often inconsistent...

  14. Risk factors and prognostic models for perinatal asphyxia at term

    NARCIS (Netherlands)

    Ensing, S.

    2015-01-01

    This thesis will focus on the risk factors and prognostic models for adverse perinatal outcome at term, with a special focus on perinatal asphyxia and obstetric interventions during labor to reduce adverse pregnancy outcomes. For the majority of the studies in this thesis we were allowed to use data

  15. Neonatal jaundice and birth asphyxia as major causes of cerebral ...

    African Journals Online (AJOL)

    McRoy

    International Journal of Medicine and Biomedical Research. Volume 2 Issue 3 September – December 2013 ... cerebral palsy in Nigeria: are doctors' wrong beliefs and practices part of the problem? Okperi B.O ... training programs. Key words: Neonatal jaundice, birth asphyxia, cerebral palsy, health institutions, practice ...

  16. Traumatic Asphyxia with Diaphragmatic Injury: A Case Report

    Directory of Open Access Journals (Sweden)

    Hussein Lateef

    2015-03-01

    Full Text Available Traumatic asphyxia, or Perthe’s syndrome, is a rare clinical syndrome characterized by cervicofacial cyanosis, petechiae, subconjunctival hemorrhage, neurological symptoms, and thoracic injury. It affects both adults and children after blunt chest traumas. The diagnosis of this condition is based mainly on the specific clinical signs, which should immediately bring to mind the severity of the trauma, the various probable types of pulmonary injuries, and the need for screening and careful assessment of other organs that might also be injured. In this report, we describe the case of a 39-year-old male who developed traumatic asphyxia after severe blunt chest trauma during his work at a construction site. The patient had multiple injuries to the chest, abdomen, head and neck, which were treated conservatively. An associated diaphragmatic injury was successfully treated by video-assisted thoracic surgery. This patient is one of five patients who were admitted to Saqr Hospital in the United Arab Emirates, diagnosed with traumatic asphyxia, and treated by mechanical ventilator, supportive measures, and fiberoptic bronchoscopy, for both diagnostic and therapeutic indications, in our unit in the period between July 2006 and June 2013. As traumatic asphyxia is a systemic injury, careful assessment of the patient and looking for other injuries is mandatory. Treatment usually involves supportive measures to the affected organs, but surgical intervention may sometimes prove to be an important part of the treatment. Bronchoscopy should be performed for diagnostic and therapeutic reasons because of the associated pulmonary and possible tracheobronchial injuries.

  17. Outcomes of neonates with perinatal asphyxia at a tertiary academic ...

    African Journals Online (AJOL)

    Over 9 million children die each year during the perinatal and neonatal periods, and nearly all of these deaths occur in developing countries.[1]. Perinatal asphyxia is a serious clinical problem globally. Every year approximately 4 million babies are born asphyxiated; this results in 1 million deaths and an equal number of.

  18. Birth Asphyxia in a Nigerian Mission Hospital in Benin City ...

    African Journals Online (AJOL)

    and-five-minute Apgar scores of 2,208 live-births were recorded. Those with low Apgar scores ( 6 at one minute) were studied and their data analyzed. Results: Birth asphyxia occurred in 83.8 per 1000 live-births. The associated significant ...

  19. Gender differences in alcohol-induced neurotoxicity and brain damage.

    Science.gov (United States)

    Alfonso-Loeches, Silvia; Pascual, María; Guerri, Consuelo

    2013-09-06

    Considerable evidence has demonstrated that women are more vulnerable than men to the toxic effects of alcohol, although the results as to whether gender differences exist in ethanol-induced brain damage are contradictory. We have reported that ethanol, by activating the neuroimmune system and Toll-like receptors 4 (TLR4), can cause neuroinflammation and brain injury. However, whether there are gender differences in alcohol-induced neuroinflammation and brain injury are currently controversial. Using the brains of TLR4(+/+) and TLR4(-/-) (TLR4-KO) mice, we report that chronic ethanol treatment induces inflammatory mediators (iNOS and COX-2), cytokines (IL-1β, TNF-α), gliosis processes, caspase-3 activation and neuronal loss in the cerebral cortex of both female and male mice. Conversely, the levels of these parameters tend to be higher in female than in male mice. Using an in vivo imaging technique, our results further evidence that ethanol treatment triggers higher GFAP levels and lower MAP-2 levels in female than in male mice, suggesting a greater effect of ethanol-induced astrogliosis and less MAP-2(+) neurons in female than in male mice. Our results further confirm the pivotal role of TLR4 in alcohol-induced neuroinflammation and brain damage since the elimination of TLR4 protects the brain of males and females against the deleterious effects of ethanol. In short, the present findings demonstrate that, during the same period of ethanol treatment, females are more vulnerable than males to the neurotoxic/neuroinflammatory effects of ethanol, thus supporting the view that women are more susceptible than men to the medical consequences of alcohol abuse. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  20. Physical Exercise Can Induce Brain Plasticity and Regulate Mental Function

    OpenAIRE

    Ichiro, KITA; Graduate School of Human Health Science, Tokyo Metropolitan University

    2014-01-01

    Physical exercise can enhance learning and memory, and improve stress-related psychiatric disorders such as depression and anxiety. There is accumulating evidence that physical exercise can induce morphological and functional alterations in the brain via changes in molecular and cellular plasticity. Thus, it is suggested that the neuroplasticity produced by physical exercise underlies the exercise-induced changes in mental function, including learning and psychological health. Although the ne...

  1. Modulation of Brain Dead Induced Inflammation by Vagus Nerve Stimulation

    NARCIS (Netherlands)

    Hoeger, S.; Bergstraesser, C.; Selhorst, J.; Fontana, J.; Birck, R.; Waldherr, R.; Beck, G.; Sticht, C.; Seelen, M. A.; van Son, W. J.; Leuvenink, H.; Ploeg, R.; Schnuelle, P.; Yard, B. A.

    Because the vagus nerve is implicated in control of inflammation, we investigated if brain death (BD) causes impairment of the parasympathetic nervous system, thereby contributing to inflammation. BD was induced in rats. Anaesthetised ventilated rats (NBD) served as control. Heart rate variability

  2. ECT: its brain enabling effects: a review of electroconvulsive therapy-induced structural brain plasticity.

    Science.gov (United States)

    Bouckaert, Filip; Sienaert, Pascal; Obbels, Jasmien; Dols, Annemieke; Vandenbulcke, Mathieu; Stek, Max; Bolwig, Tom

    2014-06-01

    Since the past 2 decades, new evidence for brain plasticity has caused a shift in both preclinical and clinical ECT research from falsifying the "brain damage hypothesis" toward exploring ECT's enabling brain (neuro)plasticity effects. By reviewing the available animal and human literature, we examined the theory that seizure-induced structural changes are crucial for the therapeutic efficacy of ECT. Both animal and human studies suggest electroconvulsive stimulation/electroconvulsive therapy (ECT)-related neuroplasticity (neurogenesis, synaptogenesis, angiogenesis, or gliogenesis). It remains unclear whether structural changes might explain the therapeutic efficacy and/or be related to the (transient) learning and memory impairment after ECT. Methods to assess in vivo brain plasticity of patients treated with ECT will be of particular importance for future longitudinal studies to give support to the currently available correlational data.

  3. Investigations of primary blast-induced traumatic brain injury

    Science.gov (United States)

    Sawyer, T. W.; Josey, T.; Wang, Y.; Villanueva, M.; Ritzel, D. V.; Nelson, P.; Lee, J. J.

    2017-09-01

    The development of an advanced blast simulator (ABS) has enabled the reproducible generation of single-pulse shock waves that simulate free-field blast with high fidelity. Studies with rodents in the ABS demonstrated the necessity of head restraint during head-only exposures. When the head was not restrained, violent global head motion was induced by pressures that would not produce similar movement of a target the size and mass of a human head. This scaling artefact produced changes in brain function that were reminiscent of traumatic brain injury (TBI) due to impact-acceleration effects. Restraint of the rodent head eliminated these, but still produced subtle changes in brain biochemistry, showing that blast-induced pressure waves do cause brain deficits. Further experiments were carried out with rat brain cell aggregate cultures that enabled the conduct of studies without the gross movement encountered when using rodents. The suspension nature of this model was also exploited to minimize the boundary effects that complicate the interpretation of primary blast studies using surface cultures. Using this system, brain tissue was found not only to be sensitive to pressure changes, but also able to discriminate between the highly defined single-pulse shock waves produced by underwater blast and the complex pressure history exposures experienced by aggregates encased within a sphere and subjected to simulated air blast. The nature of blast-induced primary TBI requires a multidisciplinary research approach that addresses the fidelity of the blast insult, its accurate measurement and characterization, as well as the limitations of the biological models used.

  4. Maturation of the mitochondrial redox response to profound asphyxia in fetal sheep.

    Directory of Open Access Journals (Sweden)

    Paul P Drury

    Full Text Available Fetal susceptibility to hypoxic brain injury increases over the last third of gestation. This study examined the hypothesis that this is associated with impaired mitochondrial adaptation, as measured by more rapid oxidation of cytochrome oxidase (CytOx during profound asphyxia.Chronically instrumented fetal sheep at 0.6, 0.7, and 0.85 gestation were subjected to either 30 min (0.6 gestational age (ga, n = 6, 25 min (0.7 ga, n = 27 or 15 min (0.85 ga, n = 17 of complete umbilical cord occlusion. Fetal EEG, cerebral impedance (to measure brain swelling and near-infrared spectroscopy-derived intra-cerebral oxygenation (ΔHb = HbO(2 - Hb, total hemoglobin (THb and CytOx redox state were monitored continuously. Occlusion was associated with profound, rapid fall in ΔHb in all groups to a plateau from 6 min, greatest at 0.85 ga compared to 0.6 and 0.7 ga (p<0.05. THb initially increased at all ages, with the greatest rise at 0.85 ga (p<0.05, followed by a progressive fall from 7 min in all groups. CytOx initially increased in all groups with the greatest rise at 0.85 ga (p<0.05, followed by a further, delayed increase in preterm fetuses, but a striking fall in the 0.85 group after 6 min of occlusion. Cerebral impedance (a measure of cytotoxic edema increased earlier and more rapidly with greater gestation. In conclusion, the more rapid rise in CytOx and cortical impedance during profound asphyxia with greater maturation is consistent with increasing dependence on oxidative metabolism leading to earlier onset of neural energy failure before the onset of systemic hypotension.

  5. Obstetric interventions and perinatal asphyxia in growth retarded term infants

    DEFF Research Database (Denmark)

    Langhoff-Roos, J; Lindmark, G

    1997-01-01

    neonatal outcome at term have been studied in relation to different types of fetal growth retardation, including sub-groups with low ponderal index or low amount of subcutaneous fat. RESULTS: The need for obstetric intervention indicated by suspected fetal asphyxia before or during labor was increased 3......BACKGROUND: The monitoring of fetal growth during pregnancy is usually justified because of the increased perinatal risk of these babies. METHODS: In 1552 infants from the Scandinavian Small for Gestational Age Study the need for obstetric interventions, risk of fetal asphyxia and immediate......-fold (6-8%) for growth retarded infants both in SGA infants in general and infants with asymmetric body proportions. The immediate perinatal outcome, however, was favorable with Apgar below 8 at 5 min in only 2% irrespective of the type of growth retardation, in spite of the fact that less than 25...

  6. Severe myocardial injury and extracorporeal membrane oxygenation following perinatal asphyxia

    Directory of Open Access Journals (Sweden)

    P. Benson Ham

    2015-05-01

    Full Text Available Perinatal asphyxia is a common cause of morbidity and mortality in the newborn and is associated with myocardial injury in a significant proportion of cases. Biomarkers, echocardiography, and rhythm disturbances are sensitive indicators of myocardial ischemia and may predict mortality. We present a case of severe myocardial dysfunction immediately after delivery managed with extracorporeal membrane oxygenation (ECMO and discuss the role of cardiac biomarkers, echocardiography, electrocardiography, and ECMO in the asphyxiated newborn.

  7. Perinatal Asphyxia: A Review from a Metabolomics Perspective

    Directory of Open Access Journals (Sweden)

    Claudia Fattuoni

    2015-04-01

    Full Text Available Perinatal asphyxia is defined as an oxygen deprivation that occurs around the time of birth, and may be caused by several perinatal events. This medical condition affects some four million neonates worldwide per year, causing the death of one million subjects. In most cases, infants successfully recover from hypoxia episodes; however, some patients may develop HIE, leading to permanent neurological conditions or impairment of different organs and systems. Given its multifactor dependency, the timing, severity and outcome of this disease, mainly assessed through Sarnat staging, are of difficult evaluation. Moreover, although the latest newborn resuscitation guideline suggests the use of a 21% oxygen concentration or room air, such an approach is still under debate. Therefore, the pathological mechanism is still not clear and a golden standard treatment has yet to be defined. In this context, metabolomics, a new discipline that has described important perinatal issues over the last years, proved to be a useful tool for the monitoring, the assessment, and the identification of potential biomarkers associated with asphyxia events. This review covers metabolomics research on perinatal asphyxia condition, examining in detail the studies reported both on animal and human models.

  8. RISK FACTORS AND DEVELOPMENTAL OUTCOME AMONG BABIES WITH PERINATAL ASPHYXIA IN A TERTIARY CARE CENTRE

    OpenAIRE

    Sudhakar; Natarajan; Bahubali; Revathy

    2016-01-01

    BACKGROUND Birth asphyxia is commonest cause of preventable cerebral injury. It is also important cause of neonatal mortality. Incidence of birth asphyxia however is higher in developing countries and leading cause of neonatal mortality. This work is undertaken to study the incidence, risk factors and outcome of birth asphyxia. METHODOLOGY This study was conducted in the neonatal intensive care Unit of tertiary care hospital. Neonates with the APGAR score of less than...

  9. Ownership of an artificial limb induced by electrical brain stimulation.

    Science.gov (United States)

    Collins, Kelly L; Guterstam, Arvid; Cronin, Jeneva; Olson, Jared D; Ehrsson, H Henrik; Ojemann, Jeffrey G

    2017-01-03

    Replacing the function of a missing or paralyzed limb with a prosthetic device that acts and feels like one's own limb is a major goal in applied neuroscience. Recent studies in nonhuman primates have shown that motor control and sensory feedback can be achieved by connecting sensors in a robotic arm to electrodes implanted in the brain. However, it remains unknown whether electrical brain stimulation can be used to create a sense of ownership of an artificial limb. In this study on two human subjects, we show that ownership of an artificial hand can be induced via the electrical stimulation of the hand section of the somatosensory (SI) cortex in synchrony with touches applied to a rubber hand. Importantly, the illusion was not elicited when the electrical stimulation was delivered asynchronously or to a portion of the SI cortex representing a body part other than the hand, suggesting that multisensory integration according to basic spatial and temporal congruence rules is the underlying mechanism of the illusion. These findings show that the brain is capable of integrating "natural" visual input and direct cortical-somatosensory stimulation to create the multisensory perception that an artificial limb belongs to one's own body. Thus, they serve as a proof of concept that electrical brain stimulation can be used to "bypass" the peripheral nervous system to induce multisensory illusions and ownership of artificial body parts, which has important implications for patients who lack peripheral sensory input due to spinal cord or nerve lesions.

  10. Zika Virus Infects Human Fetal Brain Microglia and Induces Inflammation.

    Science.gov (United States)

    Lum, Fok-Moon; Low, Donovan K S; Fan, Yiping; Tan, Jeslin J L; Lee, Bernett; Chan, Jerry K Y; Rénia, Laurent; Ginhoux, Florent; Ng, Lisa F P

    2017-04-01

    The unprecedented reemergence of Zika virus (ZIKV) has startled the world with reports of increased microcephaly in Brazil. ZIKV can infect human neural progenitors and impair brain growth. However, direct evidence of ZIKV infection in human fetal brain tissues remains elusive. Investigations were performed with brain cell preparations obtained from 9 donors. Virus infectivity was assessed by detection of virus antigen by flow cytometry together with various hematopoietic cell surface markers. Virus replication was determined by viral RNA quantification. Cytokine levels in supernatant obtained from virus-infected fetal brain cells were measured simultaneously in microbead-based immunoassays. We also show that ZIKV infection was particularly evident in hematopoietic cells with microglia, the brain-resident macrophage population being one of the main targets. Infection induces high levels of proinflammatory immune mediators such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), and monocyte chemotactic protein 1 (MCP-1). Our results highlight an important role for microglia and neuroinflammation during congenital ZIKV pathogenesis.

  11. Inflammatory mediators in perinatal asphyxia and infection.

    Science.gov (United States)

    Xanthou, M; Fotopoulos, S; Mouchtouri, A; Lipsou, N; Zika, I; Sarafidou, J

    2002-01-01

    To determine serum levels of interleukin-6 (IL-6), IL-1beta, tumor necrosis factor-alpha (TNF-alpha), soluble intercellular adhesion molecule-1 (sICAM-1) and C-reactive protein (CRP) in asphyxiated neonates and compare these inflammatory factors with those found in neonates with perinatal infection. 88 neonates were studied, of whom 36 were asphyxiated, 18 were infected and the remaining 34 were controls. Peripheral blood samples were obtained on the 1st, 3rd and 5th postnatal days. Cytokines IL-6 and IL-1beta as well as sICAM-1 serum levels did not differ between asphyxiated and infected neonates; however, at most time periods, their values were significantly higher than controls. TNF-alpha was similar in the three groups of neonates. CRP serum values were significantly higher in the infected neonates than in the asphyxiated or control subjects. Among the 54 asphyxiated and infected neonates, 15 were considered as severe cases and 39 as mild. The severe cases, at most time periods, had significantly higher IL-6, IL-1beta and sICAM-1 levels compared with the mild ones. Through receiver operating characteristic curves the cut-off points, sensitivities, and specificities for distinguishing neonates at risk or at high risk for brain damage were established. Similar increases in serum levels of IL-6, IL-1beta and sICAM-1 were found in perinatally asphyxiated and infected neonates. As these increases correlated with the severity of the perinatal insults, neonates at high risk for brain damage might be detected.

  12. Association of hypoglycemia, hypocalcemia and hypomagnesemia in neonates with perinatal asphyxia.

    Science.gov (United States)

    Saha, D; Ali, M A; Haque, M A; Ahmed, M S; Sutradhar, P K; Latif, T; Sarkar, D; Husain, F

    2015-04-01

    The clinical evidence of neurological menifestations associated with asphyxia is described as hypoxic ischaemic encephalopathy (HIE). A variety of metabolic problems are present in asphyxiated newborns including hypoglycemia, hypocalcemia, hypomagnesemia and others metabolic abnormalities. Some of these biochemical disturbances may trigger seizure or potentiate further brain damage. This cross sectional case-control study was done in Mymensingh Medical College Hospital, to identify the association of hypoglycemia, hypocalcemia, hypomagnesemia in neonates with perinatal asphyxia. Study period was six months. Sample size was 60. Among total sample 30 term asphyxiated newborns of <24 hours age were case and equal number term healthy newborns <24 hours age were control. The main clinical presentations were delayed cry after birth along with respiratory distress, convulsion and absence of cry in asphyxiated newborns. Major physical findings were cyanosis, convulsion and tachypnoea in asphyxiated group. The mean value of serum calcium level was significantly lower in asphyxiated newborns (7.37 ± 0.10mg/dl) than control value (8.04±0.09mg/dl). Hypocalcemia was found among 23.33% babies in case group. On the contrary, hypocalcemia was found in single baby among control group. The mean value of serum magnesium was significantly lower in asphyxiated newborns (1.83 ± 0.04mg/dl) than control value (1.96 ± 0.05mg/dl). Hypomagnesemia was found among 3(10%) newborns but none was found among control group. Hypoglycemia was found in 7(23.33%) cases though the mean value of blood glucose was higher in case group (5.72 ± 0.62mmol/l) than control group (4.87 ± 0.15mmol/l) difference was not statistically significant. Combined hypoglycemia, hypocalcemia and hypomagnesemia were found in 1(3.33%) case; combined hypoglycemia and hypocalcemia were found in 2(6.67%) cases; and combined hypocalcemia and hypomagnesemia were found in 1(3.33%) case. During the study period, 3(10.0%) cases

  13. The efficiency of adjusted-da-chai-ling-tang in radiation-induced brain edema in patients with brain tumors

    Directory of Open Access Journals (Sweden)

    Da-Tong Ju

    2015-01-01

    Full Text Available Background: Brain edema induced by radiotherapy is a common complication in patients with brain tumors, for which medical treatment is the treatment of choice. Adjusted-Da-Chai-Ling-Tang, a Chinese herbal formulation, has been confirmed to be protective against the radiation-induced edema. In this study, we investigated the efficiency of adjusted-Da-Chai-Ling-Tang in radiation-induced brain edema in patients with brain tumors. Materials and Methods: A total of 46 patients with brain tumors treated with radiotherapy alone or combined with surgery were enrolled. These patients were divided into two groups: The experimental group with adjusted-Da-Chai-Ling-Tang and the control group with conventional medical treatment. Clinical data including symptoms and serologic results were collected pretreatment and on the 4 th , 7 th and 10 th day posttreatment. Magnetic resonance imaging of the brain was performed to investigate changes in brain edema. Results: Clinical symptoms including headache, dizziness, nausea/vomiting and fatigue significantly improved in the experimental group (P < 0.05. No difference in serological results was observed. Brain edema was significantly reduced in the experimental group in magnetic resonance imaging (P < 0.05. Conclusion: Adjusted-Da-Chai-Ling-Tang is effective in the treatment of radiation-induced brain edema in patients with brain tumors. No obvious side effects were observed.

  14. Induced synthesis of oestrogens by glia in the songbird brain.

    Science.gov (United States)

    Saldanha, C J; Burstein, S R; Duncan, K A

    2013-11-01

    Studies on birds have long provided landmarks and touchstones in the fields of neuroendocrinology, immunology and neuroplasticity. The passerine brain is an excellent model for studying the actions of hormones, including steroids, on a diversity of behavioural endpoints. Oestrogens, for example, have profound effects on avian neuroanatomy and neurophysiology throughout life and, importantly, are synthesised at high levels within neurones of the songbird brain. More recently, aromatisation in another set of neural cells has been identified. Specifically, aromatase expression is induced in astrocytes and radial glia following disruption of the neuropil by multiple forms of perturbation. The avian brain, therefore, can be provided with high levels of oestrogens constitutively or via induction, by aromatisation in neurones and glia, respectively. In this review, we begin with the initial discovery of aromatisation by non-neuronal cells and discuss the mechanisms underlying the induction of aromatase expression in glial cells. We then focus on the emerging interactions between the neuroendocrine and neuroimmune systems with respect to brain injury. Next, we briefly review the extensive literature on the influence of glial aromatisation on neuroplasticity, and end with some recent data on sex differences in the induction of glial aromatase in the zebra finch. Throughout this review, we consider the unanswered questions and future studies that may emerge from these findings. © 2013 British Society for Neuroendocrinology.

  15. Correlates of birth asphyxia using two Apgar score classification methods.

    Science.gov (United States)

    Olusanya, Bolajoko O; Solanke, Olumuyiwa A

    2010-01-01

    Birth asphyxia is commonly indexed by low five-minute Apgar scores especially in resource-constrained settings but the impact of different classification thresholds on the associated risk factors has not been reported. To determine the potential impact of two classification methods of five-minute Apgar score as predictor for birth asphyxia. A cross-sectional study of preterm and term survivors in Lagos, Nigeria in which antepartum and intrapartum factors associated with "very low" (0-3) or "intermediate" (4-6) five-minute Apgar scores were compared with correlates of low five-minute Apgar scores (0-6) based on multinomial and binary logistic regression analyses. Of the 4281 mother-infant pairs enrolled, 3377 (78.9%) were full-term and 904 (21.1%) preterm. Apgar scores were very low in 99 (2.3%) and intermediate in 1115 (26.0%). Antenatal care, premature rupture of membranes (PROM), hypertensive disorders and mode of delivery were associated with very low and intermediate Apgar scores in all infants. Additionally, parity, antepartum haemorrhage and prolonged/obstructed labour (PROL) were predictive in term infants compared with maternal occupation and intrauterine growth restriction (IUGR) in preterm infants. Conversely, PROM in term infants and maternal occupation in preterm infants were not significantly associated with the composite low Apgar scores (0-6) while IUGR was associated with term infants. Predictors of birth asphyxia in preterm and term infants are likely to be affected by the Apgar score classification method adopted and the clinical implications for optimal resuscitation practices merit attention in resource-constrained settings.

  16. LSD-induced entropic brain activity predicts subsequent personality change.

    Science.gov (United States)

    Lebedev, A V; Kaelen, M; Lövdén, M; Nilsson, J; Feilding, A; Nutt, D J; Carhart-Harris, R L

    2016-09-01

    Personality is known to be relatively stable throughout adulthood. Nevertheless, it has been shown that major life events with high personal significance, including experiences engendered by psychedelic drugs, can have an enduring impact on some core facets of personality. In the present, balanced-order, placebo-controlled study, we investigated biological predictors of post-lysergic acid diethylamide (LSD) changes in personality. Nineteen healthy adults underwent resting state functional MRI scans under LSD (75µg, I.V.) and placebo (saline I.V.). The Revised NEO Personality Inventory (NEO-PI-R) was completed at screening and 2 weeks after LSD/placebo. Scanning sessions consisted of three 7.5-min eyes-closed resting-state scans, one of which involved music listening. A standardized preprocessing pipeline was used to extract measures of sample entropy, which characterizes the predictability of an fMRI time-series. Mixed-effects models were used to evaluate drug-induced shifts in brain entropy and their relationship with the observed increases in the personality trait openness at the 2-week follow-up. Overall, LSD had a pronounced global effect on brain entropy, increasing it in both sensory and hierarchically higher networks across multiple time scales. These shifts predicted enduring increases in trait openness. Moreover, the predictive power of the entropy increases was greatest for the music-listening scans and when "ego-dissolution" was reported during the acute experience. These results shed new light on how LSD-induced shifts in brain dynamics and concomitant subjective experience can be predictive of lasting changes in personality. Hum Brain Mapp 37:3203-3213, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  17. Neuroprotection by Caffeine in Hyperoxia-Induced Neonatal Brain Injury.

    Science.gov (United States)

    Endesfelder, Stefanie; Weichelt, Ulrike; Strauß, Evelyn; Schlör, Anja; Sifringer, Marco; Scheuer, Till; Bührer, Christoph; Schmitz, Thomas

    2017-01-18

    Sequelae of prematurity triggered by oxidative stress and free radical-mediated tissue damage have coined the term "oxygen radical disease of prematurity". Caffeine, a potent free radical scavenger and adenosine receptor antagonist, reduces rates of brain damage in preterm infants. In the present study, we investigated the effects of caffeine on oxidative stress markers, anti-oxidative response, inflammation, redox-sensitive transcription factors, apoptosis, and extracellular matrix following the induction of hyperoxia in neonatal rats. The brain of a rat pups at postnatal Day 6 (P6) corresponds to that of a human fetal brain at 28-32 weeks gestation and the neonatal rat is an ideal model in which to investigate effects of oxidative stress and neuroprotection of caffeine on the developing brain. Six-day-old Wistar rats were pre-treated with caffeine and exposed to 80% oxygen for 24 and 48 h. Caffeine reduced oxidative stress marker (heme oxygenase-1, lipid peroxidation, hydrogen peroxide, and glutamate-cysteine ligase catalytic subunit (GCLC)), promoted anti-oxidative response (superoxide dismutase, peroxiredoxin 1, and sulfiredoxin 1), down-regulated pro-inflammatory cytokines, modulated redox-sensitive transcription factor expression (Nrf2/Keap1, and NFκB), reduced pro-apoptotic effectors (poly (ADP-ribose) polymerase-1 (PARP-1), apoptosis inducing factor (AIF), and caspase-3), and diminished extracellular matrix degeneration (matrix metalloproteinases (MMP) 2, and inhibitor of metalloproteinase (TIMP) 1/2). Our study affirms that caffeine is a pleiotropic neuroprotective drug in the developing brain due to its anti-oxidant, anti-inflammatory, and anti-apoptotic properties.

  18. Peripheral nerve injury induces adult brain neurogenesis and remodelling.

    Science.gov (United States)

    Rusanescu, Gabriel; Mao, Jianren

    2017-02-01

    Unilateral peripheral nerve chronic constriction injury (CCI) has been widely used as a research model of human neuropathic pain. Recently, CCI has been shown to induce spinal cord adult neurogenesis, which may contribute to the chronic increase in nociceptive sensitivity. Here, we show that CCI also induces rapid and profound asymmetrical anatomical rearrangements in the adult rodent cerebellum and pons. This remodelling occurs throughout the hindbrain, and in addition to regions involved in pain processing, also affects other sensory modalities. We demonstrate that these anatomical changes, partially reversible in the long term, result from adult neurogenesis. Neurogenic markers Mash1, Ngn2, doublecortin and Notch3 are widely expressed in the rodent cerebellum and pons, both under normal and injured conditions. CCI-induced hindbrain structural plasticity is absent in Notch3 knockout mice, a strain with impaired neuronal differentiation, demonstrating its dependence on adult neurogenesis. Grey matter and white matter structural changes in human brain, as a result of pain, injury or learned behaviours have been previously detected using non-invasive neuroimaging techniques. Because neurogenesis-mediated structural plasticity is thought to be restricted to the hippocampus and the subventricular zone, such anatomical rearrangements in other parts of the brain have been thought to result from neuronal plasticity or glial hypertrophy. Our findings suggest the presence of extensive neurogenesis-based structural plasticity in the adult mammalian brain, which may maintain a memory of basal sensory levels, and act as an adaptive mechanism to changes in sensory inputs. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  19. Combined therapy of iron chelator and antioxidant completely restores brain dysfunction induced by iron toxicity

    National Research Council Canada - National Science Library

    Sripetchwandee, Jirapas; Pipatpiboon, Noppamas; Chattipakorn, Nipon; Chattipakorn, Siriporn

    2014-01-01

    .... We investigated the effects of iron overload induced by high iron-diet consumption on brain mitochondrial function, brain synaptic plasticity and learning and memory. Iron chelator (deferiprone) and antioxidant (n-acetyl cysteine...

  20. Impact of Low-Level Thyroid Hormone Disruption Induced by Propylthiouracil on Brain Development and Function.*

    Science.gov (United States)

    The critical role of thyroid hormone (TH) in brain development is well established, severe deficiencies leading to significant neurological dysfunction. Much less information is available on more modest perturbations of TH on brain function. The present study induced varying degr...

  1. Virtopsy versus autopsy in unusual case of asphyxia: case report.

    Science.gov (United States)

    Aquila, I; Falcone, C; Di Nunzio, C; Tamburrini, O; Boca, S; Ricci, P

    2013-06-10

    We report the case of a 70-year-old woman found dead in her apartment in the South of Italy in February 2011. The detailed data showed that the victim was affected by familiar-type paranoid schizophrenia. This finding was confirmed by the discovery of antipsychotic and tricyclic antidepressant drugs in the house and the deposition of her psychiatric therapist. Before the autopsy, a multislice computed tomography (MSCT) scanning of the thoracic and facial maxillo-cervical area was performed that has allowed anatomical identification and diagnosis of a mechanical obstruction as the cause of death. The autopsy has showed the presence of materials obstructing the trachea totally. Histological and toxicological investigations were carried out on the victim. The toxicological investigation has shown the presence of metabolites of tricyclic antidepressants and antipsychotics in the blood and urine. The histology showed the presence of foreign-origin materials (starch fibres) inside the pulmonary alveolus. The cause of death was asphyxia due to obstruction by food-origin material. In this case the radiological data have been compared with the autopsy and toxicological and histological data. The comparison of results has shown that MSCT scanning may aid in identification of occlusion and then in determination of the cause of death. In conclusion, MSCT scanning can be proposed in the cases of suspected asphyxia, as the screening procedure of first instance to produce preliminary information useful to rapidly develop the successive autopsy performance. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  2. Perinatal asphyxia and medical professional liability: A case series

    Directory of Open Access Journals (Sweden)

    Andrea Verzeletti

    2016-12-01

    Full Text Available In the context of medical professional liability, obstetrics is one of the most involved medical specialties because the unfavorable outcome of a pregnancy is difficult to accept for parents, who tend to reduce it to inappropriate care that occurred during pregnancy or birth. 32 cases of perinatal asphyxia were evaluated by the Institute of Forensic Medicine in Brescia during the period between 1999 and 2014 (13 in Civil Court and 19 in Penal Court. 9 out of the 32 pregnancies were twins, so the considerations were carried out on a total of 41 fetuses/newborns. Profiles of inadequacy were identified in 66% of cases (85% of the cases evaluated in Civil Court; 53% of the cases evaluated in Penal Court. The existence of a causal relationship between the medical conduct and the onset of asphyxia was recognized in 79% of civil cases and in 38% of penal cases. There is a “greater rigor” in the verification of causal relationship and malpractice profiles in penal cases compared to civil ones: this is in harmony with the most recent Italian Court decisions, characterized by compelling suspect’s protection in the presence of a reasonable doubt in criminal matters and by victim’s protection in civil ones.

  3. Traumatic asphyxia following stadium crowd surge: stadium factors affecting outcome.

    Science.gov (United States)

    DeAngeles, D; Schurr, M; Birnbaum, M; Harms, B

    1998-10-01

    Stadium crowd surges frequently occur following major athletic events. A recent crowd surge injured more than 80 persons by trampling and/or crushing. This incident was reviewed to identify injury patterns consistent with crush-related injury. In addition, the incident was reviewed to determine which stadium policy and design factors may have potentiated this event. A recent crowd surge occurred following a college football game. This resulted in 86 people being transported to the University of Wisconsin and other area hospitals. All charts were reviewed to evaluate patient outcomes. The stadium was examined as were security system video tapes to evaluate stadium factors that contributed to this event. Current policies were obtained through the university sports administration. Of 86 patients transported for evaluation of stadium-related injuries, 10 were treated for traumatic asphyxia. Other injuries requiring hospital admission included musculo-skeletal trauma in two patients and one grade II liver injury. Six others were admitted overnight for observation. Several stadium factors were identified that contributed to the event, and appropriate changes in crowd control policies and stadium design were instated to prevent recurrence. This report details the largest single report of traumatic asphyxia second to the England Hillsborough disaster. Several stadium factors were identified that resulted in crush-related injury. Cooperative review and modification of stadium policies and design may prevent such events in the future.

  4. Structural brain plasticity in Parkinson's disease induced by balance training.

    Science.gov (United States)

    Sehm, Bernhard; Taubert, Marco; Conde, Virginia; Weise, David; Classen, Joseph; Dukart, Juergen; Draganski, Bogdan; Villringer, Arno; Ragert, Patrick

    2014-01-01

    We investigated morphometric brain changes in patients with Parkinson's disease (PD) that are associated with balance training. A total of 20 patients and 16 healthy matched controls learned a balance task over a period of 6 weeks. Balance testing and structural magnetic resonance imaging were performed before and after 2, 4, and 6 training weeks. Balance performance was re-evaluated after ∼20 months. Balance training resulted in performance improvements in both groups. Voxel-based morphometry revealed learning-dependent gray matter changes in the left hippocampus in healthy controls. In PD patients, performance improvements were correlated with gray matter changes in the right anterior precuneus, left inferior parietal cortex, left ventral premotor cortex, bilateral anterior cingulate cortex, and left middle temporal gyrus. Furthermore, a TIME × GROUP interaction analysis revealed time-dependent gray matter changes in the right cerebellum. Our results highlight training-induced balance improvements in PD patients that may be associated with specific patterns of structural brain plasticity. In summary, we provide novel evidence for the capacity of the human brain to undergo learning-related structural plasticity even in a pathophysiological disease state such as in PD. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Regeneration, Plasticity, and Induced Molecular Programs in Adult Zebrafish Brain

    Directory of Open Access Journals (Sweden)

    Mehmet Ilyas Cosacak

    2015-01-01

    Full Text Available Regenerative capacity of the brain is a variable trait within animals. Aquatic vertebrates such as zebrafish have widespread ability to renew their brains upon damage, while mammals have—if not none—very limited overall regenerative competence. Underlying cause of such a disparity is not fully evident; however, one of the reasons could be activation of peculiar molecular programs, which might have specific roles after injury or damage, by the organisms that regenerate. If this hypothesis is correct, then there must be genes and pathways that (a are expressed only after injury or damage in tissues, (b are biologically and functionally relevant to restoration of neural tissue, and (c are not detected in regenerating organisms. Presence of such programs might circumvent the initial detrimental effects of the damage and subsequently set up the stage for tissue redevelopment to take place by modulating the plasticity of the neural stem/progenitor cells. Additionally, if transferable, those “molecular mechanisms of regeneration” could open up new avenues for regenerative therapies of humans in clinical settings. This review focuses on the recent studies addressing injury/damage-induced molecular programs in zebrafish brain, underscoring the possibility of the presence of genes that could be used as biomarkers of neural plasticity and regeneration.

  6. Food-induced brain responses and eating behaviour.

    Science.gov (United States)

    Smeets, Paul A M; Charbonnier, Lisette; van Meer, Floor; van der Laan, Laura N; Spetter, Maartje S

    2012-11-01

    The brain governs food intake behaviour by integrating many different internal and external state and trait-related signals. Understanding how the decisions to start and to stop eating are made is crucial to our understanding of (maladaptive patterns of) eating behaviour. Here, we aim to (1) review the current state of the field of 'nutritional neuroscience' with a focus on the interplay between food-induced brain responses and eating behaviour and (2) highlight research needs and techniques that could be used to address these. The brain responses associated with sensory stimulation (sight, olfaction and taste), gastric distension, gut hormone administration and food consumption are the subject of increasing investigation. Nevertheless, only few studies have examined relations between brain responses and eating behaviour. However, the neural circuits underlying eating behaviour are to a large extent generic, including reward, self-control, learning and decision-making circuitry. These limbic and prefrontal circuits interact with the hypothalamus, a key homeostatic area. Target areas for further elucidating the regulation of food intake are: (eating) habit and food preference formation and modification, the neural correlates of self-control, nutrient sensing and dietary learning, and the regulation of body adiposity. Moreover, to foster significant progress, data from multiple studies need to be integrated. This requires standardisation of (neuroimaging) measures, data sharing and the application and development of existing advanced analysis and modelling techniques to nutritional neuroscience data. In the next 20 years, nutritional neuroscience will have to prove its potential for providing insights that can be used to tackle detrimental eating behaviour.

  7. Inducible gene manipulations in brain serotonergic neurons of transgenic rats.

    Directory of Open Access Journals (Sweden)

    Tillmann Weber

    Full Text Available The serotonergic (5-HT system has been implicated in various physiological processes and neuropsychiatric disorders, but in many aspects its role in normal and pathologic brain function is still unclear. One reason for this might be the lack of appropriate animal models which can address the complexity of physiological and pathophysiological 5-HT functioning. In this respect, rats offer many advantages over mice as they have been the animal of choice for sophisticated neurophysiological and behavioral studies. However, only recently technologies for the targeted and tissue specific modification of rat genes - a prerequisite for a detailed study of the 5-HT system - have been successfully developed. Here, we describe a rat transgenic system for inducible gene manipulations in 5-HT neurons. We generated a Cre driver line consisting of a tamoxifen-inducible CreERT2 recombinase under the control of mouse Tph2 regulatory sequences. Tissue-specific serotonergic Cre recombinase expression was detected in four transgenic TPH2-CreERT2 rat founder lines. For functional analysis of Cre-mediated recombination, we used a rat Cre reporter line (CAG-loxP.EGFP, in which EGFP is expressed after Cre-mediated removal of a loxP-flanked lacZ STOP cassette. We show an in-depth characterisation of this rat Cre reporter line and demonstrate its applicability for monitoring Cre-mediated recombination in all major neuronal subpopulations of the rat brain. Upon tamoxifen induction, double transgenic TPH2-CreERT2/CAG-loxP.EGFP rats show selective and efficient EGFP expression in 5-HT neurons. Without tamoxifen administration, EGFP is only expressed in few 5-HT neurons which confirms minimal background recombination. This 5-HT neuron specific CreERT2 line allows Cre-mediated, inducible gene deletion or gene overexpression in transgenic rats which provides new opportunities to decipher the complex functions of the mammalian serotonergic system.

  8. Early neonatal deaths associated with perinatal asphyxia in infants ≥2500g in Brazil.

    Science.gov (United States)

    Almeida, Maria Fernanda Branco de; Kawakami, Mandira Daripa; Moreira, Lícia Maria Oliveira; Santos, Rosa Maria Vaz Dos; Anchieta, Lêni Márcia; Guinsburg, Ruth

    To assess the annual burden of early neonatal deaths associated with perinatal asphyxia in infants weighing ≥2500g in Brazil from 2005 to 2010. The population study enrolled all live births of infants with birth weight ≥2500g and without malformations who died up to six days after birth with perinatal asphyxia, defined as intrauterine hypoxia, asphyxia at birth, or meconium aspiration syndrome. The cause of death was written in any field of the death certificate, according to International Classification of Diseases, 10th Revision (P20.0, P21.0, and P24.0). An active search was performed in 27 Brazilian federative units. The chi-squared test for trend was applied to analyze early neonatal mortality ratios associated with perinatal asphyxia by study year. A total of 10,675 infants weighing ≥2500g without malformations died within six days after birth with perinatal asphyxia. Deaths occurred in the first 24h after birth in 71% of the infants. Meconium aspiration syndrome was reported in 4076 (38%) of these deaths. The asphyxia-specific early neonatal mortality ratio decreased from 0.81 in 2005 to 0.65 per 1000 live births in 2010 in Brazil (pperinatal asphyxia in infants in the better spectrum of birth weight and without congenital malformations are still high, and meconium aspiration syndrome plays a major role. Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  9. [Intrapartum asphyxia: Risk factors and short-term consequences].

    Science.gov (United States)

    Bouiller, J-P; Dreyfus, M; Mortamet, G; Guillois, B; Benoist, G

    2016-06-01

    Intrapartum asphyxia is a rare yet serious complication during labor with immediate consequences and possible long-term neurological impairment. The international Cerebral Palsy Task Force established criteria that attribute a cerebral palsy to intrapartum asphyxia: metabolic acidemia measured at birth with pHconsequences. Our retrospective study included all births between 2002 and 2010 in a level 3 maternity of a university hospital center. Inclusion criteria were those of the Cerebral Palsy Task Force associated with a gestational age≥34weeks of gestation. We studied the conventional markers of intrapartum asphyxia: Apgar score at 5minutes, abnormal cardiotogographic recordings whether they occurred after a sentinel hypoxic event or not before and during labor. The duration of expulsive efforts, the amniotic fluid aspects, the delivery mode as well as the preexisting pregnancy pathologies were also evaluated. On the other hand, we studied the short-term consequences at the newborns: death, multiorgan failure and especially the occurring of a neonatal encephalopathy using Sarnat and Sarnat staging. One hundred and twenty-nine newborns (0.43%) out of 29,416 live births had a pHpregnancy pathology was found in 22% of the women. Hypoxic events were noted in only 9/82 of the cases. Abnormal cardiotocographic recordings were present in 97.6% of the cases. The duration of expulsive efforts as well as the amniotic fluid aspects did not interfere with the occurring of a metabolic acidemia. Caesarean rate was at 46.3% and instrumental extraction rate was at 34.1%. Thity-eight newborns (46.3%) were admitted in neonatal intensive care in which we noted 3 deaths (3.65%), 2 multiorgan failures (2.4%) and 17 neonatal encephalopathy (20.7%). The pH value seemed to influence the occurring of an encephalopathy: 50% when pH6 (Pearly neonatal encephalopathy. This study should be continued with the evaluation of hypoxia long-term consequences on the psychomotor development

  10. A Rare and Serious Syndrome That Requires Attention in Emergency Service: Traumatic Asphyxia

    Directory of Open Access Journals (Sweden)

    Gultekin Gulbahar

    2015-01-01

    Full Text Available Traumatic asphyxia is a rare syndrome caused by blunt thoracoabdominal trauma and characterized by cyanosis, edema, and subconjunctival and petechial hemorrhage on the face, neck, upper extremities, and the upper parts of the thorax. Traumatic asphyxia is usually diagnosed by history and inspection; however, the patient should be monitored more closely due to probable complications of thoracoabdominal injuries. Treatment is conservative, but the prognosis depends on the severity of the associated injuries. Herein we present a traumatic asphyxia due to an elevator accident in a 32-year-old male patient and discuss the diagnosis, treatment, and prognosis by reviewing the relevant literature.

  11. Role of neuroinflammation in hypertension-induced brain amyloid pathology.

    Science.gov (United States)

    Carnevale, Daniela; Mascio, Giada; Ajmone-Cat, Maria Antonietta; D'Andrea, Ivana; Cifelli, Giuseppe; Madonna, Michele; Cocozza, Germana; Frati, Alessandro; Carullo, Pierluigi; Carnevale, Lorenzo; Alleva, Enrico; Branchi, Igor; Lembo, Giuseppe; Minghetti, Luisa

    2012-01-01

    Hypertension and sporadic Alzheimer's disease (AD) have been associated but clear pathophysiological links have not yet been demonstrated. Hypertension and AD share inflammation as a pathophysiological trait. Thus, we explored if modulating neuroinflammation could influence hypertension-induced β-amyloid (Aβ) deposition. Possible interactions among hypertension, inflammation and Aβ-deposition were studied in hypertensive mice with transverse aortic coarctation (TAC). Given that brain Aβ deposits are detectable as early as 4 weeks after TAC, brain pathology was analyzed in 3-week TAC mice, before Aβ deposition, and at a later time (8-week TAC mice). Microglial activation and interleukin (IL)-1β upregulation were already found in 3-week TAC mice. At a later time, along with evident Aβ deposition, microglia was still activated. Finally, immune system stimulation (LPS) or inhibition (ibuprofen), strategies described to positively or negatively modulate neuroinflammation, differently affected Aβ deposition. We demonstrate that hypertension per se triggers neuroinflammation before Aβ deposition. The finding that only immune system activation, but not its inhibition, strongly reduced amyloid burden suggests that stimulating inflammation in the appropriate time window may represent a promising strategy to limit vascular-triggered AD-pathology. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Lithium suppression of tau induces brain iron accumulation and neurodegeneration.

    Science.gov (United States)

    Lei, P; Ayton, S; Appukuttan, A T; Moon, S; Duce, J A; Volitakis, I; Cherny, R; Wood, S J; Greenough, M; Berger, G; Pantelis, C; McGorry, P; Yung, A; Finkelstein, D I; Bush, A I

    2017-03-01

    Lithium is a first-line therapy for bipolar affective disorder. However, various adverse effects, including a Parkinson-like hand tremor, often limit its use. The understanding of the neurobiological basis of these side effects is still very limited. Nigral iron elevation is also a feature of Parkinsonian degeneration that may be related to soluble tau reduction. We found that magnetic resonance imaging T2 relaxation time changes in subjects commenced on lithium therapy were consistent with iron elevation. In mice, lithium treatment lowers brain tau levels and increases nigral and cortical iron elevation that is closely associated with neurodegeneration, cognitive loss and parkinsonian features. In neuronal cultures lithium attenuates iron efflux by lowering tau protein that traffics amyloid precursor protein to facilitate iron efflux. Thus, tau- and amyloid protein precursor-knockout mice were protected against lithium-induced iron elevation and neurotoxicity. These findings challenge the appropriateness of lithium as a potential treatment for disorders where brain iron is elevated (for example, Alzheimer's disease), and may explain lithium-associated motor symptoms in susceptible patients.

  13. Induced sensorimotor brain plasticity controls pain in phantom limb patients.

    Science.gov (United States)

    Yanagisawa, Takufumi; Fukuma, Ryohei; Seymour, Ben; Hosomi, Koichi; Kishima, Haruhiko; Shimizu, Takeshi; Yokoi, Hiroshi; Hirata, Masayuki; Yoshimine, Toshiki; Kamitani, Yukiyasu; Saitoh, Youichi

    2016-10-27

    The cause of pain in a phantom limb after partial or complete deafferentation is an important problem. A popular but increasingly controversial theory is that it results from maladaptive reorganization of the sensorimotor cortex, suggesting that experimental induction of further reorganization should affect the pain, especially if it results in functional restoration. Here we use a brain-machine interface (BMI) based on real-time magnetoencephalography signals to reconstruct affected hand movements with a robotic hand. BMI training induces significant plasticity in the sensorimotor cortex, manifested as improved discriminability of movement information and enhanced prosthetic control. Contrary to our expectation that functional restoration would reduce pain, the BMI training with the phantom hand intensifies the pain. In contrast, BMI training designed to dissociate the prosthetic and phantom hands actually reduces pain. These results reveal a functional relevance between sensorimotor cortical plasticity and pain, and may provide a novel treatment with BMI neurofeedback.

  14. Xenon and Sevoflurane Provide Analgesia during Labor and Fetal Brain Protection in a Perinatal Rat Model of Hypoxia-Ischemia

    Science.gov (United States)

    Yang, Ting; Zhuang, Lei; Rei Fidalgo, António M.; Petrides, Evgenia; Terrando, Niccolo; Wu, Xinmin; Sanders, Robert D.; Robertson, Nicola J.; Johnson, Mark R.; Maze, Mervyn; Ma, Daqing

    2012-01-01

    It is not possible to identify all pregnancies at risk of neonatal hypoxic-ischemic encephalopathy (HIE). Many women use some form of analgesia during childbirth and some anesthetic agents have been shown to be neuroprotective when used as analgesics at subanesthetic concentrations. In this study we sought to understand the effects of two anesthetic agents with presumptive analgesic activity and known preconditioning-neuroprotective properties (sevoflurane or xenon), in reducing hypoxia-induced brain damage in a model of intrauterine perinatal asphyxia. The analgesic and neuroprotective effects at subanesthetic levels of sevoflurane (0.35%) or xenon (35%) were tested in a rat model of intrauterine perinatal asphyxia. Analgesic effects were measured by assessing maternal behavior and spinal cord dorsal horn neuronal activation using c-Fos. In separate experiments, intrauterine fetal asphyxia was induced four hours after gas exposure; on post-insult day 3 apoptotic cell death was measured by caspase-3 immunostaining in hippocampal neurons and correlated with the number of viable neurons on postnatal day (PND) 7. A separate cohort of pups was nurtured by a surrogate mother for 50 days when cognitive testing with Morris water maze was performed. Both anesthetic agents provided analgesia as reflected by a reduction in the number of stretching movements and decreased c-Fos expression in the dorsal horn of the spinal cord. Both agents also reduced the number of caspase-3 positive (apoptotic) neurons and increased cell viability in the hippocampus at PND7. These acute histological changes were mirrored by improved cognitive function measured remotely after birth on PND 50 compared to control group. Subanesthetic doses of sevoflurane or xenon provided both analgesia and neuroprotection in this model of intrauterine perinatal asphyxia. These data suggest that anesthetic agents with neuroprotective properties may be effective in preventing HIE and should be tested in clinical

  15. Primary blast-induced traumatic brain injury: lessons from lithotripsy

    Science.gov (United States)

    Nakagawa, A.; Ohtani, K.; Armonda, R.; Tomita, H.; Sakuma, A.; Mugikura, S.; Takayama, K.; Kushimoto, S.; Tominaga, T.

    2017-11-01

    Traumatic injury caused by explosive or blast events is traditionally divided into four mechanisms: primary, secondary, tertiary, and quaternary blast injury. The mechanisms of blast-induced traumatic brain injury (bTBI) are biomechanically distinct and can be modeled in both in vivo and in vitro systems. The primary bTBI injury mechanism is associated with the response of brain tissue to the initial blast wave. Among the four mechanisms of bTBI, there is a remarkable lack of information regarding the mechanism of primary bTBI. On the other hand, 30 years of research on the medical application of shock waves (SWs) has given us insight into the mechanisms of tissue and cellular damage in bTBI, including both air-mediated and underwater SW sources. From a basic physics perspective, the typical blast wave consists of a lead SW followed by shock-accelerated flow. The resultant tissue injury includes several features observed in primary bTBI, such as hemorrhage, edema, pseudo-aneurysm formation, vasoconstriction, and induction of apoptosis. These are well-described pathological findings within the SW literature. Acoustic impedance mismatch, penetration of tissue by shock/bubble interaction, geometry of the skull, shear stress, tensile stress, and subsequent cavitation formation are all important factors in determining the extent of SW-induced tissue and cellular injury. In addition, neuropsychiatric aspects of blast events need to be taken into account, as evidenced by reports of comorbidity and of some similar symptoms between physical injury resulting in bTBI and the psychiatric sequelae of post-traumatic stress. Research into blast injury biophysics is important to elucidate specific pathophysiologic mechanisms of blast injury, which enable accurate differential diagnosis, as well as development of effective treatments. Herein we describe the requirements for an adequate experimental setup when investigating blast-induced tissue and cellular injury; review SW physics

  16. Compound mechanism hypothesis on +Gz induced brain injury and dysfunction of learning and memory

    Science.gov (United States)

    Sun, Xi-Qing; Li, Jin-Sheng; Cao, Xin-Sheng; Wu, Xing-Yu

    2005-08-01

    We systematically studied the effect of high- sustained +Gz on the brain and its mechanism in past ten years by animal centrifuge experiments. On the basis of the facts we observed and the more recent advances in acceleration physiology, we put forward a compound mechanism hypothesis to offer a possible explanation for +Gz-induced brain injury and dysfunction of learning and memory. It states that, ischemia during high G exposure might be the main factor accounting for +Gz-induced brain injury and dysfunction of learning and memory, including transient depression of brain energy metabolism, disturbance of ion homeostasis, increased blood-brain barrier permeability, increased brain nitric oxide synthase expression, and the protective effect of heat shock protein 70. In addition, the large rapid change of intracranial pressure and increased stress during +Gz exposure, and the hemorrheologic change after +Gz exposure might be one of the important factors accounting for +Gz-induced brain injury and dysfunction of learning and memory.

  17. Mechanisms of blast induced brain injuries, experimental studies in rats.

    Science.gov (United States)

    Risling, M; Plantman, S; Angeria, M; Rostami, E; Bellander, B-M; Kirkegaard, M; Arborelius, U; Davidsson, J

    2011-01-01

    Traumatic brain injuries (TBI) potentially induced by blast waves from detonations result in significant diagnostic problems. It may be assumed that several mechanisms contribute to the injury. This study is an attempt to characterize the presumed components of the blast induced TBI. Our experimental models include a blast tube in which an anesthetized rat can be exposed to controlled detonations of explosives that result in a pressure wave with a magnitude between 130 and 260 kPa. In this model, the animal is fixed with a metal net to avoid head acceleration forces. The second model is a controlled penetration of a 2mm thick needle. In the third model the animal is subjected to a high-speed sagittal rotation angular acceleration. Immunohistochemical labeling for amyloid precursor protein revealed signs of diffuse axonal injury (DAI) in the penetration and rotation models. Signs of punctuate inflammation were observed after focal and rotation injury. Exposure in the blast tube did not induce DAI or detectable cell death, but functional changes. Affymetrix Gene arrays showed changes in the expression in a large number of gene families including cell death, inflammation and neurotransmitters in the hippocampus after both acceleration and penetration injuries. Exposure to the primary blast wave induced limited shifts in gene expression in the hippocampus. The most interesting findings were a downregulation of genes involved in neurogenesis and synaptic transmission. These experiments indicate that rotational acceleration may be a critical factor for DAI and other acute changes after blast TBI. The further exploration of the mechanisms of blast TBI will have to include a search for long-term effects. Copyright © 2010 Elsevier Inc. All rights reserved.

  18. Surge of Peripheral Arginine Vasopressin in a Rat Model of Birth Asphyxia

    Science.gov (United States)

    Summanen, Milla; Bäck, Susanne; Voipio, Juha; Kaila, Kai

    2018-01-01

    Mammalian birth is accompanied by a period of obligatory asphyxia, which consists of hypoxia (drop in blood O2 levels) and hypercapnia (elevation of blood CO2 levels). Prolonged, complicated birth can extend the asphyxic period, leading to a pathophysiological situation, and in humans, to the diagnosis of clinical birth asphyxia, the main cause of hypoxic-ischemic encephalopathy (HIE). The neuroendocrine component of birth asphyxia, in particular the increase in circulating levels of arginine vasopressin (AVP), has been extensively studied in humans. Here we show for the first time that normal rat birth is also accompanied by an AVP surge, and that the fetal AVP surge is further enhanced in a model of birth asphyxia, based on exposing 6-day old rat pups to a gas mixture containing 4% O2 and 20% CO2 for 45 min. Instead of AVP, which is highly unstable with a short plasma half-life, we measured the levels of copeptin, the C-terminal part of prepro-AVP that is biochemically much more stable. In our animal model, the bulk of AVP/copeptin release occurred at the beginning of asphyxia (mean 7.8 nM after 15 min of asphyxia), but some release was still ongoing even 90 min after the end of the 45 min experimental asphyxia (mean 1.2 nM). Notably, the highest copeptin levels were measured after hypoxia alone (mean 14.1 nM at 45 min), whereas copeptin levels were low during hypercapnia alone (mean 2.7 nM at 45 min), indicating that the hypoxia component of asphyxia is responsible for the increase in AVP/copeptin release. Alternating the O2 level between 5 and 9% (CO2 at 20%) with 5 min intervals to mimic intermittent asphyxia during prolonged labor resulted in a slower but quantitatively similar rise in copeptin (peak of 8.3 nM at 30 min). Finally, we demonstrate that our rat model satisfies the standard acid-base criteria for birth asphyxia diagnosis, namely a drop in blood pH below 7.0 and the formation of a negative base excess exceeding −11.2 mmol/l. The mechanistic

  19. Surge of Peripheral Arginine Vasopressin in a Rat Model of Birth Asphyxia

    Directory of Open Access Journals (Sweden)

    Milla Summanen

    2018-01-01

    Full Text Available Mammalian birth is accompanied by a period of obligatory asphyxia, which consists of hypoxia (drop in blood O2 levels and hypercapnia (elevation of blood CO2 levels. Prolonged, complicated birth can extend the asphyxic period, leading to a pathophysiological situation, and in humans, to the diagnosis of clinical birth asphyxia, the main cause of hypoxic-ischemic encephalopathy (HIE. The neuroendocrine component of birth asphyxia, in particular the increase in circulating levels of arginine vasopressin (AVP, has been extensively studied in humans. Here we show for the first time that normal rat birth is also accompanied by an AVP surge, and that the fetal AVP surge is further enhanced in a model of birth asphyxia, based on exposing 6-day old rat pups to a gas mixture containing 4% O2 and 20% CO2 for 45 min. Instead of AVP, which is highly unstable with a short plasma half-life, we measured the levels of copeptin, the C-terminal part of prepro-AVP that is biochemically much more stable. In our animal model, the bulk of AVP/copeptin release occurred at the beginning of asphyxia (mean 7.8 nM after 15 min of asphyxia, but some release was still ongoing even 90 min after the end of the 45 min experimental asphyxia (mean 1.2 nM. Notably, the highest copeptin levels were measured after hypoxia alone (mean 14.1 nM at 45 min, whereas copeptin levels were low during hypercapnia alone (mean 2.7 nM at 45 min, indicating that the hypoxia component of asphyxia is responsible for the increase in AVP/copeptin release. Alternating the O2 level between 5 and 9% (CO2 at 20% with 5 min intervals to mimic intermittent asphyxia during prolonged labor resulted in a slower but quantitatively similar rise in copeptin (peak of 8.3 nM at 30 min. Finally, we demonstrate that our rat model satisfies the standard acid-base criteria for birth asphyxia diagnosis, namely a drop in blood pH below 7.0 and the formation of a negative base excess exceeding −11.2 mmol/l. The

  20. Effects of chronic intermittent asphyxia on haematocrit, pulmonary arterial pressure and skeletal muscle structure in rats.

    Science.gov (United States)

    Bradford, Aidan

    2004-01-01

    Sleep-disordered breathing in humans is a common condition associated with serious cardiovascular and other abnormalities. The prevalence and pathogenesis of increased haematocrit and pulmonary hypertension is controversial and it has been suggested that these changes only occur in patients who also have daytime continuous hypoxaemia. The hypothesis tested here is that the chronic intermittent hypoxia and asphyxia associated with sleep-disordered breathing causes erythropoiesis and pulmonary hypertension and that this occurs in the absence of periods of continuous hypoxia. In humans and animals with obstructive sleep apnoea, there are abnormalities of upper airway muscle structure that have been ascribed to increased load placed on these muscles. An alternative hypothesis is that chronic intermittent hypoxia and asphyxia cause changes in upper airway muscle structure and function. To test these hypotheses, rats were exposed to intermittent hypoxia and asphyxia for 8 h per day for 5 weeks. This caused an increase in haematocrit, right ventricular weight and pulmonary arterial pressure. There were only slight changes in diaphragm, upper airway and limb muscle structure and force production but in general, muscle fatigability was increased. In conclusion chronic intermittent hypoxia and asphyxia cause an increase in haematocrit and pulmonary arterial pressure in the absence of periods of continuous hypoxia. Chronic intermittent hypoxia and asphyxia have little effect on skeletal muscle structure and force production but increase muscle fatigue. Increased upper airway muscle fatigue could lead to a vicious cycle of further compromise in upper airway patency and further hypoxia and asphyxia.

  1. Brain death induces renal expression of heme oxygenase-1 and heat shock protein 70

    Directory of Open Access Journals (Sweden)

    van Dullemen Leon FA

    2013-01-01

    Full Text Available Abstract Background Kidneys derived from brain dead donors have lower graft survival and higher graft-function loss compared to their living donor counterpart. Heat Shock Proteins (HSP are a large family of stress proteins involved in maintaining cell homeostasis. We studied the role of stress-inducible genes Heme Oxygenase-1 (HO-1, HSP27, HSP40, and HSP70 in the kidney following a 4 hour period of brain death. Methods Brain death was induced in rats (n=6 by inflating a balloon catheter in the epidural space. Kidneys were analysed for HSPs using RT-PCR, Western blotting, and immunohistochemistry. Results RT-PCR data showed a significant increase in gene expression for HO-1 and HSP70 in kidneys of brain dead rats. Western blotting revealed a massive increase in HO-1 protein in brain dead rat kidneys. Immunohistochemistry confirmed these findings, showing extensive HO-1 protein expression in the renal cortical tubules of brain dead rats. HSP70 protein was predominantly increased in renal distal tubules of brain dead rats treated for hypotension. Conclusion Renal stress caused by brain death induces expression of the cytoprotective genes HO-1 and HSP70, but not of HSP27 and HSP40. The upregulation of these cytoprotective genes indicate that renal damage occurs during brain death, and could be part of a protective or recuperative mechanism induced by brain death-associated stress.

  2. Inflammation‐induced sensitization of the brain in term infants

    National Research Council Canada - National Science Library

    Fleiss, Bobbi; Tann, Cally J; Degos, Vincent; Sigaut, Stéphanie; Van Steenwinckel, Juliette; Schang, Anne‐Laure; Kichev, Anton; Robertson, Nicola J; Mallard, Carina; Hagberg, Henrik; Gressens, Pierre

    2015-01-01

    ...), and seizure disorders. The events leading to perinatal brain injury are multifactorial. This review describes how one subinjurious factor affecting the brain sensitizes it to a second injurious factor, causing an exacerbated injurious cascade...

  3. Measuring and Inducing Brain Plasticity in Chronic Aphasia

    Science.gov (United States)

    Fridriksson, Julius

    2011-01-01

    Brain plasticity associated with anomia recovery in aphasia is poorly understood. Here, I review four recent studies from my lab that focused on brain modulation associated with long-term anomia outcome, its behavioral treatment, and the use of transcranial brain stimulation to enhance anomia treatment success in individuals with chronic aphasia…

  4. [Birth asphyxia and hypoxic ischemic encephalopathy, incidence and obstetric risk factors].

    Science.gov (United States)

    Palsdottir, Kolbrun; Dagbjartsson, Atli; Thorkelsson, Thordur; Hardardottir, Hildur

    2007-09-01

    Modern medical practice has changed dramatically during the past decades because of improved technology. Still, fetal surveillance during labor is relatively unchanged since 1960 s when fetal heart rate monitoring (FHR) became standard practice. Newborn infants are still suffering from birth asphyxia and in severe cases leading to hypoxic ischemic encephalopathy (HIE) which sometimes results in permanent neurological damage. The incidence of birth asphyxia and HIE in Iceland is unknown and so are the risk factors for severe asphyxia. The objective of this study was to assess the incidence, obstetric risk factors and the sequela of severe asphyxia at Landspitali university hospital (LSH). All term infants born at LSH from 1.1.1997- 31.12.2001 with birth asphyxia, defined as five minute Apgar score %lt;6, were included in the study (n=127). Clinical information were collected retrospectively from maternal records on maternal diseases during pregnancy, cardiotocogram (CTG), type of birth, the presence of meconium and operative delivery rates. Information was also collected regarding birth asphyxia and HIE in the neonatal period. The incidence of birth asphyxia was 9.4/1000 live term births during the study period, with increasing incidence during the three last years. The incidence of HIE was 1.4/ 1,000 live term births. Severe maternal diseases during pregnancy were not a significant risk factor for asphyxia. The amniotic fluid was meconium stained in fifty percent of cases and the umbilical cord was wrapped around the fetal neck in 41% of cases. Abnormal CTG tracing was observed in 66% of cases in the study group and in 79% of the HIE cases. Operative deliveries were significantly more common in the study cohort compared with other deliveries at LSH at the same time: ventouse delivery 22% vs 6.8% (pdiseases does not correlate with increased incidence of asphyxia, presumably due to increased surveillance of these pregnancies and a lower treshold for intervention

  5. Rapid treatment-induced brain changes in pediatric CRPS.

    Science.gov (United States)

    Erpelding, Nathalie; Simons, Laura; Lebel, Alyssa; Serrano, Paul; Pielech, Melissa; Prabhu, Sanjay; Becerra, Lino; Borsook, David

    2016-03-01

    To date, brain structure and function changes in children with complex regional pain syndrome (CRPS) as a result of disease and treatment remain unknown. Here, we investigated (a) gray matter (GM) differences between patients with CRPS and healthy controls and (b) GM and functional connectivity (FC) changes in patients following intensive interdisciplinary psychophysical pain treatment. Twenty-three patients (13 females, 9 males; average age ± SD = 13.3 ± 2.5 years) and 21 healthy sex- and age-matched controls underwent magnetic resonance imaging. Compared to controls, patients had reduced GM in the primary motor cortex, premotor cortex, supplementary motor area, midcingulate cortex, orbitofrontal cortex, dorsolateral prefrontal cortex (dlPFC), posterior cingulate cortex, precuneus, basal ganglia, thalamus, and hippocampus. Following treatment, patients had increased GM in the dlPFC, thalamus, basal ganglia, amygdala, and hippocampus, and enhanced FC between the dlPFC and the periaqueductal gray, two regions involved in descending pain modulation. Accordingly, our results provide novel evidence for GM abnormalities in sensory, motor, emotional, cognitive, and pain modulatory regions in children with CRPS. Furthermore, this is the first study to demonstrate rapid treatment-induced GM and FC changes in areas implicated in sensation, emotion, cognition, and pain modulation.

  6. Rapid Treatment-Induced Brain Changes in Pediatric CRPS

    Science.gov (United States)

    Erpelding, Nathalie; Simons, Laura; Lebel, Alyssa; Serrano, Paul; Pielech, Melissa; Prabhu, Sanjay; Becerra, Lino; Borsook, David

    2014-01-01

    To date, brain structure and function changes in children with complex regional pain syndrome (CRPS) as a result of disease and treatment remain unknown. Here, we investigated (a) gray matter (GM) differences between patients with CRPS and healthy controls and (b) GM and functional connectivity (FC) changes in patients following intensive interdisciplinary psychophysical pain treatment. Twenty-three patients (13 females, 9 males; average age ± SD = 13.3 ± 2.5 years) and 21 healthy sex-and age-matched controls underwent magnetic resonance imaging. Compared to controls, patients had reduced GM in the primary motor cortex, premotor cortex, supplementary motor area, midcingulate cortex, orbitofrontal cortex, dorsolateral prefrontal cortex (dlPFC), posterior cingulate cortex, precuneus, basal ganglia, thalamus, and hippocampus. Following treatment, patients had increased GM in the dlPFC, thalamus, basal ganglia, amygdala, and hippocampus, and enhanced FC between the dlPFC and the periaqueductal gray (PAG), two regions involved in descending pain modulation. Accordingly, our results provide novel evidence for GM abnormalities in sensory, motor, emotional, cognitive, and pain modulatory regions in children with CRPS. Furthermore, this is the first study to demonstrate rapid treatment-induced GM and FC changes in areas implicated in sensation, emotion, cognition, and pain modulation. PMID:25515312

  7. Labetalol Prevents Intestinal Dysfunction Induced by Traumatic Brain Injury.

    Science.gov (United States)

    Lang, Yuhuang; Fu, Fengming; Sun, Dalong; Xi, Chenhui; Chen, Fengyuan

    2015-01-01

    Beta-adrenergic blockade has been hypothesized to have a protective effect on intestinal dysfunction and increased intestinal permeability associated with the epinephrine surge after traumatic brain injury (TBI). Wister rats were subjected to either a weight drop TBI, and intraperitoneally injected or not with labetalol, or a sham procedure (18 rats per group). After 3, 6, or 12h (6 rats per subgroup), intestinal permeability to 4.4 kDa FITC-Dextran and plasma epinephrine levels were measured as was intestinal tight junction protein ZO-1 expression at 12h. Terminal ileum was harvested to measure levels of intestinal tumor necrosis factor (TNF)-α and to evaluate histopathology. In TBI group vs. sham group, intestinal permeability (Plabetalol group, 1) intestinal permeability was significantly lower at 6 and 12h (94.31±7.64 vs. 102.16±6.40 μg/mL; 110.21±7.52 vs. 118.95±7.11 μg/mL, respectively); 2) levels of plasma epinephrine and intestinal TNF-α were significantly lower at 3, 6 and 12h; and 3) intestinal ZO-1 expression was higher at 3, 6 and 12h (p=0.018). Histopathological evaluation showed that labetalol use preserved intestinal architecture throughout. In a rat model of TBI, labetalol reduced TBI-induced sympathetic hyperactivity, and prevented histopathological intestinal injury accompanied by changes in gut permeability and gut TNF-α expression.

  8. ECT: its brain enabling effects. A review of electroconvulsive therapy-induced structural brain plasticity

    NARCIS (Netherlands)

    Bouckaert, F.; Sienaert, P.; Obbels, J.; Dols, A.; Vandenbulcke, M.; Stek, M.L.; Bolwig, T.

    2014-01-01

    BACKGROUND: Since the past 2 decades, new evidence for brain plasticity has caused a shift in both preclinical and clinical ECT research from falsifying the "brain damage hypothesis" toward exploring ECT's enabling brain (neuro)plasticity effects. METHODS: By reviewing the available animal and human

  9. Mice Brain Tissue Injury Induced by Diisononyl Phthalate Exposure and the Protective Application of Vitamin E.

    Science.gov (United States)

    Peng, Ling

    2015-07-01

    As a widely used plasticizer in plastic industry, the data of diisononyl phthalate (DINP) toxicity due to exposure are insufficient. This work investigated the brain tissue injury induced by DINP exposure. Through oral exposure to DINP, oxidative stress, inflammatory responses, apoptosis, and hippocampus pathological alterations were found in the mice brain. And through the Morris water maze test, cognitive deficits were tested. Our data also showed that these exacerbations were counteracted by vitamin E. These results above indicated that oral exposure of mice to DINP induced brain damage, and oxidative stress, inflammation, and the consequential apoptosis jointly constituted the potential mechanisms of such induced toxicity. © 2015 Wiley Periodicals, Inc.

  10. Management of foetal asphyxia by intrauterine foetal resuscitation

    Directory of Open Access Journals (Sweden)

    S Velayudhareddy

    2010-01-01

    Full Text Available Management of foetal distress is a subject of gynaecological interest, but an anaesthesiologist should know about resuscitation, because he should be able to treat the patient, whenever he is directly involved in managing the parturient patient during labour analgesia and before an emergency operative delivery. Progressive asphyxia is known as foetal distress; the foetus does not breathe directly from the atmosphere, but depends on maternal circulation for its oxygen requirement. The oxygen delivery to the foetus depends on the placental (maternal side, placental transfer and foetal circulation. Oxygen transport to the foetus is reduced physiologically during uterine contractions in labour. Significant impairment of oxygen transport to the foetus, either temporary or permanent may cause foetal distress, resulting in progressive hypoxia and acidosis. Intrauterine foetal resuscitation comprises of applying measures to a mother in active labour, with the intention of improving oxygen delivery to the distressed foetus to the base line, if the placenta is functioning normally. These measures include left lateral recumbent position, high flow oxygen administration, tocolysis to reduce uterine contractions, rapid intravenous fluid administration, vasopressors for correction of maternal hypotension and amnioinfusion for improving uterine blood flow. Intrauterine Foetal Resuscitation measures are easy to perform and do not require extensive resources, but the results are encouraging in improving the foetal well-being. The anaesthesiologist plays a major role in the application of intrauterine foetal resuscitation measures.

  11. The logistic score: a criterion for hypothermia after perinatal asphyxia?

    Science.gov (United States)

    Wayenberg, Jean-Louis

    2010-05-01

    To identify during the first hour of life the asphyxiated term neonates who further develop moderate or severe neonatal encephalopathy. In 75 asphyxiated term infants, we measured postnatal arterial base deficit (BD30), assigned an early neurological score (ENS) according to their level of consciousness, respiration pattern and neonatal reflexes at 30 min of life and calculated the logistic score (LS) = (0.33 x BD30) - ENS. The receiver operating characteristics (ROC) methodology was applied to analyze the ability of the LS to correctly classify patients into two groups: normal or mild encephalopathy (60 patients) versus moderate or severe encephalopathy (15 patients). The area under the ROC curve of the LS for moderate or severe encephalopathy (+/- standard error) was 94.4 +/- 3.6%. At the threshold value of 1.2, the LS provided 87.5% sensitivity and 73.7% positive predictive value (PPV). The PPV of LS reaches 100% for a value >3.2, but this threshold allowed only 53.3% sensitivity. The LS is predictive of the neonatal neurological evolution after birth asphyxia and may help to select the high risk patients who are potential candidates for hypothermia therapy.

  12. Perinatal asphyxia syndrome in the foal: review and a case report

    Science.gov (United States)

    2004-01-01

    This report presented a brief overview of the literature on the perinatal asphyxia syndrome (PAS) in foals as a prelude to a description of the investigation and treatment of acute onset seizures in a 24-hour-old Thoroughbred colt foal. PAS can cause a wide variety of clinical abnormalities, of which seizures due to encephalopathy are the most significant. The structural and biochemical components of CNS neurones are disrupted by the shift from oxidative to anaerobic metabolism, with a resultant deficit in cellular energy. The cells succumb to the combined effects of acidosis, neurotoxic activities of glutamate, nitric oxide and free radicals, lipid peroxidation, accumulation of intracellular calcium and destructive overactivity of intracellular enzymes. Concurrently, the hypoxia affects other organ systems and management of foals presenting with CNS signs requires the veterinarian to undertake a thorough clinical examination and to institute appropriate therapy for the various derangements induced by the hypoxic-ischaemic episode. Diazepam (0.1 to 0.2 mg/kg bwt) can be used for short-term control of seizures; phenobarbital (2 to 10 mg/kg bwt) may be required for more prolonged treatment of recurrent seizures. The needs of the affected foal for nutrients, fluids and electrolytes, antimicrobial therapy and ancillary therapies were discussed in the literature review and illustrated in the case report. PMID:21851654

  13. Perinatal asphyxia syndrome in the foal: review and a case report

    Directory of Open Access Journals (Sweden)

    Galvin Noreen

    2004-12-01

    Full Text Available This report presented a brief overview of the literature on the perinatal asphyxia syndrome (PAS in foals as a prelude to a description of the investigation and treatment of acute onset seizures in a 24-hour-old Thoroughbred colt foal. PAS can cause a wide variety of clinical abnormalities, of which seizures due to encephalopathy are the most significant. The structural and biochemical components of CNS neurones are disrupted by the shift from oxidative to anaerobic metabolism, with a resultant deficit in cellular energy. The cells succumb to the combined effects of acidosis, neurotoxic activities of glutamate, nitric oxide and free radicals, lipid peroxidation, accumulation of intracellular calcium and destructive overactivity of intracellular enzymes. Concurrently, the hypoxia affects other organ systems and management of foals presenting with CNS signs requires the veterinarian to undertake a thorough clinical examination and to institute appropriate therapy for the various derangements induced by the hypoxic-ischaemic episode. Diazepam (0.1 to 0.2 mg/kg bwt can be used for short-term control of seizures; phenobarbital (2 to 10 mg/kg bwt may be required for more prolonged treatment of recurrent seizures. The needs of the affected foal for nutrients, fluids and electrolytes, antimicrobial therapy and ancillary therapies were discussed in the literature review and illustrated in the case report.

  14. Tunicamycin-induced unfolded protein response in the developing mouse brain

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Haiping; Wang, Xin [Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536 (United States); Ke, Zun-Ji [Department of Biochemistry, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203 (China); Comer, Ashley L.; Xu, Mei; Frank, Jacqueline A. [Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536 (United States); Zhang, Zhuo; Shi, Xianglin [Graduate Center for Toxicology, University of Kentucky College of Medicine, Lexington, KY 40536 (United States); Luo, Jia, E-mail: jialuo888@uky.edu [Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536 (United States)

    2015-03-15

    Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) causes ER stress, resulting in the activation of the unfolded protein response (UPR). ER stress and UPR are associated with many neurodevelopmental and neurodegenerative disorders. The developing brain is particularly susceptible to environmental insults which may cause ER stress. We evaluated the UPR in the brain of postnatal mice. Tunicamycin, a commonly used ER stress inducer, was administered subcutaneously to mice of postnatal days (PDs) 4, 12 and 25. Tunicamycin caused UPR in the cerebral cortex, hippocampus and cerebellum of mice of PD4 and PD12, which was evident by the upregulation of ATF6, XBP1s, p-eIF2α, GRP78, GRP94 and MANF, but failed to induce UPR in the brain of PD25 mice. Tunicamycin-induced UPR in the liver was observed at all stages. In PD4 mice, tunicamycin-induced caspase-3 activation was observed in layer II of the parietal and optical cortex, CA1–CA3 and the subiculum of the hippocampus, the cerebellar external germinal layer and the superior/inferior colliculus. Tunicamycin-induced caspase-3 activation was also shown on PD12 but to a much lesser degree and mainly located in the dentate gyrus of the hippocampus, deep cerebellar nuclei and pons. Tunicamycin did not activate caspase-3 in the brain of PD25 mice and the liver of all stages. Similarly, immature cerebellar neurons were sensitive to tunicamycin-induced cell death in culture, but became resistant as they matured in vitro. These results suggest that the UPR is developmentally regulated and the immature brain is more susceptible to ER stress. - Highlights: • Tunicamycin caused a development-dependent UPR in the mouse brain. • Immature brain was more susceptible to tunicamycin-induced endoplasmic reticulum stress. • Tunicamycin caused more neuronal death in immature brain than mature brain. • Tunicamycin-induced neuronal death is region-specific.

  15. Early neonatal deaths associated with perinatal asphyxia in infants ≥2500 g in Brazil,

    Directory of Open Access Journals (Sweden)

    Maria Fernanda Branco de Almeida

    Full Text Available Abstract Objective: To assess the annual burden of early neonatal deaths associated with perinatal asphyxia in infants weighing ≥2500 g in Brazil from 2005 to 2010. Methods: The population study enrolled all live births of infants with birth weight ≥2500 g and without malformations who died up to six days after birth with perinatal asphyxia, defined as intrauterine hypoxia, asphyxia at birth, or meconium aspiration syndrome. The cause of death was written in any field of the death certificate, according to International Classification of Diseases,10th Revision (P20.0, P21.0, and P24.0. An active search was performed in 27 Brazilian federative units. The chi-squared test for trend was applied to analyze early neonatal mortality ratios associated with perinatal asphyxia by study year. Results: A total of 10,675 infants weighing ≥2500 g without malformations died within six days after birth with perinatal asphyxia. Deaths occurred in the first 24 h after birth in 71% of the infants. Meconium aspiration syndrome was reported in 4076 (38% of these deaths. The asphyxia-specific early neonatal mortality ratio decreased from 0.81 in 2005 to 0.65 per 1000 live births in 2010 in Brazil (p < 0.001; the meconium aspiration syndrome-specific early neonatal mortality ratio remained between 0.20 and 0.29 per 1000 live births during the study period. Conclusions: Despite the decreasing rates in Brazil from 2005 to 2010, early neonatal mortality rates associated with perinatal asphyxia in infants in the better spectrum of birth weight and without congenital malformations are still high, and meconium aspiration syndrome plays a major role.

  16. The changes of oligodendrocytes induced by anesthesia during brain development

    National Research Council Canada - National Science Library

    Danye Jiang Sanghee Lim Minhye Kwak Yun Kyoung Ryu C. David Mintz

    2015-01-01

    ...) concluded that while many questions remain un- answered, there is strong evidence from laboratory studies that commonly used anesthetics interfere with brain development and that clinical studies...

  17. Reductions in Calcium Uptake Induced in Rat Brain Synaptosomes by Ionizing Radiation

    Science.gov (United States)

    1991-01-01

    located in the brain and heart using nimodipine and Reductions in Calcium Uptake Induced in Rat Brain Synapto- nifedipine (I1-13). Nimodipine binding...was also reduced by radiation exposure. Nimodipine binding to dihydropyridine (DHP) L-type calcium uptake after irradiation in wh31e-brain, cortical...resistant to the direct effects of MATERIALS AND METHODS ionizing radiation, exposure to ionizing radiation can have Materials. Bay K 8644 and nimodipine

  18. The Role of Exercise-Induced Cardiovascular Adaptation in Brain Health.

    Science.gov (United States)

    Tarumi, Takashi; Zhang, Rong

    2015-10-01

    Regular aerobic exercise improves brain health; however, a potential dose-response relationship and the underling physiological mechanisms remain unclear. Existing data support the following hypotheses: 1) exercise-induced cardiovascular adaptation plays an important role in improving brain perfusion, structure, and function, and 2) a hormetic relation seems to exist between the intensity of exercise and brain health, which needs to be further elucidated.

  19. Labetalol Prevents Intestinal Dysfunction Induced by Traumatic Brain Injury.

    Directory of Open Access Journals (Sweden)

    Yuhuang Lang

    Full Text Available Beta-adrenergic blockade has been hypothesized to have a protective effect on intestinal dysfunction and increased intestinal permeability associated with the epinephrine surge after traumatic brain injury (TBI.Wister rats were subjected to either a weight drop TBI, and intraperitoneally injected or not with labetalol, or a sham procedure (18 rats per group. After 3, 6, or 12h (6 rats per subgroup, intestinal permeability to 4.4 kDa FITC-Dextran and plasma epinephrine levels were measured as was intestinal tight junction protein ZO-1 expression at 12h. Terminal ileum was harvested to measure levels of intestinal tumor necrosis factor (TNF-α and to evaluate histopathology.In TBI group vs. sham group, intestinal permeability (P<0.01 was significantly higher at all time-points, and intestinal ZO-1 expression was lower at 12h. In TBI with vs. without labetalol group, 1 intestinal permeability was significantly lower at 6 and 12h (94.31±7.64 vs. 102.16±6.40 μg/mL; 110.21±7.52 vs. 118.95±7.11 μg/mL, respectively; 2 levels of plasma epinephrine and intestinal TNF-α were significantly lower at 3, 6 and 12h; and 3 intestinal ZO-1 expression was higher at 3, 6 and 12h (p=0.018. Histopathological evaluation showed that labetalol use preserved intestinal architecture throughout.In a rat model of TBI, labetalol reduced TBI-induced sympathetic hyperactivity, and prevented histopathological intestinal injury accompanied by changes in gut permeability and gut TNF-α expression.

  20. CELECOXIB ATTENUATES SYSTEMIC LIPOPOLYSACCHARIDE-INDUCED BRAIN INFLAMMATION AND WHITE MATTER INJURY IN THE NEONATAL RATS

    Science.gov (United States)

    FAN, L.-W.; KAIZAKI, A.; TIEN, L.-T.; PANG, Y.; TANAKA, S.; NUMAZAWA, S.; BHATT, A. J.; CAI, Z.

    2013-01-01

    Lipopolysaccharide (LPS)-induced white matter injury in the neonatal rat brain is associated with inflammatory processes. Cyclooxygenase-2 (COX-2) can be induced by inflammatory stimuli, such as cytokines and pro-inflammatory molecules, suggesting that COX-2 may be considered as the target for anti-inflammation. The objective of the present study was to examine whether celecoxib, a selective COX-2 inhibitor, can reduce systemic LPS-induced brain inflammation and brain damage. Intraperitoneal (i.p.) injection of LPS (2 mg/kg) was performed in postnatal day 5 (P5) of Sprague-Dawley rat pups and celecoxib (20 mg/kg) or vehicle was administered i.p. 5 min after LPS injection. The body weight and wire hanging maneuver test were performed 24 hr after the LPS exposure, and brain injury was examined after these tests. Systemic LPS exposure resulted in an impairment of behavioral performance and acute brain injury, as indicated by apoptotic death of oligodendrocytes (OLs) and loss of OL immunoreactivity in the neonatal rat brain. Treatments with celecoxib significantly reduced systemic LPS-induced neurobehavioral disturbance and brain damage. Celecoxib administration significantly attenuated systemic LPS-induced increments in the number of activated microglia and astrocytes, concentrations of IL-1β and TNFα, and protein levels of phosphorylated-p38 MAPK in the neonatal rat brain. The protection of celecoxib was also associated with a reduction of systemic LPS-induced COX-2+ cells which were double labeled with GFAP+ (astrocyte) cells. The overall results suggest that celecoxib was capable of attenuating the brain injury and neurobehavioral disturbance induced by systemic LPS exposure, and the protective effects are associated with its anti-inflammatory properties. PMID:23485816

  1. Diet-Induced Changes in Membrane Gangliosides in Rat Intestinal Mucosa, Plasma and Brain

    National Research Council Canada - National Science Library

    Park, Eek Joong; Suh, Miyoung; Ramanujam, Kal; Steiner, Kurt; Begg, David; Clandinin, M Thomas

    2005-01-01

    OBJECTIVES:The objective of this study was to determine if dietary gangliosides induce changes in the ganglioside content of intestinal mucosa, plasma and brain and to identify where GM3 and GD3 are localized...

  2. Retinoic Acid Induces Blood-Brain Barrier Development

    NARCIS (Netherlands)

    Mizee, M.R.; Wooldrik, D.; Lakeman, K.A.M.; van het Hof, B.; Drexhage, J.A.R.; Geerts, D.; Bugiani, M.; Aronica, E.; Mebius, R.E.; Prat, A.; de Vries, H.E.; Reijerkerk, A.

    2013-01-01

    The blood- brain barrier (BBB) is crucial in the maintenance of a controlled environment within the brain to safeguard optimal neuronal function. The endothelial cells (ECs) of theBBBpossess specific properties that restrict the entry of cells and metabolites into the CNS. The specialized BBB

  3. Retinoic acid induces blood-brain barrier development

    NARCIS (Netherlands)

    Mizee, Mark R.; Wooldrik, Desiree; Lakeman, Kim A. M.; van het Hof, Bert; Drexhage, Joost A. R.; Geerts, Dirk; Bugiani, Marianna; Aronica, Eleonora; Mebius, Reina E.; Prat, Alexandre; de Vries, Helga E.; Reijerkerk, Arie

    2013-01-01

    The blood-brain barrier (BBB) is crucial in the maintenance of a controlled environment within the brain to safeguard optimal neuronal function. The endothelial cells (ECs) of the BBB possess specific properties that restrict the entry of cells and metabolites into the CNS. The specialized BBB

  4. Functional MRI of food-induced brain responses

    NARCIS (Netherlands)

    Smeets, P.A.M.

    2006-01-01

    The ultimate goal of this research was to find central biomarkers of satiety, i.e., physiological measures in the brain that relate to subjectively rated appetite, actual food intake, or both. This thesis describes the changes in brain activity in response to food stimuli as measured by functional

  5. Potential Asphyxia and Brainstem Abnormalities in Sudden and Unexpected Death in Infants

    Science.gov (United States)

    Randall, Bradley B.; Paterson, David S.; Haas, Elisabeth A.; Broadbelt, Kevin G.; Duncan, Jhodie R.; Mena, Othon J.; Krous, Henry F.; Trachtenberg, Felicia L.

    2013-01-01

    OBJECTIVE: Sudden and unexplained death is a leading cause of infant mortality. Certain characteristics of the sleep environment increase the risk for sleep-related sudden and unexplained infant death. These characteristics have the potential to generate asphyxial conditions. We tested the hypothesis that infants may be exposed to differing degrees of asphyxia in sleep environments, such that vulnerable infants with a severe underlying brainstem deficiency in serotonergic, γ-aminobutyric acid-ergic, or 14-3-3 transduction proteins succumb even without asphyxial triggers (eg, supine), whereas infants with intermediate or borderline brainstem deficiencies require asphyxial stressors to precipitate death. METHODS: We classified cases of sudden infant death into categories relative to a “potential asphyxia” schema in a cohort autopsied at the San Diego County Medical Examiner’s Office. Controls were infants who died with known causes of death established at autopsy. Analysis of covariance tested for differences between groups. RESULTS: Medullary neurochemical abnormalities were present in both infants dying suddenly in circumstances consistent with asphyxia and infants dying suddenly without obvious asphyxia-generating circumstances. There were no differences in the mean neurochemical measures between these 2 groups, although mean measures were both significantly lower (P infants dying suddenly and unexpectedly. Brainstem abnormalities were associated with both asphyxia-generating and non–asphyxia generating conditions. Heeding safe sleep messages is essential for all infants, especially given our current inability to detect underlying vulnerabilities. PMID:24218471

  6. Xenon augmented hypothermia reduces early lactate/N-acetylaspartate and cell death in perinatal asphyxia.

    Science.gov (United States)

    Faulkner, Stuart; Bainbridge, Alan; Kato, Takenori; Chandrasekaran, Manigandan; Kapetanakis, Andrew B; Hristova, Mariya; Liu, Mengyan; Evans, Samantha; De Vita, Enrico; Kelen, Dorottya; Sanders, Robert D; Edwards, A David; Maze, Mervyn; Cady, Ernest B; Raivich, Gennadij; Robertson, Nicola J

    2011-07-01

    Additional treatments for therapeutic hypothermia are required to maximize neuroprotection for perinatal asphyxial encephalopathy. We assessed neuroprotective effects of combining inhaled xenon with therapeutic hypothermia after transient cerebral hypoxia-ischemia in a piglet model of perinatal asphyxia using magnetic resonance spectroscopy (MRS) biomarkers supported by immunohistochemistry. Thirty-six newborn piglets were randomized (all groups n = 9), with intervention from 2 to 26 hours, to: (1) normothermia; (2) normothermia + 24 hours 50% inhaled xenon; (3) 24 hours hypothermia (33.5°C); or (4) 24 hours hypothermia (33.5°C) + 24 hours 50% inhaled xenon. Serial MRS was acquired before, during, and up to 48 hours after hypoxia-ischemia. Mean arterial blood pressure was lower in all treatment groups compared with normothermia (p 40mmHg); the combined therapy group required more fluid boluses (p xenon-augmented hypothermia reduced the temporal regression slope magnitudes for phosphorus-MRS inorganic phosphate/exchangeable phosphate pool (EPP) and phosphocreatine/EPP (both p xenon-augmented hypothermia reduced the slope (p Xenon-augmented hypothermia also reduced transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)(+) nuclei and caspase 3 immunoreactive cells in parasagittal cortex and putamen and increased microglial ramification in midtemporal cortex compared with the no treatment group (p xenon-augmented hypothermia reduced cerebral MRS abnormalities and cell death markers in some brain regions. Compared with hypothermia, xenon-augmented hypothermia did not reach statistical significance for any measure. The safety and possible improved efficacy support phase II trials. Copyright © 2011 American Neurological Association.

  7. Additive Manufacturing of Cranial Simulants for Blast Induced Traumatic Brain Injury

    Science.gov (United States)

    2017-08-28

    REPORT TYPE 08/28/2017 Poster 4. TITLE AND SUBTITLE Additive Manufacturing of Cranial Sin1ulants for Blast Induced Traumatic Brain Injut’y 6...devices (IEOs) in warfare has resulted in devastating injuries to United States military personnel, with blast induced traumat ic brain Injury...hrgher fidelity 1es1 object. Mold and Oalllsllc Gelatin Sample of Rcanstic Brain Geomelrv I Acknowledgements Sandia N1tional 1.ahor:.t.ori" r ..uuhcr f’"""" Clwllltr\\M Paul ’""" (PE = ..

  8. Dose-dependent neuroprotective effect of enoxaparin on cold-induced traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Ilknur Keskin

    2017-01-01

    Full Text Available Recent evidence exists that enoxaparin can reduce brain injury because of its anticoagulant activity. To investigate the potential therapeutic effect of enoxaparin on cold-induced traumatic brain injury, at 20 minutes after modeling, male BALB/c mouse models of cold-induced traumatic brain injury were intraperitoneally administered 3 and 10 mg/kg enoxaparin or isotonic saline solution. Twenty-four hours later, enoxaparin at 10 mg/kg greatly reduced infarct volume, decreased cell apoptosis in the cortex and obviously increased serum level of total antioxidant status. By contrast, administration of enoxaparin at 3 mg/kg did not lead to these changes. These findings suggest that enoxaparin exhibits neuroprotective effect on cold-induced traumatic brain injury in a dose-dependent manner.

  9. Perinatal risk factors for neonatal asphyxia in Vali-e-Asr hospital, Tehran-Iran

    Directory of Open Access Journals (Sweden)

    Fatemeh Nayeri

    2012-01-01

    Full Text Available Background: Asphyxia is a medical condition in which placental or pulmonary gas exchange is impaired or they cease all together, typically producing a combination of progressive hypoxemia and hypercapnea. Objective: In addition to regional differences in its etiology; it is important to know its risk factors. Materials and Methods: This is a case-control study, all neonates born from May 2002 to September 2005 in Vali-e-Asr Hospital were studied. 9488 newborns were born of which 6091 of the live patients were hospitalized in NICU. 546 newborns were studied as case and control group. 260 neonates (48% were female and 286 neonates (52% were male. Among the neonates who were admitted, 182 of them were diagnosed with asphyxia and twice of them (364 newborns were selected as a control group. The variables consist of; gestational age, type of delivery, birth weight, prenatal care, pregnancy and peripartum complications and neonatal disorders. Results: Our studies showed that 35 (19.2% patients had mild asphyxia, 107 (58.8% had moderate asphyxia and 40 (22% were diagnosed as severe asphyxia. Mean maternal age was 34.23±4.29yr; (range: 23-38 yr; and mean of parity was 2±1.2; (range: 1-8. Risk factors in our study included emergent Caesarian Section, preterm labor (<37w, low birth weight (<2500g, 5 minute Apgar (less than 6, need for resuscitation, nuchal cord, impaired Biophysical Profile, neonatal anemia, and maternal infertility. Conclusion: All risk factors listed above play a role in asphyxia. The majority of these factors are avoidable by means of good perinatal care

  10. Sumoylation of hypoxia-inducible factor-1α ameliorates failure of brain stem cardiovascular regulation in experimental brain death.

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    Julie Y H Chan

    2011-03-01

    Full Text Available One aspect of brain death is cardiovascular deregulation because asystole invariably occurs shortly after its diagnosis. A suitable neural substrate for mechanistic delineation of this aspect of brain death resides in the rostral ventrolateral medulla (RVLM. RVLM is the origin of a life-and-death signal that our laboratory detected from blood pressure of comatose patients that disappears before brain death ensues. At the same time, transcriptional upregulation of heme oxygenase-1 in RVLM by hypoxia-inducible factor-1α (HIF-1α plays a pro-life role in experimental brain death, and HIF-1α is subject to sumoylation activated by transient cerebral ischemia. It follows that sumoylation of HIF-1α in RVLM in response to hypoxia may play a modulatory role on brain stem cardiovascular regulation during experimental brain death.A clinically relevant animal model that employed mevinphos as the experimental insult in Sprague-Dawley rat was used. Biochemical changes in RVLM during distinct phenotypes in systemic arterial pressure spectrum that reflect maintained or defunct brain stem cardiovascular regulation were studied. Western blot analysis, EMSA, ELISA, confocal microscopy and immunoprecipitation demonstrated that drastic tissue hypoxia, elevated levels of proteins conjugated by small ubiquitin-related modifier-1 (SUMO-1, Ubc9 (the only known conjugating enzyme for the sumoylation pathway or HIF-1α, augmented sumoylation of HIF-1α, nucleus-bound translocation and enhanced transcriptional activity of HIF-1α in RVLM neurons took place preferentially during the pro-life phase of experimental brain death. Furthermore, loss-of-function manipulations by immunoneutralization of SUMO-1, Ubc9 or HIF-1α in RVLM blunted the upregulated nitric oxide synthase I/protein kinase G signaling cascade, which sustains the brain stem cardiovascular regulatory machinery during the pro-life phase.We conclude that sumoylation of HIF-1α in RVLM ameliorates brain stem

  11. Training your brain to be more creative: brain functional and structural changes induced by divergent thinking training.

    Science.gov (United States)

    Sun, Jiangzhou; Chen, Qunlin; Zhang, Qinglin; Li, Yadan; Li, Haijiang; Wei, Dongtao; Yang, Wenjing; Qiu, Jiang

    2016-10-01

    Creativity is commonly defined as the ability to produce something both novel and useful. Stimulating creativity has great significance for both individual success and social improvement. Although increasing creative capacity has been confirmed to be possible and effective at the behavioral level, few longitudinal studies have examined the extent to which the brain function and structure underlying creativity are plastic. A cognitive stimulation (20 sessions) method was used in the present study to train subjects and to explore the neuroplasticity induced by training. The behavioral results revealed that both the originality and the fluency of divergent thinking were significantly improved by training. Furthermore, functional changes induced by training were observed in the dorsal anterior cingulate cortex (dACC), dorsal lateral prefrontal cortex (DLPFC), and posterior brain regions. Moreover, the gray matter volume (GMV) was significantly increased in the dACC after divergent thinking training. These results suggest that the enhancement of creativity may rely not only on the posterior brain regions that are related to the fundamental cognitive processes of creativity (e.g., semantic processing, generating novel associations), but also on areas that are involved in top-down cognitive control, such as the dACC and DLPFC. Hum Brain Mapp 37:3375-3387, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  12. Deformation of the human brain induced by mild acceleration.

    Science.gov (United States)

    Bayly, P V; Cohen, T S; Leister, E P; Ajo, D; Leuthardt, E C; Genin, G M

    2005-08-01

    Rapid deformation of brain matter caused by skull acceleration is most likely the cause of concussion, as well as more severe traumatic brain injury (TBI). The inability to measure deformation directly has led to disagreement and confusion about the biomechanics of concussion and TBI. In the present study, brain deformation in human volunteers was measured directly during mild, but rapid, deceleration of the head (20-30 m/sec2 peak, approximately 40 msec duration), using an imaging technique originally developed to measure cardiac deformation. Magnetic resonance image sequences with imposed "tag" lines were obtained at high frame rates by repeating the deceleration and acquiring a subset of image data each repetition. Displacements of points on tag lines were used to estimate the Lagrangian strain tensor field. Qualitative (visual) and quantitative (strain) results illustrate clearly the deformation of brain matter due to occipital deceleration. Strains of 0.02-0.05 were typical during these events (0.05 strain corresponds roughly to a 5% change in the dimension of a local tissue element). Notably, compression in frontal regions and stretching in posterior regions were observed. The motion of the brain appears constrained by structures at the frontal base of the skull; it must pull away from such constraints before it can compress against the occipital bone. This mechanism is consistent with observations of contrecoup injury in occipital impact.

  13. Blood Brain Barrier Dysfunction and Delayed Neurological Deficits in Mild Traumatic Brain Injury Induced by Blast Shock Waves

    Directory of Open Access Journals (Sweden)

    Ashok K Shetty

    2014-08-01

    Full Text Available Mild traumatic brain injury (mTBI resulting from exposure to blast shock waves (BSWs is one of the most predominant causes of illnesses among veterans who served in the recent Iraq and Afghanistan wars. Such mTBI can also happen to civilians if exposed to shock waves of bomb attacks by terrorists. While cognitive problems, memory dysfunction, depression, anxiety and diffuse white matter injury have been observed at both early and/or delayed time-points, an initial brain pathology resulting from exposure to BSWs appears to be the dysfunction or disruption of the blood-brain barrier (BBB. Studies in animal models suggest that exposure to relatively milder BSWs (123 kPa initially induces free radical generating enzymes in and around brain capillaries, which enhances oxidative stress resulting in loss of tight junction proteins, edema formation, and leakiness of BBB with disruption or loss of its components pericytes and astrocyte end-feet. On the other hand, exposure to more intense BSWs (145-323 kPa causes acute disruption of the BBB with vascular lesions in the brain. Both of these scenarios lead to apoptosis of endothelial and neural cells and neuroinflammation in and around capillaries, which may progress into chronic traumatic encephalopathy and/or a variety of neurological impairments, depending on brain regions that are afflicted with such lesions. This review discusses studies that examined alterations in the brain milieu causing dysfunction or disruption of the BBB and neuroinflammation following exposure to different intensities of BSWs. Furthermore, potential of early intervention strategies capable of easing oxidative stress, repairing the BBB or blocking inflammation for minimizing delayed neurological deficits resulting from exposure to BSWs is conferred.

  14. Blood brain barrier dysfunction and delayed neurological deficits in mild traumatic brain injury induced by blast shock waves.

    Science.gov (United States)

    Shetty, Ashok K; Mishra, Vikas; Kodali, Maheedhar; Hattiangady, Bharathi

    2014-01-01

    Mild traumatic brain injury (mTBI) resulting from exposure to blast shock waves (BSWs) is one of the most predominant causes of illnesses among veterans who served in the recent Iraq and Afghanistan wars. Such mTBI can also happen to civilians if exposed to shock waves of bomb attacks by terrorists. While cognitive problems, memory dysfunction, depression, anxiety and diffuse white matter injury have been observed at both early and/or delayed time-points, an initial brain pathology resulting from exposure to BSWs appears to be the dysfunction or disruption of the blood-brain barrier (BBB). Studies in animal models suggest that exposure to relatively milder BSWs (123 kPa) initially induces free radical generating enzymes in and around brain capillaries, which enhances oxidative stress resulting in loss of tight junction (TJ) proteins, edema formation, and leakiness of BBB with disruption or loss of its components pericytes and astrocyte end-feet. On the other hand, exposure to more intense BSWs (145-323 kPa) causes acute disruption of the BBB with vascular lesions in the brain. Both of these scenarios lead to apoptosis of endothelial and neural cells and neuroinflammation in and around capillaries, which may progress into chronic traumatic encephalopathy (CTE) and/or a variety of neurological impairments, depending on brain regions that are afflicted with such lesions. This review discusses studies that examined alterations in the brain milieu causing dysfunction or disruption of the BBB and neuroinflammation following exposure to different intensities of BSWs. Furthermore, potential of early intervention strategies capable of easing oxidative stress, repairing the BBB or blocking inflammation for minimizing delayed neurological deficits resulting from exposure to BSWs is conferred.

  15. Fabp1 gene ablation inhibits high-fat diet-induced increase in brain endocannabinoids.

    Science.gov (United States)

    Martin, Gregory G; Landrock, Danilo; Chung, Sarah; Dangott, Lawrence J; Seeger, Drew R; Murphy, Eric J; Golovko, Mikhail Y; Kier, Ann B; Schroeder, Friedhelm

    2017-01-01

    The endocannabinoid system shifts energy balance toward storage and fat accumulation, especially in the context of diet-induced obesity. Relatively little is known about factors outside the central nervous system that may mediate the effect of high-fat diet (HFD) on brain endocannabinoid levels. One candidate is the liver fatty acid binding protein (FABP1), a cytosolic protein highly prevalent in liver, but not detected in brain, which facilitates hepatic clearance of fatty acids. The impact of Fabp1 gene ablation (LKO) on the effect of high-fat diet (HFD) on brain and plasma endocannabinoid levels was examined and data expressed for each parameter as the ratio of high-fat diet/control diet. In male wild-type mice, HFD markedly increased brain N-acylethanolamides, but not 2-monoacylglycerols. LKO blocked these effects of HFD in male mice. In female wild-type mice, HFD slightly decreased or did not alter these endocannabinoids as compared with male wild type. LKO did not block the HFD effects in female mice. The HFD-induced increase in brain arachidonic acid-derived arachidonoylethanolamide in males correlated with increased brain-free and total arachidonic acid. The ability of LKO to block the HFD-induced increase in brain arachidonoylethanolamide correlated with reduced ability of HFD to increase brain-free and total arachidonic acid in males. In females, brain-free and total arachidonic acid levels were much less affected by either HFD or LKO in the context of HFD. These data showed that LKO markedly diminished the impact of HFD on brain endocannabinoid levels, especially in male mice. © 2016 International Society for Neurochemistry.

  16. Epsilon Aminocaproic Acid Pretreatment Provides Neuroprotection Following Surgically Induced Brain Injury in a Rat Model.

    Science.gov (United States)

    Komanapalli, Esther S; Sherchan, Prativa; Rolland, William; Khatibi, Nikan; Martin, Robert D; Applegate, Richard L; Tang, Jiping; Zhang, John H

    2016-01-01

    Neurosurgical procedures can damage viable brain tissue unintentionally by a wide range of mechanisms. This surgically induced brain injury (SBI) can be a result of direct incision, electrocauterization, or tissue retraction. Plasmin, a serine protease that dissolves fibrin blood clots, has been shown to enhance cerebral edema and hemorrhage accumulation in the brain through disruption of the blood brain barrier. Epsilon aminocaproic acid (EAA), a recognized antifibrinolytic lysine analogue, can reduce the levels of active plasmin and, in doing so, potentially can preserve the neurovascular unit of the brain. We investigated the role of EAA as a pretreatment neuroprotective modality in a SBI rat model, hypothesizing that EAA therapy would protect brain tissue integrity, translating into preserved neurobehavioral function. Male Sprague-Dawley rats were randomly assigned to one of four groups: sham (n = 7), SBI (n = 7), SBI with low-dose EAA, 150 mg/kg (n = 7), and SBI with high-dose EAA, 450 mg/kg (n = 7). SBI was induced by partial right frontal lobe resection through a frontal craniotomy. Postoperative assessment at 24 h included neurobehavioral testing and measurement of brain water content. Results at 24 h showed both low- and high-dose EAA reduced brain water content and improved neurobehavioral function compared with the SBI groups. This suggests that EAA may be a useful pretherapeutic modality for SBI. Further studies are needed to clarify optimal therapeutic dosing and to identify mechanisms of neuroprotection in rat SBI models.

  17. Cold-inducible RNA-binding protein is an important mediator of alcohol-induced brain inflammation.

    Science.gov (United States)

    Rajayer, Salil R; Jacob, Asha; Yang, Weng-Lang; Zhou, Mian; Chaung, Wayne; Wang, Ping

    2013-01-01

    Binge drinking has been associated with cerebral dysfunction. Ethanol induced microglial activation initiates an inflammatory process that causes upregulation of proinflammatory cytokines which in turn creates neuronal inflammation and damage. However, the molecular mechanism is not fully understood. We postulate that cold-inducible RNA-binding protein (CIRP), a novel proinflammatory molecule, can contribute to alcohol-induced neuroinflammation. To test this theory male wild-type (WT) mice were exposed to alcohol at concentrations consistent to binge drinking and blood and brain tissues were collected. At 5 h after alcohol, a significant increase of 53% in the brain of CIRP mRNA was observed and its expression remained elevated at 10 h and 15 h. Brain CIRP protein levels were increased by 184% at 10 h and remained high at 15 h. We then exposed male WT and CIRP knockout (CIRP(-/-)) mice to alcohol, and blood and brain tissues were collected at 15 h post-alcohol infusion. Serum levels of tissue injury markers (AST, ALT and LDH) were significantly elevated in alcohol-exposed WT mice while they were less increased in the CIRP(-/-) mice. Brain TNF-α mRNA and protein expressions along with IL-1β protein levels were significantly increased in WT mice, which was not seen in the CIRP(-/-) mice. In cultured BV2 cells (mouse microglia), ethanol at 100 mM showed an increase of CIRP mRNA by 274% and 408% at 24 h and 48 h respectively. Corresponding increases in TNF-α and IL-1β were also observed. CIRP protein levels were markedly increased in the medium, suggesting that CIRP was secreted by the BV2 cells. From this we conclude that alcohol exposure activates microglia to produce and secrete CIRP and possibly induce pro-inflammatory response and thereby causing neuroinflammation. CIRP could be a novel mediator of alcohol-induced brain inflammation.

  18. Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction.

    Science.gov (United States)

    Kiyatkin, Eugene A; Ren, Suelynn; Wakabayashi, Ken T; Baumann, Michael H; Shaham, Yavin

    2016-01-01

    MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results.

  19. Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction

    Science.gov (United States)

    Kiyatkin, Eugene A; Ren, Suelynn; Wakabayashi, Ken T; Baumann, Michael H; Shaham, Yavin

    2016-01-01

    MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results. PMID:26105141

  20. Manifesto for the current understanding and management of traumatic brain injury-induced hypopituitarism.

    LENUS (Irish Health Repository)

    Tanriverdi, F

    2011-01-01

    Traumatic brain injury (TBI)-induced hypopituitarism remains a relevant medical problem, because it may affect a significant proportion of the population. In the last decade important studies have been published investigating pituitary dysfunction after TBI. Recently, a group of experts gathered and revisited the topic of TBI-induced hypopituitarism. During the 2-day meeting, the main issues of this topic were presented and discussed, and current understanding and management of TBI-induced hypopituitarism are summarized here.

  1. Manifesto for the current understanding and management of traumatic brain injury-induced hypopituitarism

    DEFF Research Database (Denmark)

    Tanriverdi, F; Agha, A; Aimaretti, G

    2011-01-01

    Traumatic brain injury (TBI)-induced hypopituitarism remains a relevant medical problem, because it may affect a significant proportion of the population. In the last decade important studies have been published investigating pituitary dysfunction after TBI. Recently, a group of experts gathered...... and revisited the topic of TBI-induced hypopituitarism. During the 2-day meeting, the main issues of this topic were presented and discussed, and current understanding and management of TBI-induced hypopituitarism are summarized here....

  2. Acetyl-L-carnitine protects neuronal function from alcohol-induced oxidative damage in the brain.

    Science.gov (United States)

    Rump, Travis J; Abdul Muneer, P M; Szlachetka, Adam M; Lamb, Allyson; Haorei, Catherine; Alikunju, Saleena; Xiong, Huangui; Keblesh, James; Liu, Jianuo; Zimmerman, Matthew C; Jones, Jocelyn; Donohue, Terrence M; Persidsky, Yuri; Haorah, James

    2010-11-30

    The studies presented here demonstrate the protective effect of acetyl-L-carnitine (ALC) against alcohol-induced oxidative neuroinflammation, neuronal degeneration, and impaired neurotransmission. Our findings reveal the cellular and biochemical mechanisms of alcohol-induced oxidative damage in various types of brain cells. Chronic ethanol administration to mice caused an increase in inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine adduct formation in frontal cortical neurons but not in astrocytes from brains of these animals. Interestingly, alcohol administration caused a rather selective activation of NADPH oxidase (NOX), which, in turn, enhanced levels of reactive oxygen species (ROS) and 4-hydroxynonenal, but these were predominantly localized in astrocytes and microglia. Oxidative damage in glial cells was accompanied by their pronounced activation (astrogliosis) and coincident neuronal loss, suggesting that inflammation in glial cells caused neuronal degeneration. Immunohistochemistry studies indicated that alcohol consumption induced different oxidative mediators in different brain cell types. Thus, nitric oxide was mostly detected in iNOS-expressing neurons, whereas ROS were predominantly generated in NOX-expressing glial cells after alcohol ingestion. Assessment of neuronal activity in ex vivo frontal cortical brain tissue slices from ethanol-fed mice showed a reduction in long-term potentiation synaptic transmission compared with slices from controls. Coadministration of ALC with alcohol showed a significant reduction in oxidative damage and neuronal loss and a restoration of synaptic neurotransmission in this brain region, suggesting that ALC protects brain cells from ethanol-induced oxidative injury. These findings suggest the potential clinical utility of ALC as a neuroprotective agent that prevents alcohol-induced brain damage and development of neurological disorders. Published by Elsevier Inc.

  3. Background Noise Contributes to Organic Solvent Induced Brain Dysfunction.

    Science.gov (United States)

    Guthrie, O'neil W; Wong, Brian A; McInturf, Shawn M; Reboulet, James E; Ortiz, Pedro A; Mattie, David R

    2016-01-01

    Occupational exposure to complex blends of organic solvents is believed to alter brain functions among workers. However, work environments that contain organic solvents are also polluted with background noise which raises the issue of whether or not the noise contributed to brain alterations. The purpose of the current study was to determine whether or not repeated exposure to low intensity noise with and without exposure to a complex blend of organic solvents would alter brain activity. Female Fischer344 rats served as subjects in these experiments. Asynchronous volume conductance between the midbrain and cortex was evaluated with a slow vertex recording technique. Subtoxic solvent exposure, by itself, had no statistically significant effects. However, background noise significantly suppressed brain activity and this suppression was exacerbated with solvent exposure. Furthermore, combined exposure produced significantly slow neurotransmission. These abnormal neurophysiologic findings occurred in the absence of hearing loss and detectable damage to sensory cells. The observations from the current experiment raise concern for all occupations where workers are repeatedly exposed to background noise or noise combined with organic solvents. Noise levels and solvent concentrations that are currently considered safe may not actually be safe and existing safety regulations have failed to recognize the neurotoxic potential of combined exposures.

  4. Practice induces function-specific changes in brain activity.

    Science.gov (United States)

    van Raalten, Tamar R; Ramsey, Nick F; Duyn, Jeff; Jansma, Johan M

    2008-10-01

    Practice can have a profound effect on performance and brain activity, especially if a task can be automated. Tasks that allow for automatization typically involve repeated encoding of information that is paired with a constant response. Much remains unknown about the effects of practice on encoding and response selection in an automated task. To investigate function-specific effects of automatization we employed a variant of a Sternberg task with optimized separation of activity associated with encoding and response selection by means of m-sequences. This optimized randomized event-related design allows for model free measurement of BOLD signals over the course of practice. Brain activity was measured at six consecutive runs of practice and compared to brain activity in a novel task. Prompt reductions were found in the entire cortical network involved in encoding after a single run of practice. Changes in the network associated with response selection were less robust and were present only after the third run of practice. This study shows that automatization causes heterogeneous decreases in brain activity across functional regions that do not strictly track performance improvement. This suggests that cognitive performance is supported by a dynamic allocation of multiple resources in a distributed network. Our findings may bear importance in understanding the role of automatization in complex cognitive performance, as increased encoding efficiency in early stages of practice possibly increases the capacity to otherwise interfering information.

  5. Practice induces function-specific changes in brain activity.

    Directory of Open Access Journals (Sweden)

    Tamar R van Raalten

    2008-10-01

    Full Text Available Practice can have a profound effect on performance and brain activity, especially if a task can be automated. Tasks that allow for automatization typically involve repeated encoding of information that is paired with a constant response. Much remains unknown about the effects of practice on encoding and response selection in an automated task.To investigate function-specific effects of automatization we employed a variant of a Sternberg task with optimized separation of activity associated with encoding and response selection by means of m-sequences. This optimized randomized event-related design allows for model free measurement of BOLD signals over the course of practice. Brain activity was measured at six consecutive runs of practice and compared to brain activity in a novel task.Prompt reductions were found in the entire cortical network involved in encoding after a single run of practice. Changes in the network associated with response selection were less robust and were present only after the third run of practice.This study shows that automatization causes heterogeneous decreases in brain activity across functional regions that do not strictly track performance improvement. This suggests that cognitive performance is supported by a dynamic allocation of multiple resources in a distributed network. Our findings may bear importance in understanding the role of automatization in complex cognitive performance, as increased encoding efficiency in early stages of practice possibly increases the capacity to otherwise interfering information.

  6. Modafinil-Induced Increases in Brain Dopamine Levels

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2009-04-01

    Full Text Available The acute effects of modafinil on extracellular dopamine and on dopamine transporters in the male human brain were measured by PET study in 10 healthy subjects at Brookhaven National Laboratory and National Institute on Drug Abuse, Bethesda, MD.

  7. Early adrenaline administration does not improve circulatory recovery during resuscitation from severe asphyxia in newborn piglets.

    Science.gov (United States)

    Linner, Rikard; Werner, Olof; Perez-de-Sa, Valeria; Cunha-Goncalves, Doris

    2012-10-01

    To investigate the effects of early intravenous adrenaline administration on circulatory recovery, cerebral reoxygenation, and plasma catecholamine concentrations, after severe asphyxia-induced bradycardia and hypotension. One-day-old piglets were left in apnoea until heart rate and mean arterial pressure were less than 50 min(-1) and 25 mmHg, respectively. They randomly received adrenaline, 10 μgkg(-1) (n=16) or placebo (n=15) and were resuscitated with air ventilation and, when needed, closed-chest cardiac massage (CCCM). Eight not asphyxiated animals served as time controls. CCCM was required in 13 piglets given adrenaline and in 13 given placebo. Time to return of spontaneous circulation was: 72 (66-85)s vs. 77 (64-178)s [median (quartile range)] (p=0.35). Time until cerebral regional oxygen saturation (CrSO(2)) had increased to 30% was 86 (79-152)s vs. 126 (88-309)s (p=0.30). The two groups did not differ significantly in CrSO(2), heart rate, arterial pressure, right common carotid artery blood flow, or number of survivors: 13 vs. 11 animals. Plasma concentration of adrenaline, 2.5 min after resuming ventilation, was 498 (268-868)nmoll(-1) vs. 114 (80-306)nmoll(-1) (p=0.01). Corresponding noradrenaline concentrations were 1799 (1058-4182)nmoll(-1)vs. 1385 (696-3118)nmoll(-1) (ns). In the time controls, the concentrations were 0.4 (0.2-0.6)nmoll(-1) of adrenaline and 1.8 (1.3-2.4)nmoll(-1) of noradrenaline. The high endogenous catecholamine levels, especially those of noradrenaline, may explain why early administered adrenaline did not significantly improve resuscitation outcome. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  8. Pilot Study of Propofol-induced Slow Waves as a Pharmacologic Test for Brain Dysfunction after Brain Injury.

    Science.gov (United States)

    Kortelainen, Jukka; Väyrynen, Eero; Huuskonen, Usko; Laurila, Jouko; Koskenkari, Juha; Backman, Janne T; Alahuhta, Seppo; Seppänen, Tapio; Ala-Kokko, Tero

    2017-01-01

    Slow waves (less than 1 Hz) are the most important electroencephalogram signatures of nonrapid eye movement sleep. While considered to have a substantial importance in, for example, providing conditions for single-cell rest and preventing long-term neural damage, a disturbance in this neurophysiologic phenomenon is a potential indicator of brain dysfunction. Since, in healthy individuals, slow waves can be induced with anesthetics, the authors tested the possible association between hypoxic brain injury and slow-wave activity in comatose postcardiac arrest patients (n = 10) using controlled propofol exposure. The slow-wave activity was determined by calculating the low-frequency (less than 1 Hz) power of the electroencephalograms recorded approximately 48 h after cardiac arrest. To define the association between the slow waves and the potential brain injury, the patients' neurologic recovery was then followed up for 6 months. In the patients with good neurologic outcome (n = 6), the low-frequency power of electroencephalogram representing the slow-wave activity was found to substantially increase (mean ± SD, 190 ± 83%) due to the administration of propofol. By contrast, the patients with poor neurologic outcome (n = 4) were unable to generate propofol-induced slow waves. In this experimental pilot study, the comatose postcardiac arrest patients with poor neurologic outcome were unable to generate normal propofol-induced electroencephalographic slow-wave activity 48 h after cardiac arrest. The finding might offer potential for developing a pharmacologic test for prognostication of brain injury by measuring the electroencephalographic response to propofol.

  9. Brain Tumor Tropism of Transplanted Human Neural Stem Cells Is Induced by Vascular Endothelial Growth Factor

    Directory of Open Access Journals (Sweden)

    Nils Ole Schmidt

    2005-06-01

    Full Text Available The transplantation of neural stem cells (NSCs offers a new potential therapeutic approach as a cell-based delivery system for gene therapy in brain tumors. This is based on the unique capacity of NSCs to migrate throughout the brain and to target invading tumor cells. However, the signals controlling the targeted migration of transplanted NSCs are poorly defined. We analyzed the in vitro and in vivo effects of angiogenic growth factors and protein extracts from surgical specimens of brain tumor patients on NSC migration. Here, we demonstrate that vascular endothelial growth factor (VEGF is able to induce a long-range attraction of transplanted human NSCs from distant sites in the adult brain. Our results indicate that tumorupregulated VEGF and angiogenic-activated microvasculature are relevant guidance signals for NSC tropism toward brain tumors.

  10. [Assessment of levels of otoacoustic emission response in neonates with perinatal asphyxia].

    Science.gov (United States)

    Ribeiro, Georgea Espindola; da Silva, Daniela Polo Camargo; Montovani, Jair Cortez

    2014-09-01

    To evaluate the effects of perinatal asphyxia on the level of the response to transient otoacoustic emissions in infants. Otoacoustic emissions in 154 neonates were performed: 54 infants who suffered asphyxia at birth, measured by Apgar score and medical diagnosis, and 100 infants without risk were compared. Scores less than 4 in the first minute and/or less than 6 in the fifth minute were considered as "low Apgar". Statistical analysis of the data was performed using the Kruskal, Wilcoxon, and Mann-Whitney nonparametric tests. Lower levels of response were observed in transient otoacoustic emission in the group that suffered perinatal asphyxia, with significant values for the frequencies 2,000, 3,000, and 4,000Hz in the right ear, and 2,000 and 4,000Hz in the left ear. The analysis of the intrinsic characteristics of the otoacoustic emissions evidenced low performance of outer hair cells in neonates who had perinatal asphyxia, which may affect the development of listening skills in this population. Copyright © 2014 Sociedade de Pediatria de São Paulo. Publicado por Elsevier Editora Ltda. All rights reserved.

  11. intrapartum-related birth asphyxia in south africa- lessons from the ...

    African Journals Online (AJOL)

    The high rates of perinatal death from intrapartum-related birth asphyxia in South Africa are . typical of those in underdeveloped countries, with the most serious deficiencies in rural areas. Most of these .deaths are avoidable and the reduction of these rates presents an important challenge to providers of perinatal care in this.

  12. Intrapartum-related birth asphyxia in South Africa lessons From the ...

    African Journals Online (AJOL)

    Background. The recent amalgamation of data by users of the Perinatal Problem Identification Programme (PPIP) throughout South Africa has culminated in the publication of the Saving Babies report. Objectives. To determine the absolute rate of death from intrapartum-related birth asphyxia, and the contribution of ...

  13. Pediatric constrictive asphyxia a rare form of child abuse: A report of two cases

    NARCIS (Netherlands)

    Vester, M. E. M.; Bilo, R. A. C.; Nijs, H. G. T.; van Rijn, R. R.

    2018-01-01

    We present two cases of infants who died under suspicious circumstances. After clinical and legal investigations, non-accidental constrictive asphyxia inflicted by one of the parents was established. The first case presents a to date not yet reported, unique mechanism of trauma. In order to stop his

  14. BIRTH ASPHYXIA - PRESENTING THE CASE FOR'A STITCH IN TIME'

    African Journals Online (AJOL)

    CP) rates at a teaching hospital in a developing country, and to place these rates within the context of the current caesarean section (CS) rate. To determine the number of cases of birth asphyxia that are preventable. Design. Retrospective ...

  15. Voluntary exercise protects against methamphetamine-induced oxidative stress in brain microvasculature and disruption of the blood-brain barrier.

    Science.gov (United States)

    Toborek, Michal; Seelbach, Melissa J; Rashid, Cetewayo S; András, Ibolya E; Chen, Lei; Park, Minseon; Esser, Karyn A

    2013-06-24

    There is no effective therapeutic intervention developed targeting cerebrovascular toxicity of drugs of abuse, including methamphetamine (METH). We hypothesize that exercise protects against METH-induced disruption of the blood-brain barrier (BBB) by enhancing the antioxidant capacity of cerebral microvessels and modulating caveolae-associated signaling. Mice were subjected to voluntary wheel running for 5 weeks resembling the voluntary pattern of human exercise, followed by injection with METH (10 mg/kg). The frequency, duration, and intensity of each running session were monitored for each mouse via a direct data link to a computer and the running data are analyzed by Clock lab™ Analysis software. Controls included mice sedentary that did not have access to running wheels and/or injections with saline. METH induced oxidative stress in brain microvessels, resulting in up regulation of caveolae-associated NAD(P)H oxidase subunits, and phosphorylation of mitochondrial protein 66Shc. Treatment with METH disrupted also the expression and colocalization of tight junction proteins. Importantly, exercise markedly attenuated these effects and protected against METH-induced disruption of the BBB integrity. The obtained results indicate that exercise is an important modifiable behavioral factor that can protect against METH-induced cerebrovascular toxicity. These findings may provide new strategies in preventing the toxicity of drug of abuse.

  16. Restraint stress-induced morphological changes at the blood-brain barrier in adult rats

    Directory of Open Access Journals (Sweden)

    Petra eSántha

    2016-01-01

    Full Text Available Stress is well known to contribute to the development of both neurological and psychiatric diseases. While the role of the blood-brain barrier is increasingly recognised in the development of neurodegenerative disorders, such as Alzheimer’s disease, dysfunction of the blood-brain barrier has been linked to stress-related psychiatric diseases only recently. In the present study the effects of restraint stress with different duration (1, 3 and 21 days were investigated on the morphology of the blood-brain barrier in male adult Wistar rats. Frontal cortex and hippocampus sections were immunostained for markers of brain endothelial cells (claudin-5, occludin and glucose transporter-1 and astroglia (GFAP. Staining pattern and intensity were visualized by confocal microscopy and evaluated by several types of image analysis. The ultrastructure of brain capillaries was investigated by electron microscopy. Morphological changes and intensity alterations in brain endothelial tight junction proteins claudin-5 and occludin were induced by stress. Following restraint stress significant increases in the fluorescence intensity of glucose transporter-1 were detected in brain endothelial cells in the frontal cortex and hippocampus. Significant reductions in GFAP fluorescence intensity were observed in the frontal cortex in all stress groups. As observed by electron microscopy, one-day acute stress induced morphological changes indicating damage in capillary endothelial cells in both brain regions. After 21 days of stress thicker and irregular capillary basal membranes in the hippocampus and edema in astrocytes in both regions were seen. These findings indicate that stress exerts time-dependent changes in the staining pattern of tight junction proteins occludin, claudin-5 and glucose transporter-1 at the level of brain capillaries and in the ultrastructure of brain endothelial cells and astroglial endfeet, which may contribute to neurodegenerative processes

  17. Induced sensorimotor brain plasticity controls pain in phantom limb patients

    OpenAIRE

    Yanagisawa, Takufumi; Fukuma, Ryohei; Seymour, Ben; Hosomi, Koichi; Kishima, Haruhiko; Shimizu, Takeshi; Yokoi, Hiroshi; Hirata, Masayuki; Yoshimine, Toshiki; Kamitani, Yukiyasu; Saitoh, Youichi

    2016-01-01

    The cause of pain in a phantom limb after partial or complete deafferentation is an important problem. A popular but increasingly controversial theory is that it results from maladaptive reorganization of the sensorimotor cortex, suggesting that experimental induction of further reorganization should affect the pain, especially if it results in functional restoration. Here we use a brain-machine interface (BMI) based on real-time magnetoencephalography signals to reconstruct affected hand mov...

  18. Practice Induces Function-Specific Changes in Brain Activity

    OpenAIRE

    Tamar R van Raalten; Ramsey, Nick F; Jeff Duyn; Jansma, Johan M.

    2008-01-01

    BACKGROUND: Practice can have a profound effect on performance and brain activity, especially if a task can be automated. Tasks that allow for automatization typically involve repeated encoding of information that is paired with a constant response. Much remains unknown about the effects of practice on encoding and response selection in an automated task. METHODOLOGY: To investigate function-specific effects of automatization we employed a variant of a Sternberg task with optimized separation...

  19. Brain tissue modifications induced by cholinergic therapy in Alzheimer's disease.

    Science.gov (United States)

    Bozzali, Marco; Parker, Geoff J M; Spanò, Barbara; Serra, Laura; Giulietti, Giovanni; Perri, Roberta; Magnani, Giuseppe; Marra, Camillo; G Vita, Maria; Caltagirone, Carlo; Cercignani, Mara

    2013-12-01

    A previous preliminary investigation based on a novel MRI approach to map anatomical connectivity revealed areas of increased connectivity in Alzheimer's disease (AD) but not in mild cognitive impairment patients. This prompted the hypothesis tested here, that these areas might reflect phenomena of brain plasticity driven by acetylcholinesterase inhibitors (AChEIs). Thirty-eight patients with probable AD (19 under medication with AChEIs and 19 drug-naïve) were recruited together with 11 healthy controls. All subjects had MRI scanning at 3T, including volumetric and diffusion-weighted scans. Probabilistic tractography was used to initiate streamlines from all parenchymal voxels, and anatomical connectivity maps (ACMs) were obtained by counting, among the total number of streamlines initiated, the fraction passing through each brain voxel. After normalization into standard space, ACMs were used to test for between-group comparisons, and for interactions between the exposure to AChEIs and global level of cognition. Patients with AD had reduced ACM values in the fornix, cingulum, and supramarginal gyri. The ACM value was strongly associated with the AChEI dosage-x-duration product in the anterior limb (non-motor pathway) of the internal capsule. Tractography from this region identified the anterior thalamic radiation as the main white matter (WM) tract passing through it. The reduced connectivity in WM bundles connecting the hippocampi with the rest of the brain (fornix/cingulum) suggests a possible mechanism for the spread of AD pathology. An intriguing explanation for the interaction between AChEIs and ACM is related to the mechanisms of brain plasticity, partially driven by neurotrophic properties of acetylcholine replacement. Copyright © 2012 Wiley Periodicals, Inc.

  20. Maternal education, prematurity and the risk of birth asphyxia in selected hospitals in Jakarta

    Directory of Open Access Journals (Sweden)

    Cicih Opitasari

    2016-03-01

    Full Text Available AbstrakLatar belakang: Asfiksia dapat menyebabkan kerusakan organ berat dan berakibat fatal pada bayi barulahir. Berdasarkan hasil analisis lanjut Riskesdas 2007, asfiksia merupakan penyebab kematian keduapada bayi setelah infeksi. Tujuan penelitian ini adalah untuk mengidentifikasi faktor risiko yang berkaitandengan kejadian bayi asfiksia pada bayi baru lahir.Metode: Data diambil dari rekam medik wanita hamil yang melahirkan di dua rumah sakit (RS diJakarta, yang dipilih secara purposif di antara yang melahirkan pada periode 1 Januari sampai 31Desember 2011. Kelahiran asfiksia ialah bayi baru lahir dengan skor Apgar kurang dari tujuh, satu menitsetelah lahir. Analisis data dilakukan dengan menggunakan regresi logistik.Hasil: Pada analisis ini diperoleh 2777 sampel dari 4191 yang memiliki data lengkap. Proporsi asfiksiapada bayi baru lahir adalah 6,5%. Jika dibandingkan wanita berpendidikan tinggi, wanita berpendidikanrendah memiliki risiko melahirkan bayi asfiksia 4,3 kali lebih tinggi [rasio odds suaian (ORa = 4,31;P=0,000], sedangkan wanita berpendidikan menengah dibandingkan dengan yang tinggi berisiko 3,3kali lebih tinggi melahirkan bayi dengan asfiksia (ORa=3,31; P=0,000.Selanjutnya, jika dibandingkan bayi cukup bulan, bayi prematur memiliki risiko 3,1 kali lebih tinggimengalami asfiksia (ORa=3,07; P=0,000, sedangkan bayi postmatur 63% (namun tidak signifikan lebihtinggi berisiko mengalami asfiksia (P=0.118.Kesimpulan: Wanita yang memiliki tingkat pendidikan rendah dan menengah serta bayi prematur memiliki risikolebih tinggi mempunyai bayi baru lahir yang asfiksia. (Health Science Journal of Indonesia 2015;6:111-5Kata kunci: pendidikan, prematur, asfiksia bayi baru lahir AbstractBackground: Birth asphyxia can causes hypoxic ischemic organ damage in neonates. According toadvanced Indonesian Basic Health Research 2007, asphyxia was the second highest cause of infant deathafter infection (13.8%. This study aimed to identify several risk

  1. Gluten-induced cognitive impairment ("brain fog") in coeliac disease.

    Science.gov (United States)

    Yelland, Gregory W

    2017-03-01

    Much is known about the serious neurological effects of gluten ingestion in coeliac disease patients, such as sporadic ataxia and peripheral neuropathy, although the causal links to gluten are still under debate. However, such disorders are observed in only a small percentage of coeliac patients. Much less is known about the transient cognitive impairments to memory, attention, executive function, and the speed of cognitive processing reported by the majority of patients with coeliac disease. These mild degradations of cognitive functions, referred to as "brain fog," are yet to be formally recognized as a medical or psychological condition. However, subtle tests of cognitive function are measurable in untreated patients with coeliac disease and improve over the first 12 months' therapy with a gluten-free diet. Such deficits also occur in patients with Crohn's disease, particularly in association with systemic inflammatory activity. Thus, cognitive impairments associated with brain fog are psychologically and neurologically real and improve with adherence to a gluten-free diet. There is not yet sufficient evidence to provide a definitive account of the mechanism by which gluten ingestion causes the impairments to cognitive function associated with brain fog, but current evidence suggests that it is more likely that the causal factor is not directly related to exposure to gluten. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  2. Molecular, Cellular and Functional Effects of Radiation-Induced Brain Injury: A Review.

    Science.gov (United States)

    Balentova, Sona; Adamkov, Marian

    2015-11-24

    Radiation therapy is the most effective non-surgical treatment of primary brain tumors and metastases. Preclinical studies have provided valuable insights into pathogenesis of radiation-induced injury to the central nervous system. Radiation-induced brain injury can damage neuronal, glial and vascular compartments of the brain and may lead to molecular, cellular and functional changes. Given its central role in memory and adult neurogenesis, the majority of studies have focused on the hippocampus. These findings suggested that hippocampal avoidance in cranial radiotherapy prevents radiation-induced cognitive impairment of patients. However, multiple rodent studies have shown that this problem is more complex. As the radiation-induced cognitive impairment reflects hippocampal and non-hippocampal compartments, it is of critical importance to investigate molecular, cellular and functional modifications in various brain regions as well as their integration at clinically relevant doses and schedules. We here provide a literature overview, including our previously published results, in order to support the translation of preclinical findings to clinical practice, and improve the physical and mental status of patients with brain tumors.

  3. Molecular, Cellular and Functional Effects of Radiation-Induced Brain Injury: A Review

    Directory of Open Access Journals (Sweden)

    Sona Balentova

    2015-11-01

    Full Text Available Radiation therapy is the most effective non-surgical treatment of primary brain tumors and metastases. Preclinical studies have provided valuable insights into pathogenesis of radiation-induced injury to the central nervous system. Radiation-induced brain injury can damage neuronal, glial and vascular compartments of the brain and may lead to molecular, cellular and functional changes. Given its central role in memory and adult neurogenesis, the majority of studies have focused on the hippocampus. These findings suggested that hippocampal avoidance in cranial radiotherapy prevents radiation-induced cognitive impairment of patients. However, multiple rodent studies have shown that this problem is more complex. As the radiation-induced cognitive impairment reflects hippocampal and non-hippocampal compartments, it is of critical importance to investigate molecular, cellular and functional modifications in various brain regions as well as their integration at clinically relevant doses and schedules. We here provide a literature overview, including our previously published results, in order to support the translation of preclinical findings to clinical practice, and improve the physical and mental status of patients with brain tumors.

  4. Xenon protects against blast-induced traumatic brain injury in an in vitro model.

    Science.gov (United States)

    Campos-Pires, Rita; Koziakova, Mariia; Yonis, Amina; Pau, Ashni; Macdonald, Warren; Harris, Katie; Edge, Christopher; Franks, Nicholas P; Mahoney, Peter; Dickinson, Robert

    2017-12-29

    The aim of this study was to evaluate the neuroprotective efficacy of the inert gas xenon as a treatment for blast-induced traumatic brain injury in an in vitro laboratory model. We developed a novel blast traumatic brain injury model using C57BL/6N mouse organotypic hippocampal brain-slice cultures exposed to a single shockwave, with the resulting injury quantified using propidium iodide fluorescence. A shock tube blast generator was used to simulate open field explosive blast shockwaves, modeled by the Friedlander waveform. Exposure to blast shockwave resulted in significant (pBlast-induced propidium iodide fluorescence overlapped with cleaved caspase 3 immunofluorescence, indicating that shockwave-induced cell death involves apoptosis. Xenon (50% atm) applied 1 hour following blast exposure reduced injury 24 hours (pblast traumatic brain injury reduces initial injury and prevents subsequent injury development in vitro. Our findings support the idea that xenon may be a potential first-line treatment for blast-induced traumatic brain injury.

  5. Fatores associados à asfixia perinatal Factors associated with perinatal asphyxia

    Directory of Open Access Journals (Sweden)

    Alfredo de Almeida Cunha

    2004-12-01

    stepwise logistic regression model. RESULTS: there were 39 (14% depressed newborns which were compared to 238 (86% not depressed babies. The final analysis (multivariate showed an association between low Apgar score and previous case of stillbirth (OR=52.6, preterm labor threat (OR=33.8, low birth weight, less than 2,500 g body weight (OR=11.2 and previous cesarean section (OR=7.4. Some factors acted as a protection, including birth weight, in grams (OR=0.9, female sex of the newborn (OR=0.1, medical complications (OR=0.4 and prematurity (gestational age < 37 weeks, OR=0.1. CONCLUSION: the study may help in the identification of fetuses at great risk of asphyxia, allowing proper reference within the health system and planning of effective assistance in neonatal intensive care units.

  6. Does aid induce brain drain? A panel data analysis

    National Research Council Canada - National Science Library

    Ugarte Ontiveros, Darwin; Verardi, Vincenzo

    2012-01-01

    Recent evidence suggests that aid induces migration. This result is nevertheless not very informative from a policy perspective since what counts in terms of welfare consequences is the composition of migration...

  7. DAMP signaling is a key pathway inducing immune modulation after brain injury.

    Science.gov (United States)

    Liesz, Arthur; Dalpke, Alexander; Mracsko, Eva; Antoine, Daniel J; Roth, Stefan; Zhou, Wei; Yang, Huan; Na, Shin-Young; Akhisaroglu, Mustafa; Fleming, Thomas; Eigenbrod, Tatjana; Nawroth, Peter P; Tracey, Kevin J; Veltkamp, Roland

    2015-01-14

    Acute brain lesions induce profound alterations of the peripheral immune response comprising the opposing phenomena of early immune activation and subsequent immunosuppression. The mechanisms underlying this brain-immune signaling are largely unknown. We used animal models for experimental brain ischemia as a paradigm of acute brain lesions and additionally investigated a large cohort of stroke patients. We analyzed release of HMGB1 isoforms by mass spectrometry and investigated its inflammatory potency and signaling pathways by immunological in vivo and in vitro techniques. Features of the complex behavioral sickness behavior syndrome were characterized by homecage behavior analysis. HMGB1 downstream signaling, particularly with RAGE, was studied in various transgenic animal models and by pharmacological blockade. Our results indicate that the cytokine-inducing, fully reduced isoform of HMGB1 was released from the ischemic brain in the hyperacute phase of stroke in mice and patients. Cytokines secreted in the periphery in response to brain injury induced sickness behavior, which could be abrogated by inhibition of the HMGB1-RAGE pathway or direct cytokine neutralization. Subsequently, HMGB1-release induced bone marrow egress and splenic proliferation of bone marrow-derived suppressor cells, inhibiting the adaptive immune responses in vivo and vitro. Furthermore, HMGB1-RAGE signaling resulted in functional exhaustion of mature monocytes and lymphopenia, the hallmarks of immune suppression after extensive ischemia. This study introduces the HMGB1-RAGE-mediated pathway as a key mechanism explaining the complex postischemic brain-immune interactions. Copyright © 2015 the authors 0270-6474/15/350583-16$15.00/0.

  8. Ethanol-Induced Neurodegeneration and Glial Activation in the Developing Brain

    Directory of Open Access Journals (Sweden)

    Mariko Saito

    2016-08-01

    Full Text Available Ethanol induces neurodegeneration in the developing brain, which may partially explain the long-lasting adverse effects of prenatal ethanol exposure in fetal alcohol spectrum disorders (FASD. While animal models of FASD show that ethanol-induced neurodegeneration is associated with glial activation, the relationship between glial activation and neurodegeneration has not been clarified. This review focuses on the roles of activated microglia and astrocytes in neurodegeneration triggered by ethanol in rodents during the early postnatal period (equivalent to the third trimester of human pregnancy. Previous literature indicates that acute binge-like ethanol exposure in postnatal day 7 (P7 mice induces apoptotic neurodegeneration, transient activation of microglia resulting in phagocytosis of degenerating neurons, and a prolonged increase in glial fibrillary acidic protein-positive astrocytes. In our present study, systemic administration of a moderate dose of lipopolysaccharides, which causes glial activation, attenuates ethanol-induced neurodegeneration. These studies suggest that activation of microglia and astrocytes by acute ethanol in the neonatal brain may provide neuroprotection. However, repeated or chronic ethanol can induce significant proinflammatory glial reaction and neurotoxicity. Further studies are necessary to elucidate whether acute or sustained glial activation caused by ethanol exposure in the developing brain can affect long-lasting cellular and behavioral abnormalities observed in the adult brain.

  9. T lymphocytes facilitate brain metastasis of breast cancer by inducing Guanylate-Binding Protein 1 expression.

    Science.gov (United States)

    Mustafa, Dana A M; Pedrosa, Rute M S M; Smid, Marcel; van der Weiden, Marcel; de Weerd, Vanja; Nigg, Alex L; Berrevoets, Cor; Zeneyedpour, Lona; Priego, Neibla; Valiente, Manuel; Luider, Theo M; Debets, Reno; Martens, John W M; Foekens, John A; Sieuwerts, Anieta M; Kros, Johan M

    2018-01-19

    The discovery of genes and molecular pathways involved in the formation of brain metastasis would direct the development of therapeutic strategies to prevent this deadly complication of cancer. By comparing gene expression profiles of Estrogen Receptor negative (ER-) primary breast tumors between patients who developed metastasis to brain and to organs other than brain, we found that T lymphocytes promote the formation of brain metastases. To functionally test the ability of T cells to promote brain metastasis, we used an in vitro blood-brain barrier (BBB) model. By co-culturing T lymphocytes with breast cancer cells, we confirmed that T cells increase the ability of breast cancer cells to cross the BBB. Proteomics analysis of the tumor cells revealed Guanylate-Binding Protein 1 (GBP1) as a key T lymphocyte-induced protein that enables breast cancer cells to cross the BBB. The GBP1 gene appeared to be up-regulated in breast cancer of patients who developed brain metastasis. Silencing of GBP1 reduced the ability of breast cancer cells to cross the in vitro BBB model. In addition, the findings were confirmed in vivo in an immunocompetent syngeneic mouse model. Co-culturing of ErbB2 tumor cells with activated T cells induced a significant increase in Gbp1 expression by the cancer cells. Intracardial inoculation of the co-cultured tumor cells resulted in preferential seeding to brain. Moreover, intracerebral outgrowth of the tumor cells was demonstrated. The findings point to a role of T cells in the formation of brain metastases in ER- breast cancers, and provide potential targets for intervention to prevent the development of cerebral metastases.

  10. Signals from the brain induce variation in avian facial shape.

    Science.gov (United States)

    Hu, Diane; Young, Nathan M; Xu, Qiuping; Jamniczky, Heather; Green, Rebecca M; Mio, Washington; Marcucio, Ralph S; Hallgrimsson, Benedikt

    2015-04-22

    How developmental mechanisms generate the phenotypic variation that is the raw material for evolution is largely unknown. Here, we explore whether variation in a conserved signaling axis between the brain and face contributes to differences in morphogenesis of the avian upper jaw. In amniotes, including both mice and avians, signals from the brain establish a signaling center in the ectoderm (the Frontonasal ectodermal zone or "FEZ") that directs outgrowth of the facial primordia. Here we show that the spatial organization of this signaling center differs among avians, and these correspond to Sonic hedgehog (Shh) expression in the basal forebrain and embryonic facial shape. In ducks this basal forebrain domain is present almost the entire width, while in chickens it is restricted to the midline. When the duck forebrain is unilaterally transplanted into stage matched chicken embryos the face on the treated side resembles that of the donor. Combined with previous findings, these results demonstrate that variation in a highly conserved developmental pathway has the potential to contribute to evolutionary differences in avian upper jaw morphology. Developmental Dynamics, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  11. Constraint-induced movement therapy promotes brain functional reorganization in stroke patients with hemiplegia

    Science.gov (United States)

    Wang, Wenqing; Wang, Aihui; Yu, Limin; Han, Xuesong; Jiang, Guiyun; Weng, Changshui; Zhang, Hongwei; Zhou, Zhiqiang

    2012-01-01

    Stroke patients with hemiplegia exhibit flexor spasms in the upper limb and extensor spasms in the lower limb, and their movement patterns vary greatly. Constraint-induced movement therapy is an upper limb rehabilitation technique used in stroke patients with hemiplegia; however, studies of lower extremity rehabilitation are scarce. In this study, stroke patients with lower limb hemiplegia underwent conventional Bobath therapy for 4 weeks as baseline treatment, followed by constraint-induced movement therapy for an additional 4 weeks. The 10-m maximum walking speed and Berg balance scale scores significantly improved following treatment, and lower extremity motor function also improved. The results of functional MRI showed that constraint-induced movement therapy alleviates the reduction in cerebral functional activation in patients, which indicates activation of functional brain regions and a significant increase in cerebral blood perfusion. These results demonstrate that constraint-induced movement therapy promotes brain functional reorganization in stroke patients with lower limb hemiplegia. PMID:25337108

  12. Constraint-induced movement therapy promotes brain functional reorganization in stroke patients with hemiplegia.

    Science.gov (United States)

    Wang, Wenqing; Wang, Aihui; Yu, Limin; Han, Xuesong; Jiang, Guiyun; Weng, Changshui; Zhang, Hongwei; Zhou, Zhiqiang

    2012-11-15

    Stroke patients with hemiplegia exhibit flexor spasms in the upper limb and extensor spasms in the lower limb, and their movement patterns vary greatly. Constraint-induced movement therapy is an upper limb rehabilitation technique used in stroke patients with hemiplegia; however, studies of lower extremity rehabilitation are scarce. In this study, stroke patients with lower limb hemiplegia underwent conventional Bobath therapy for 4 weeks as baseline treatment, followed by constraint-induced movement therapy for an additional 4 weeks. The 10-m maximum walking speed and Berg balance scale scores significantly improved following treatment, and lower extremity motor function also improved. The results of functional MRI showed that constraint-induced movement therapy alleviates the reduction in cerebral functional activation in patients, which indicates activation of functional brain regions and a significant increase in cerebral blood perfusion. These results demonstrate that constraint-induced movement therapy promotes brain functional reorganization in stroke patients with lower limb hemiplegia.

  13. Vanadyl sulfate administration protects the streptozotocin-induced oxidative damage to brain tissue in rats.

    Science.gov (United States)

    Yanardag, Refiye; Tunali, Sevim

    2006-06-01

    Diabetes mellitus manifests itself in a wide variety of complications and the symptoms of the disease are multifactorial. The present study was carried out to investigate the effects of vanadyl sulfate on biochemical parameters, enzyme activities and brain lipid peroxidation, glutathione and nonenzymatic glycosylation of normal- and streptozotocin-diabetic rats. Streptozotocin (STZ) was administered as a single dose (65 mg/kg) to induce diabetes. A dose of 100 mg/kg vanadyl sulfate was orally administered daily to STZ-diabetic and normal rats, separately until the end of the experiment, at day 60. In STZ-diabetic group, blood glucose, serum sialic and uric acid levels, serum catalase (CAT) and lactate dehydrogenase (LDH) activities, brain lipid peroxidation (LPO) and nonenzymatic glycosylation (NEG) increased, while brain glutathione (GSH) level and body weight decreased. In the diabetic group given vanadyl sulfate, blood glucose, serum sialic and uric acid levels, serum CAT and LDH activities and brain LPO and NEG levels decreased, but brain GSH and body weight increased. The present study showed that vanadyl sulfate exerted antioxidant effects and consequently may prevent brain damage caused by streptozotocin-induced diabetes.

  14. Biomechanical analysis of silicon microelectrode-induced strain in the brain

    Science.gov (United States)

    Lee, Hyunjung; Bellamkonda, Ravi V.; Sun, Wei; Levenston, Marc E.

    2005-12-01

    The ability to successfully interface the brain to external electrical systems is important both for fundamental understanding of our nervous system and for the development of neuroprosthetics. Silicon microelectrode arrays offer great promise in realizing this potential. However, when they are implanted into the brain, recording sensitivity is lost due to inflammation and astroglial scarring around the electrode. The inflammation and astroglial scar are thought to result from acute injury during electrode insertion as well as chronic injury caused by micromotion around the implanted electrode. To evaluate the validity of this assumption, the finite element method (FEM) was employed to analyze the strain fields around a single Michigan Si microelectrode due to simulated micromotion. Micromotion was mimicked by applying a force to the electrode, fixing the boundaries of the brain region and applying appropriate symmetry conditions to nodes lying on symmetry planes. Characteristics of the deformation fields around the electrode including maximum electrode displacement, strain fields and relative displacement between the electrode and the adjacent tissue were examined for varying degrees of physical coupling between the brain and the electrode. Our analysis demonstrates that when physical coupling between the electrode and the brain increases, the micromotion-induced strain of tissue around the electrode decreases as does the relative slip between the electrode and the brain. These results support the use of neuro-integrative coatings on electrode arrays as a means to reduce the micromotion-induced injury response.

  15. Functional photoacoustic tomography for neonatal brain imaging: developments and challenges

    Science.gov (United States)

    Hariri, Ali; Tavakoli, Emytis; Adabi, Saba; Gelovani, Juri; Avanaki, Mohammad R. N.

    2017-03-01

    Transfontanelle ultrasound imaging (TFUSI) is a routine diagnostic brain imaging method in infants who are born prematurely, whose skull bones have not completely fused together and have openings between them, so-called fontanelles. Open fontanelles in neonates provide acoustic windows, allowing the ultrasound beam to freely pass through. TFUSI is used to rule out neurological complications of premature birth including subarachnoid hemorrhage (SAH), intraventricular (IVH), subependimal (SEPH), subdural (SDH) or intracerebral (ICH) hemorrhages, as well as hypoxic brain injuries. TFUSI is widely used in the clinic owing to its low cost, safety, accessibility, and noninvasive nature. Nevertheless, the accuracy of TFUSI is limited. To address several limitations of current clinical imaging modalities, we develop a novel transfontanelle photoacoustic imaging (TFPAI) probe, which, for the first time, should allow for non-invasive structural and functional imaging of the infant brain. In this study, we test the feasibility of TFPAI for detection of experimentally-induced intra ventricular and Intraparenchymal hemorrhage phantoms in a sheep model with a surgically-induced cranial window which will serve as a model of neonatal fontanelle. This study is towards using the probe we develop for bedside monitoring of neonates with various disease conditions and complications affecting brain perfusion and oxygenation, including apnea, asphyxia, as well as for detection of various types of intracranial hemorrhages (SAH, IVH, SEPH, SDH, ICH).

  16. Induced Pluripotent Stem Cell-Derived Neural Cells Survive and Mature in the Nonhuman Primate Brain

    Directory of Open Access Journals (Sweden)

    Marina E. Emborg

    2013-03-01

    Full Text Available The generation of induced pluripotent stem cells (iPSCs opens up the possibility for personalized cell therapy. Here, we show that transplanted autologous rhesus monkey iPSC-derived neural progenitors survive for up to 6 months and differentiate into neurons, astrocytes, and myelinating oligodendrocytes in the brains of MPTP-induced hemiparkinsonian rhesus monkeys with a minimal presence of inflammatory cells and reactive glia. This finding represents a significant step toward personalized regenerative therapies.

  17. Diffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge.

    Science.gov (United States)

    Rowe, Rachel K; Ellis, Gavin I; Harrison, Jordan L; Bachstetter, Adam D; Corder, Gregory F; Van Eldik, Linda J; Taylor, Bradley K; Marti, Francesc; Lifshitz, Jonathan

    2016-01-01

    Nociceptive and neuropathic pain occurs as part of the disease process after traumatic brain injury (TBI) in humans. Central and peripheral inflammation, a major secondary injury process initiated by the traumatic brain injury event, has been implicated in the potentiation of peripheral nociceptive pain. We hypothesized that the inflammatory response to diffuse traumatic brain injury potentiates persistent pain through prolonged immune dysregulation. To test this, adult, male C57BL/6 mice were subjected to midline fluid percussion brain injury or to sham procedure. One cohort of mice was analyzed for inflammation-related cytokine levels in cortical biopsies and serum along an acute time course. In a second cohort, peripheral inflammation was induced seven days after surgery/injury with an intraplantar injection of carrageenan. This was followed by measurement of mechanical hyperalgesia, glial fibrillary acidic protein and Iba1 immunohistochemical analysis of neuroinflammation in the brain, and flow cytometric analysis of T-cell differentiation in mucosal lymph. Traumatic brain injury increased interleukin-6 and chemokine ligand 1 levels in the cortex and serum that peaked within 1-9 h and then resolved. Intraplantar carrageenan produced mechanical hyperalgesia that was potentiated by traumatic brain injury. Further, mucosal T cells from brain-injured mice showed a distinct deficiency in the ability to differentiate into inflammation-suppressing regulatory T cells (Tregs). We conclude that traumatic brain injury increased the inflammatory pain associated with cutaneous inflammation by contributing to systemic immune dysregulation. Regulatory T cells are immune suppressors and failure of T cells to differentiate into regulatory T cells leads to unregulated cytokine production which may contribute to the potentiation of peripheral pain through the excitation of peripheral sensory neurons. In addition, regulatory T cells are identified as a potential target for

  18. Electrical bioimpedance enabling prompt intervention in traumatic brain injury

    Science.gov (United States)

    Seoane, Fernando; Atefi, S. Reza

    2017-05-01

    Electrical Bioimpedance (EBI) is a well spread technology used in clinical practice across the world. Advancements in Textile material technology with conductive textile fabrics and textile-electronics integration have allowed exploring potential applications for Wearable Measurement Sensors and Systems exploiting. The sensing principle of electrical bioimpedance is based on the intrinsic passive dielectric properties of biological tissue. Using a pair of electrodes, tissue is electrically stimulated and the electrical response can be sensed with another pair of surface electrodes. EBI spectroscopy application for cerebral monitoring of neurological conditions such as stroke and perinatal asphyxia in newborns have been justified using animal studies and computational simulations. Such studies have shown proof of principle that neurological pathologies indeed modify the dielectric composition of the brain that is detectable via EBI. Similar to stroke, Traumatic Brain Injury (TBI) also affects the dielectric properties of brain tissue that can be detected via EBI measurements. Considering the portable and noninvasive characteristics of EBI it is potentially useful for prehospital triage of TBI patients where. In the battlefield blast induced Traumatic Brain Injuries are very common. Brain damage must be assessed promptly to have a chance to prevent severe damage or eventually death. The relatively low-complexity of the sensing hardware required for EBI sensing and the already proven compatibility with textile electrodes suggest the EBI technology is indeed a candidate for developing a handheld device equipped with a sensorized textile cap to produce an examination in minutes for enabling medically-guided prompt intervention.

  19. Neuroprotective profile of pyruvate against ethanol-induced neurodegeneration in developing mice brain.

    Science.gov (United States)

    Ullah, Najeeb; Naseer, Muhammad Imran; Ullah, Ikram; Kim, Tae Hyun; Lee, Hae Young; Kim, Myeong Ok

    2013-12-01

    Exposure to ethanol during developmental stages leads to several types of neurological disorders. Apoptotic neurodegeneration due to ethanol exposure is a main feature in alcoholism. Exposure of developing animals to alcohol induces apoptotic neuronal death and causes fetal alcohol syndrome. In the present study, we observed the possible protective effect of pyruvate against ethanol-induced neurodegeneration. Exposure of developing mice to ethanol (2.5 g/kg) induces apoptotic neurodegeneration and widespread neuronal cell death in the cortex and thalamus. Co-treatment of pyruvate (500 mg/kg) protects neuronal cell against ethanol by the reduced expression of caspase-3 in these brain regions. Immunohistochemical analysis and TUNNEL at 24 h showed that apoptotic cell death induced by ethanol in the cortex and thalamus is reduced by pyruvate. Histomorphological analysis at 24 h with cresyl violet staining also proved that pyruvate reduced the number of neuronal cell loss in the cortex and thalamus. The results showed that ethanol increased the expression of caspase-3 and thus induced apoptotic neurodegeneration in the developing mice cortex and thalamus, while co-treatment of pyruvate inhibits the induction of caspase-3 and reduced the cell death in these brain regions. These findings, therefore, showed that treatment of pyruvate inhibits ethanol-induced neuronal cell loss in the postnatal seven (P7) developing mice brain and may appear as a safe neuroprotectant for treating neurodegenerative disorders in newborns and infants.

  20. Melatonin attenuated brain death tissue extract-induced cardiac damage by suppressing DAMP signaling.

    Science.gov (United States)

    Sung, Pei-Hsun; Lee, Fan-Yen; Lin, Ling-Chun; Chen, Kuan-Hung; Lin, Hung-Sheng; Shao, Pei-Lin; Li, Yi-Chen; Chen, Yi-Ling; Lin, Kun-Chen; Yuen, Chun-Man; Chang, Hsueh-Wen; Lee, Mel S; Yip, Hon-Kan

    2018-01-09

    We tested the hypothesis that melatonin prevents brain death (BD) tissue extract (BDEX)-induced cardiac damage by suppressing inflammatory damage-associated molecular pattern (DAMP) signaling in rats. Six hours after BD induction, levels of a DAMP component (HMGB1) and inflammatory markers (TLR-2, TLR-4, MYD88, IκB, NF-κB, IL-1β, IFN-γ, TNF-α and IL-6) were higher in brain tissue from BD animals than controls. Levels of HMGB1 and inflammatory markers were higher in BDEX-treated H9C2 cardiac myoblasts than in cells treated with healthy brain tissue extract. These increases were attenuated by melatonin but re-induced with luzindole (all P DAMP inflammatory axis.

  1. Effect of Bupropion Treatment on Brain Activation Induced by Cigarette-Related Cues in Smokers

    Science.gov (United States)

    Culbertson, Christopher S.; Bramen, Jennifer; Cohen, Mark S.; London, Edythe D.; Olmstead, Richard E.; Gan, Joanna J.; Costello, Matthew R.; Shulenberger, Stephanie; Mandelkern, Mark A.; Brody, Arthur L.

    2011-01-01

    Context Nicotine-dependent smokers exhibit craving and brain activation in the prefrontal and limbic regions when presented with cigarette-related cues. Bupropion hydrochloride treatment reduces cue-induced craving in cigarette smokers; however, the mechanism by which bupropion exerts this effect has not yet been described. Objective To assess changes in regional brain activation in response to cigarette-related cues from before to after treatment with bupropion (vs placebo). Design Randomized, double-blind, before-after controlled trial. Setting Academic brain imaging center. Participants Thirty nicotine-dependent smokers (paid volunteers). Interventions Participants were randomly assigned to receive 8 weeks of treatment with either bupropion or a matching placebo pill (double-blind). Main Outcome Measures Subjective cigarette craving ratings and regional brain activations (blood oxygen level-dependent response) in response to viewing cue videos. Results Bupropion-treated participants reported less craving and exhibited reduced activation in the left ventral striatum, right medial orbitofrontal cortex, and bilateral anterior cingulate cortex from before to after treatment when actively resisting craving compared with placebo-treated participants. When resisting craving, reduction in self-reported craving correlated with reduced regional brain activation in the bilateral medial orbitofrontal and left anterior cingulate cortices in all participants. Conclusions Treatment with bupropion is associated with improved ability to resist cue-induced craving and a reduction in cue-induced activation of limbic and prefrontal brain regions, while a reduction in craving, regardless of treatment type, is associated with reduced activation in prefrontal brain regions. PMID:21199957

  2. Neuroprotective effect of ginger in the brain of streptozotocin-induced diabetic rats.

    Science.gov (United States)

    El-Akabawy, Gehan; El-Kholy, Wael

    2014-05-01

    Diabetes mellitus results in neuronal damage caused by increased intracellular glucose leading to oxidative stress. Recent evidence revealed the potential of ginger for reducing diabetes-induced oxidative stress markers. The aim of this study is to investigate, for the first time, whether the antioxidant properties of ginger has beneficial effects on the structural brain damage associated with diabetes. We investigated the observable neurodegenerative changes in the frontal cortex, dentate gyrus, and cerebellum after 4, 6, and 8 weeks of streptozotocin (STZ)-induced diabetes in rats and the effect(s) of ginger (500 mg/kg/day). Sections of frontal cortex, dentate gyrus, and cerebellum were stained with hematoxylin and eosin and examined using light microscopy. In addition, quantitative immunohistochemical assessments of the expression of inducible NO synthase (iNOS), tumor necrosis factor (TNF)-α, caspase-3, glial fibrillary acidic protein (GFAP), acetylcholinesterase (AChE), and Ki67 were performed. Our results revealed a protective role of ginger on the diabetic brain via reducing oxidative stress, apoptosis, and inflammation. In addition, this study revealed that the beneficial effect of ginger was also mediated by modulating the astroglial response to the injury, reducing AChE expression, and improving neurogenesis. These results represent a new insight into the beneficial effects of ginger on the structural alterations of diabetic brain and suggest that ginger might be a potential therapeutic strategy for the treatment of diabetic-induced damage in brain. Copyright © 2014 Elsevier GmbH. All rights reserved.

  3. Red wine prevents brain oxidative stress and nephropathy in streptozotocin-induced diabetic rats.

    Science.gov (United States)

    Montilla, Pedro; Barcos, Montserrat; Munoz, Maria C; Bujalance, Inmaculada; Munoz-Castaneda, Juan R; Tunez, Isaac

    2005-09-30

    We have studied the effects of red wine on brain oxidative stress and nephropathy in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced in Wistar rats with a single intraperitonally injection of STZ (50 mg/kg). Two weeks before and four weeks after injection, red wine was given orally in both normal and diabetic rats. Blood samples were taken from the neck vascular trunk in order to determine the glucose, triglycerides, total cholesterol, HDL-cholesterol (HDL-c), atherogenic index (AI), total protein, blood urea nitrogen (BUN), creatinine, insulin, lipid peroxidation products, reduced glutathione (GSH) and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. As well, we estimated the lipid peroxidtion, GSH and SOD, GSH-Px and catalase activities in brain and renal homogenates, and the excretion of albumin, proteins and glucose in urine over 24 h period. The administration of STZ caused significant increases in levels of glycosuria, proteinuria, albuminuria, glycemia, total cholesterol and AI, as well as in lipid peroxidation products in the brain, plasma and kidney, whereas it decreased the GSH content and SOD, GSH-Px and catalase activities. Treatment with red wine significantly prevented the changes induced by STZ. These data suggested that red wine has a protective effect against brain oxidative stress, diabetic nephropathy and diabetes induced by STZ, as well as it protects against hypercholesterolemia and atherogenic risk.

  4. Using non-invasive brain stimulation to augment motor training-induced plasticity

    Directory of Open Access Journals (Sweden)

    Pascual-Leone Alvaro

    2009-03-01

    Full Text Available Abstract Therapies for motor recovery after stroke or traumatic brain injury are still not satisfactory. To date the best approach seems to be the intensive physical therapy. However the results are limited and functional gains are often minimal. The goal of motor training is to minimize functional disability and optimize functional motor recovery. This is thought to be achieved by modulation of plastic changes in the brain. Therefore, adjunct interventions that can augment the response of the motor system to the behavioural training might be useful to enhance the therapy-induced recovery in neurological populations. In this context, noninvasive brain stimulation appears to be an interesting option as an add-on intervention to standard physical therapies. Two non-invasive methods of inducing electrical currents into the brain have proved to be promising for inducing long-lasting plastic changes in motor systems: transcranial magnetic stimulation (TMS and transcranial direct current stimulation (tDCS. These techniques represent powerful methods for priming cortical excitability for a subsequent motor task, demand, or stimulation. Thus, their mutual use can optimize the plastic changes induced by motor practice, leading to more remarkable and outlasting clinical gains in rehabilitation. In this review we discuss how these techniques can enhance the effects of a behavioural intervention and the clinical evidence to date.

  5. Using non-invasive brain stimulation to augment motor training-induced plasticity.

    Science.gov (United States)

    Bolognini, Nadia; Pascual-Leone, Alvaro; Fregni, Felipe

    2009-03-17

    Therapies for motor recovery after stroke or traumatic brain injury are still not satisfactory. To date the best approach seems to be the intensive physical therapy. However the results are limited and functional gains are often minimal. The goal of motor training is to minimize functional disability and optimize functional motor recovery. This is thought to be achieved by modulation of plastic changes in the brain. Therefore, adjunct interventions that can augment the response of the motor system to the behavioural training might be useful to enhance the therapy-induced recovery in neurological populations. In this context, noninvasive brain stimulation appears to be an interesting option as an add-on intervention to standard physical therapies. Two non-invasive methods of inducing electrical currents into the brain have proved to be promising for inducing long-lasting plastic changes in motor systems: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). These techniques represent powerful methods for priming cortical excitability for a subsequent motor task, demand, or stimulation. Thus, their mutual use can optimize the plastic changes induced by motor practice, leading to more remarkable and outlasting clinical gains in rehabilitation. In this review we discuss how these techniques can enhance the effects of a behavioural intervention and the clinical evidence to date.

  6. Change in brain network connectivity during PACAP38-induced migraine attacks

    DEFF Research Database (Denmark)

    Amin, Faisal Mohammad; Hougaard, Anders; Magon, Stefano

    2016-01-01

    , and visual cortices) and decreased (right cerebellum and left frontal lobe) connectivity with DMN. We found no resting-state network changes after VIP (n = 15). CONCLUSIONS: PACAP38-induced migraine attack is associated with altered connectivity of several large-scale functional networks of the brain....

  7. Neuropsychological consequences of very low birth weight and asphyxia at term: follow-up until school-age.

    Science.gov (United States)

    Korkman, M; Liikanen, A; Fellman, V

    1996-04-01

    This prospective, longitudinal study examined neuropsychological consequences of different conditions associated with risks of perinatal asphyxia. Four groups of children, 5 to 9 years of age, were studied: (1) very low birth weight (VLBW) children born small for gestational age (SGA) (n = 34); (2) VLBW children born appropriate for gestational age (AGA) (n = 43); (3) children with signs of birth asphyxia at term (birth asphyxia) (n = 36), and (4) control children (n = 45). Moderately and severely disabled children were excluded. The WISC-R and the NEPSY, a new neuropsychological assessment consisting of attention, language, motor, sensory, visuospatial, and memory subtests, were administered. The VLBW-SGA group had the poorest test results. The VLBW-AGA group was somewhat less impaired, whereas the birth asphyxia group performed at the control group level. Impairment, when present, tended to be diffuse in all groups, affecting psychometric intelligence, naming, visuo-motor performance, tactile finger discrimination, attention, and phonological analysis.

  8. Galectin-1 suppresses methamphetamine induced neuroinflammation in human brain microvascular endothelial cells: Neuroprotective role in maintaining blood brain barrier integrity.

    Science.gov (United States)

    Parikh, Neil U; Aalinkeel, R; Reynolds, J L; Nair, B B; Sykes, D E; Mammen, M J; Schwartz, S A; Mahajan, S D

    2015-10-22

    Methamphetamine (Meth) abuse can lead to the breakdown of the blood-brain barrier (BBB) integrity leading to compromised CNS function. The role of Galectins in the angiogenesis process in tumor-associated endothelial cells (EC) is well established; however no data are available on the expression of Galectins in normal human brain microvascular endothelial cells and their potential role in maintaining BBB integrity. We evaluated the basal gene/protein expression levels of Galectin-1, -3 and -9 in normal primary human brain microvascular endothelial cells (BMVEC) that constitute the BBB and examined whether Meth altered Galectin expression in these cells, and if Galectin-1 treatment impacted the integrity of an in-vitro BBB. Our results showed that BMVEC expressed significantly higher levels of Galectin-1 as compared to Galectin-3 and -9. Meth treatment increased Galectin-1 expression in BMVEC. Meth induced decrease in TJ proteins ZO-1, Claudin-3 and adhesion molecule ICAM-1 was reversed by Galectin-1. Our data suggests that Galectin-1 is involved in BBB remodeling and can increase levels of TJ proteins ZO-1 and Claudin-3 and adhesion molecule ICAM-1 which helps maintain BBB tightness thus playing a neuroprotective role. Galectin-1 is thus an important regulator of immune balance from neurodegeneration to neuroprotection, which makes it an important therapeutic agent/target in the treatment of drug addiction and other neurological conditions. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Fatty Acid Induced Insulin Resistance in the Brain

    OpenAIRE

    Oh, Hyoung Il

    2013-01-01

    The prevalence of obesity, which is considered as a disease, has been increasing uncontrollably over the last two decades. Obesity is a state of disregulated energy homeostasis characterized by hypothalamic resistance to adiposity signals (insulin and leptin). While many factors are involved in the development of obesity, excess dietary fat has been proposed as one of the main causal factors. This causes disrupted energy homeostasis by inducing both leptin and insulin resistance in the centra...

  10. Bitter taste stimuli induce differential neural codes in mouse brain.

    Directory of Open Access Journals (Sweden)

    David M Wilson

    Full Text Available A growing literature suggests taste stimuli commonly classified as "bitter" induce heterogeneous neural and perceptual responses. Here, the central processing of bitter stimuli was studied in mice with genetically controlled bitter taste profiles. Using these mice removed genetic heterogeneity as a factor influencing gustatory neural codes for bitter stimuli. Electrophysiological activity (spikes was recorded from single neurons in the nucleus tractus solitarius during oral delivery of taste solutions (26 total, including concentration series of the bitter tastants quinine, denatonium benzoate, cycloheximide, and sucrose octaacetate (SOA, presented to the whole mouth for 5 s. Seventy-nine neurons were sampled; in many cases multiple cells (2 to 5 were recorded from a mouse. Results showed bitter stimuli induced variable gustatory activity. For example, although some neurons responded robustly to quinine and cycloheximide, others displayed concentration-dependent activity (p<0.05 to quinine but not cycloheximide. Differential activity to bitter stimuli was observed across multiple neurons recorded from one animal in several mice. Across all cells, quinine and denatonium induced correlated spatial responses that differed (p<0.05 from those to cycloheximide and SOA. Modeling spatiotemporal neural ensemble activity revealed responses to quinine/denatonium and cycloheximide/SOA diverged during only an early, at least 1 s wide period of the taste response. Our findings highlight how temporal features of sensory processing contribute differences among bitter taste codes and build on data suggesting heterogeneity among "bitter" stimuli, data that challenge a strict monoguesia model for the bitter quality.

  11. Mecamylamine attenuates dexamethasone-induced anxiety-like behavior in association with brain derived neurotrophic factor upregulation in rat brains.

    Science.gov (United States)

    Park, Dong Ik; Kim, Hong Gi; Jung, Woo Ram; Shin, Min Kyoo; Kim, Kil Lyong

    2011-01-01

    Mecamylamine (MEC), which was initially developed as a ganglionic blocker for the treatment of hypertension has been investigated as a potent antagonist for most types of nicotinic acetylcholine receptors (nAChRs). Most studies of MEC have focused on its inhibitory effects for nAChRs; however its biological uses have recently been expanded to the treatment of psychological disorders accompanying anxiety-related symptoms. Although MEC shows obvious anxiolytic action, there is no clear evidence on its function. In this study, we investigated whether MEC affects brain derived neurotrophic factor (BDNF) expression in vitro and in vivo. MEC increased BDNF expression in differentiated SH-SY5Y cells and the cerebral cortex region of rat brains. To determine if the anxiolytic effect of MEC is associated with BDNF upregulation, the elevated plus maze (EPM) task was conducted in a dexamethasone (DEX)-induced anxiety model. MEC reduced DEX-induced anxiety-like behavior, and increased BDNF expression in the cerebral cortex of rats. These results suggest that the anxiolytic effect of MEC in EPM might be associated with BDNF upregulation in the cerebral cortex region of rats. The therapeutic efficacy of MEC for anxiety might be partly dependent on BDNF modulation. Copyright © 2011. Published by Elsevier Ltd.

  12. Protection from cyanide-induced brain injury by the Nrf2 transcriptional activator carnosic acid.

    Science.gov (United States)

    Zhang, Dongxian; Lee, Brian; Nutter, Anthony; Song, Paul; Dolatabadi, Nima; Parker, James; Sanz-Blasco, Sara; Newmeyer, Traci; Ambasudhan, Rajesh; McKercher, Scott R; Masliah, Eliezer; Lipton, Stuart A

    2015-06-01

    Cyanide is a life-threatening, bioterrorist agent, preventing cellular respiration by inhibiting cytochrome c oxidase, resulting in cardiopulmonary failure, hypoxic brain injury, and death within minutes. However, even after treatment with various antidotes to protect cytochrome oxidase, cyanide intoxication in humans can induce a delayed-onset neurological syndrome that includes symptoms of Parkinsonism. Additional mechanisms are thought to underlie cyanide-induced neuronal damage, including generation of reactive oxygen species. This may account for the fact that antioxidants prevent some aspects of cyanide-induced neuronal damage. Here, as a potential preemptive countermeasure against a bioterrorist attack with cyanide, we tested the CNS protective effect of carnosic acid (CA), a pro-electrophilic compound found in the herb rosemary. CA crosses the blood-brain barrier to up-regulate endogenous antioxidant enzymes via activation of the Nrf2 transcriptional pathway. We demonstrate that CA exerts neuroprotective effects on cyanide-induced brain damage in cultured rodent and human-induced pluripotent stem cell-derived neurons in vitro, and in vivo in various brain areas of a non-Swiss albino mouse model of cyanide poisoning that simulates damage observed in the human brain. Cyanide, a potential bioterrorist agent, can produce a chronic delayed-onset neurological syndrome that includes symptoms of Parkinsonism. Here, cyanide poisoning treated with the proelectrophillic compound carnosic acid, results in reduced neuronal cell death in both in vitro and in vivo models through activation of the Nrf2/ARE transcriptional pathway. Carnosic acid is therefore a potential treatment for the toxic central nervous system (CNS) effects of cyanide poisoning. ARE, antioxidant responsive element; Nrf2 (NFE2L2, Nuclear factor (erythroid-derived 2)-like 2). © 2015 International Society for Neurochemistry.

  13. Neuroprotective effects of cactus polysaccharide on oxygen and glucose deprivation induced damage in rat brain slices.

    Science.gov (United States)

    Huang, Xianju; Li, Qin; Zhang, Yingpei; Lü, Qing; Guo, Lianjun; Huang, Lin; He, Zhi

    2008-06-01

    1. The neuroprotective effect of cactus polysaccharide (CP) on oxygen and glucose deprivation (OGD) and reoxygenation (REO)-induced damage in the cortical and hippocampal slices of rat brain was investigated. 2. Cell viability was evaluated by using the 2, 3, 5-triphenyl tetrazolium chloride (TTC) method. The fluorescence of propidium iodide (PI) staining was used for quantification of cellular survival, and lactate dehydrogenase (LDH) activity in incubation medium was assessed by LDH assay to evaluate the degree of injury. 3. The OGD ischemic condition significantly decreased cellular viability and increased LDH release in the incubation medium. CP (0.2 mg/l approximately 2 mg/l) protected brain slices from OGD injury in a dosage dependent manner as demonstrated by increased A 490 value of TTC, decreased PI intensity and LDH release. At the above concentration, CP also prevented the increase of nitric oxide (NO) content and inducible nitric oxide synthase (iNOS) activity induced by OGD. 4. CP can protect the brain slices (cortical and hippocampus) against injury induced by OGD. Its neuroprotective effect may be partly mediated by the NO/iNOS system induced by OGD insult.

  14. [Protective effect of salidroside against high altitude hypoxia-induced brain injury in rats].

    Science.gov (United States)

    Dong, Xiaoru; Zhang, Xiangnan; Li, Dan; Li, Bin; Wang, Jiye; Meng, Shanshan; Luo, Wenjing; Zhang, Wenbin

    2015-10-01

    To observe the protective effect of salidroside against brain injury in rats exposed to hypobaric hypoxia, and investigate the molecular mechanism of salidroside in the prevention of hypobaric hypoxia-induced brain injury. Rats were placed in experiment module simulating 6000 m altitude to establish acute hypobaric hypoxia-induced brain injury models. Their respiratory frequency was observed and recorded. Cell apoptosis in the hippocampal dentate gyrus (DG) was detected by TUNEL assay; the expressions of Ras homolog family member A (RhoA), phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated c-Jun N-terminal kinase (p-JNK) were detected by Western blotting. After acute exposure to 6000 m altitude, the respiratory frequency of the rats increased remarkably. The simulation of hypobaric hypoxia induced cell apoptosis in hippocampal DG region, and salidroside intervention inhibited the process of cell apoptosis. The expressions of RhoA, p-ERK, p-JNK decreased after hypobaric hypoxia exposure. Salidroside intervention reversed RhoA expression and raised the levels of p-ERK and p-JNK. Acute exposure to hypobaric hypoxia can induce cell apoptosis in rat hippocampal DG, and salidroside can protect the cells from the exposure-induced apoptosis.

  15. Transcriptional Profile of HIV-induced Nuclear Translocation of Amyloid β in Brain Endothelial Cells

    Science.gov (United States)

    András, Ibolya E.; Rampersaud, Evadnie; Eum, Sung Yong; Toborek, Michal

    2015-01-01

    Background and Aims Increased amyloid deposition in HIV-infected brains may contribute to the pathogenesis of neurocognitive dysfunction in infected patients. We have previously shown that exposure to HIV results in enhanced amyloid β (Aβ) levels in human brain microvascular endothelial cells, suggesting that brain endothelial cells contribute to accumulation of Aβ in HIV-infected brains. Importantly, Aβ not only accumulates in the cytoplasm of HIV-exposed cells but also enters the nuclei of brain endothelial cells. Methods cDNA microarray analysis was performed in order to examine changes in the transcriptional profile associated with Aβ nuclear entry in the presence of HIV-1. Results Gene network analysis indicated that inhibition of nuclear entry of Aβ resulted in enrichment in gene sets involved in apoptosis and survival, endoplasmic reticulum stress response, immune response, cell cycle, DNA damage, oxidative stress, cytoskeleton remodeling and transforming growth factor b (TGFβ) receptor signaling. Conclusions The obtained data indicate that HIV-induced Aβ nuclear uptake affects several cellular stress-related pathways relevant for HIV-induced Aβ pathology. PMID:25446617

  16. Erythropoietin protects the in vitro blood-brain barrier against VEGF-induced permeability.

    Science.gov (United States)

    Martínez-Estrada, Ofelia María; Rodríguez-Millán, Elisabeth; González-De Vicente, Esther; Reina, Manuel; Vilaró, Senén; Fabre, Myriam

    2003-11-01

    The blood-brain barrier (BBB) ensures the homeostasis of the brain microenvironment, mostly through complex tight junctions between brain endothelial cells that prevent the passage of hydrophilic molecules from blood to brain and vice versa. A recent study has shown in vivo that systemic administration of erythropoietin (Epo) protects against brain injury. Using an in vitro model of the bovine BBB, we observed that the expression of the Epo receptor is modulated by its ligand and hypoxic stimuli such as vascular endothelial growth factor (VEGF) treatment. In addition, Epo protects against the VEGF-induced permeability of the BBB, decreases the levels of endothelial nitric oxide synthase and restores junction proteins. The kinetic transport experiments revealed the capacity of Epo to cross the in vitro BBB in a saturable and specific way. Our results suggest a new mechanism for Epo-induced neuroprotection, in which circulating Epo controls and maintains the BBB through an Epo receptor signalling pathway and the re-establishment of cell junctions.

  17. Asphyxia-related risk factors and their timing in spastic cerebral palsy

    DEFF Research Database (Denmark)

    Nielsen, Lene F.; Schendel, Diana; Grove, Jakob

    2008-01-01

    Objective To investigate the association of asphyxia-related conditions (reducing blood flow or blood oxygen levels in the fetus) with spastic cerebral palsy (CP) considering different gestational age groups and the timing of risk. Design Population-based case-control study. Setting Danish Cerebral...... Palsy Register in eastern Denmark and Danish Medical Birth Register. Population or Sample 271 singletons with spastic CP and 217 singleton controls, frequency matched by gestational age group, born 1982-1990 in eastern Denmark. Methods Data were abstracted from medical records, and a priori asphyxia...... an especially high risk for spastic quadriplegia. Placental and cord complications were present in 21% of cases and 12% of controls. Conclusions The risk for spastic quadriplegia from placental infarction may be linked in some cases with abnormal fetal growth (17% of all children with spastic quadriplegia and 3...

  18. Pheromone-induced odor learning modifies Fos expression in the newborn rabbit brain.

    Science.gov (United States)

    Charra, R; Datiche, F; Gigot, V; Schaal, B; Coureaud, G

    2013-01-15

    Associative learning contributes crucially to adjust the behavior of neonates to the permanently changing environment. In the European rabbit, the mammary pheromone (MP) excreted in milk triggers sucking behavior in newborns, and additionally promotes very rapid learning of initially neutral odor cues. Such stimuli become then as active as the MP itself to elicit the orocephalic motor responses involved in suckling. In this context, the rabbit is an interesting model to address the question of brain circuits early engaged by learning and memory. Here, we evaluated the brain activation (olfactory bulb and central regions) induced in 4-day-old pups by an odorant (ethyl acetoacetate, EAA) after single pairing with the MP and its subsequent acquired ability to elicit sucking-related behavior (conditioned group) or after mere exposure to EAA alone (unconditioned group). The brain-wide mapping of c-Fos expression was used to compare neural activation patterns in both groups. Evidence of high immunostaining to odorant EAA occurred in the mitral+granule cells layer of the main olfactory bulb in pups previously exposed to EAA in association with the MP. These pups also showed higher expression of Fos in the piriform cortex, the hypothalamic lateral preoptic area and the amygdala (cortical and basal nuclei). Thus, MP-induced odor learning induces rapid brain modifications in rabbit neonates. The cerebral framework supporting the acquisition appears however different compared to the circuit involved in the processing of the MP itself. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. Modafinil Reverses Phencyclidine-Induced Deficits in Cognitive Flexibility, Cerebral Metabolism, and Functional Brain Connectivity

    Science.gov (United States)

    Dawson, Neil; Thompson, Rhiannon J.; McVie, Allan; Thomson, David M.; Morris, Brian J.; Pratt, Judith A.

    2012-01-01

    Objective: In the present study, we employ mathematical modeling (partial least squares regression, PLSR) to elucidate the functional connectivity signatures of discrete brain regions in order to identify the functional networks subserving PCP-induced disruption of distinct cognitive functions and their restoration by the procognitive drug modafinil. Methods: We examine the functional connectivity signatures of discrete brain regions that show overt alterations in metabolism, as measured by semiquantitative 2-deoxyglucose autoradiography, in an animal model (subchronic phencyclidine [PCP] treatment), which shows cognitive inflexibility with relevance to the cognitive deficits seen in schizophrenia. Results: We identify the specific components of functional connectivity that contribute to the rescue of this cognitive inflexibility and to the restoration of overt cerebral metabolism by modafinil. We demonstrate that modafinil reversed both the PCP-induced deficit in the ability to switch attentional set and the PCP-induced hypometabolism in the prefrontal (anterior prelimbic) and retrosplenial cortices. Furthermore, modafinil selectively enhanced metabolism in the medial prelimbic cortex. The functional connectivity signatures of these regions identified a unifying functional subsystem underlying the influence of modafinil on cerebral metabolism and cognitive flexibility that included the nucleus accumbens core and locus coeruleus. In addition, these functional connectivity signatures identified coupling events specific to each brain region, which relate to known anatomical connectivity. Conclusions: These data support clinical evidence that modafinil may alleviate cognitive deficits in schizophrenia and also demonstrate the benefit of applying PLSR modeling to characterize functional brain networks in translational models relevant to central nervous system dysfunction. PMID:20810469

  20. Ascorbic acid glucoside reduces neurotoxicity and glutathione depletion in mouse brain induced by nitrotriazole radiosensitazer.

    Science.gov (United States)

    Cherdyntseva, Nadezda V; Ivanova, Anna A; Ivanov, Vladimir V; Cherdyntsev, Evgeny; Nair, Cherupally Krishnan Krishnan; Kagiya, Tsutomu V

    2013-01-01

    To investigate the potential of the anti-oxidant ascorbic acid glucoside (AA-2G) to modulate neurotoxicity induced by high doses of nitrotriazole radiosensitizer. Male and female C56Bl/6xCBA hybrid mice aged 8-14 weeks (weight 18-24 g) were used. Nitrotriazole drug radiosensitizer sanazole at a high dose of 2, 1 g/kg was per os administered to induce neurotoxicity at mice. Ascorbic acid glucoside was given 30 min before the sanazole administration. Serum ascorbic acid, brain glutathione level, as well as behavioral performance using open field apparatus were measured. Administration of high (non-therapeutic) doses of the nitrotriazole drug sanazole results in neurotoxicity in mice as evidenced from behavioral performance, emotional activity and depletion of the cellular antioxidant, glutathione, in the brain. The serum levels of ascorbic acid was also found reduced in high dose sanazole treated animals. Per os administration of ascorbic acid glucoside significantly reduced the neurotoxicity. This effect was associated with the prevention of glutathione depletion in mouse brain and restoring the ascorbic acid level in serum. Administration of ascorbic acid glucoside, but not ascorbic acid, before sanazole administration protected from sanazole-induced neurotoxicity by preventing the decrease in the brain reduced glutathione level and providing high level of ascorbic acid in plasma.

  1. Ascorbic acid glucoside reduces neurotoxicity and glutathione depletion in mouse brain induced by nitrotriazole radiosensitazer

    Directory of Open Access Journals (Sweden)

    Nadezda V Cherdyntseva

    2013-01-01

    Full Text Available Aim: To investigate the potential of the anti-oxidant ascorbic acid glucoside (AA-2G to modulate neurotoxicity induced by high doses of nitrotriazole radiosensitizer. Materials and Methods: Male and female C56Bl/6xCBA hybrid mice aged 8-14 weeks (weight 18-24 g were used. Nitrotriazole drug radiosensitizer sanazole at a high dose of 2, 1 g/kg was per os administered to induce neurotoxicity at mice. Ascorbic acid glucoside was given 30 min before the sanazole administration. Serum ascorbic acid, brain glutathione level, as well as behavioral performance using open field apparatus were measured. Results: Administration of high (non-therapeutic doses of the nitrotriazole drug sanazole results in neurotoxicity in mice as evidenced from behavioral performance, emotional activity and depletion of the cellular antioxidant, glutathione, in the brain. The serum levels of ascorbic acid was also found reduced in high dose sanazole treated animals. Per os administration of ascorbic acid glucoside significantly reduced the neurotoxicity. This effect was associated with the prevention of glutathione depletion in mouse brain and restoring the ascorbic acid level in serum. Conclusion: Administration of ascorbic acid glucoside, but not ascorbic acid, before sanazole administration protected from sanazole-induced neurotoxicity by preventing the decrease in the brain reduced glutathione level and providing high level of ascorbic acid in plasma.

  2. Neuroprotective Effect of Dexmedetomidine on Hyperoxia-Induced Toxicity in the Neonatal Rat Brain

    Directory of Open Access Journals (Sweden)

    Marco Sifringer

    2015-01-01

    Full Text Available Dexmedetomidine is a highly selective agonist of α2-receptors with sedative, anxiolytic, analgesic, and anesthetic properties. Neuroprotective effects of dexmedetomidine have been reported in various brain injury models. In the present study, we investigated the effects of dexmedetomidine on neurodegeneration, oxidative stress markers, and inflammation following the induction of hyperoxia in neonatal rats. Six-day-old Wistar rats received different concentrations of dexmedetomidine (1, 5, or 10 µg/kg bodyweight and were exposed to 80% oxygen for 24 h. Sex-matched littermates kept in room air and injected with normal saline or dexmedetomidine served as controls. Dexmedetomidine pretreatment significantly reduced hyperoxia-induced neurodegeneration in different brain regions of the neonatal rat. In addition, dexmedetomidine restored the reduced/oxidized glutathione ratio and attenuated the levels of malondialdehyde, a marker of lipid peroxidation, after exposure to high oxygen concentration. Moreover, administration of dexmedetomidine induced downregulation of IL-1β on mRNA and protein level in the developing rat brain. Dexmedetomidine provides protections against toxic oxygen induced neonatal brain injury which is likely associated with oxidative stress signaling and inflammatory cytokines. Our results suggest that dexmedetomidine may have a therapeutic potential since oxygen administration to neonates is sometimes inevitable.

  3. Application of a classification system focusing on potential asphyxia for cases of sudden unexpected infant death.

    Science.gov (United States)

    Randall, Brad; Donelan, Kent; Koponen, Mark; Sens, Mary Ann; Krous, Henry F

    2012-03-01

    Current classification schemes for sudden unexpected infant death (SUID) may not be optimal for capturing scene events that potentially predispose to asphyxia. (1) To compare causes of death in a group of SUID cases assigned by multiple reviewers using our recently published classification scheme for SUID that is based on asphyxial risk at the death scene, and (2) To compare these newly assigned causes of death to that originally assigned by the medical examiners of record who performed the autopsies. Five reviewers independently assigned causes of death for 117 cases of SUID, including 83 originally diagnosed as sudden infant death syndrome (SIDS), accessioned into the San Diego SIDS/SUDC Research Project from the San Diego County Medical Examiner's Office. The diagnostic categories are: A: SIDS; B: Unexplained-Potentially Asphyxia; C: Unexplained-Other Potential Causes of Death; D: Unclassified-Other; E: Unclassified; and F: Known Cause of Death. The reviewers collectively opined that conditions at the death scene contributed to or caused death in 32-50% of all of the 117 cases as well as in 40-59% of the 83 originally diagnosed SIDS cases. Another cause of death was considered plausible in 2-12% of the SIDS cases. Application of this new classification system resulted in 55-69% decrease in SIDS diagnoses. Asphyxia as a potential contributor to, or as the specific cause of death, appears to exist in a large percentage of cases designated as SIDS using other classification schemes. When certifiers use a classification system that focuses upon potential asphyxia in determining the cause of death the incidence of SIDS dramatically declines.

  4. The "Bermuda triangle" of neonatal neurology: cerebral palsy, neonatal encephalopathy, and intrapartum asphyxia.

    Science.gov (United States)

    Shevell, Michael I

    2004-03-01

    The terms "cerebral palsy," "neonatal encephalopathy," and "intrapartum asphyxia" are frequently used in pediatric neurology. This article presents concise, verifiable definitions for each of these entities based on our current understanding and formulates the nature of the interrelationships between them. The aim is to provide a level of clarity that will enhance diagnostic and pathogenetic precision and minimize conceptual misunderstanding. This should aid future therapeutic and research efforts in this important area.

  5. PACAP38/PAC1 signaling induces bone marrow-derived cells homing to ischemic brain.

    Science.gov (United States)

    Lin, Chen-Huan; Chiu, Lian; Lee, Hsu-Tung; Chiang, Chun-Wei; Liu, Shih-Ping; Hsu, Yung-Hsiang; Lin, Shinn-Zong; Hsu, Chung Y; Hsieh, Chia-Hung; Shyu, Woei-Cherng

    2015-04-01

    Understanding stem cell homing, which is governed by environmental signals from the surrounding niche, is important for developing effective stem cell-based repair strategies. The molecular mechanism by which the brain under ischemic stress recruits bone marrow-derived cells (BMDCs) to the vascular niche remains poorly characterized. Here we report that hypoxia-inducible factor-1α (HIF-1α) activation upregulates pituitary adenylate cyclase-activating peptide 38 (PACAP38), which in turn activates PACAP type 1 receptor (PAC1) under hypoxia in vitro and cerebral ischemia in vivo. BMDCs homing to endothelial cells in the ischemic brain are mediated by HIF-1α activation of the PACAP38-PAC1 signaling cascade followed by upregulation of cellular prion protein and α6-integrin to enhance the ability of BMDCs to bind laminin in the vascular niche. Exogenous PACAP38 confers a similar effect in facilitating BMDCs homing into the ischemic brain, resulting in reduction of ischemic brain injury. These findings suggest a novel HIF-1α-activated PACAP38-PAC1 signaling process in initiating BMDCs homing into the ischemic brain for reducing brain injury and enhancing functional recovery after ischemic stroke. © 2015 The Authors. STEM CELLS Published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

  6. Induced sensorimotor brain plasticity controls pain in phantom limb patients

    Science.gov (United States)

    Yanagisawa, Takufumi; Fukuma, Ryohei; Seymour, Ben; Hosomi, Koichi; Kishima, Haruhiko; Shimizu, Takeshi; Yokoi, Hiroshi; Hirata, Masayuki; Yoshimine, Toshiki; Kamitani, Yukiyasu; Saitoh, Youichi

    2016-01-01

    The cause of pain in a phantom limb after partial or complete deafferentation is an important problem. A popular but increasingly controversial theory is that it results from maladaptive reorganization of the sensorimotor cortex, suggesting that experimental induction of further reorganization should affect the pain, especially if it results in functional restoration. Here we use a brain–machine interface (BMI) based on real-time magnetoencephalography signals to reconstruct affected hand movements with a robotic hand. BMI training induces significant plasticity in the sensorimotor cortex, manifested as improved discriminability of movement information and enhanced prosthetic control. Contrary to our expectation that functional restoration would reduce pain, the BMI training with the phantom hand intensifies the pain. In contrast, BMI training designed to dissociate the prosthetic and phantom hands actually reduces pain. These results reveal a functional relevance between sensorimotor cortical plasticity and pain, and may provide a novel treatment with BMI neurofeedback. PMID:27807349

  7. Copeptin concentration in cord blood in infants with early-onset sepsis, chorioamnionitis and perinatal asphyxia

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    Aebi Christoph

    2011-05-01

    Full Text Available Abstract Background Vasopressin is one of the most important physiological stress and shock hormones. Copeptin, a stable vasopressin precursor, is a promising sepsis marker in adults. In contrast, its involvement in neonatal diseases remains unknown. The aim of this study was to establish copeptin concentrations in neonates of different stress states such as sepsis, chorioamnionitis and asphyxia. Methods Copeptin cord blood concentration was determined using the BRAHMS kryptor assay. Neonates with early-onset sepsis (EOS, n = 30, chorioamnionitis (n = 33 and asphyxia (n = 25 were compared to a control group of preterm and term (n = 155 neonates. Results Median copeptin concentration in cord blood was 36 pmol/l ranging from undetectable to 5498 pmol/l (IQR 7 - 419. Copeptin cord blood concentrations were non-normally distributed and increased with gestational age (p Conclusions Copeptin concentrations were strongly related to factors associated with perinatal stress such as birth acidosis, asphyxia and vaginal delivery. In contrast, copeptin appears to be unsuitable for the diagnosis of EOS.

  8. Prognostic correlative values of the late-infancy MRI pattern in term infants with perinatal asphyxia.

    Science.gov (United States)

    Tekgul, Hasan; Serdaroglu, Gul; Yalman, Osman; Tutuncuoglu, Sarenur

    2004-07-01

    The aim of this study was to define the risk ratios of the late-infancy magnetic resonance imaging pattern for long-term outcome in term infants with perinatal asphyxia. We evaluated 65 term infants with perinatal asphyxia and performed magnetic resonance imaging examinations between 4-12 months of age. Magnetic resonance imaging scans were classified as follows: (1) periventricular leukomalacia in 21 (32%) infants, (2) marked cortical atrophy in 17 (26%) infants, (3) multicystic encephalomalacia in 10 (15%) infants, (4) deep gray matter involvement in 8 (12%) infants, (5) focal cortical involvement in 6 (9%) infants, (6) myelination delay in 3 (5%) infants. The overall outcome was favorable in 19 (29%) of 65 infants. Infants with diffuse cortical involvement (multicystic encephalomalacia and marked cortical atrophy) are four times (odds ratio: 4.4 and 4.1 respectively) more likely to attain the unfavorable outcome than the infants with other patterns of magnetic resonance imaging. Infants with focal cortical involvement had relatively favorable outcome in 60% of the cases. In conclusion, it appears that the overall outcome of infants with perinatal asphyxia correlated well with the magnetic resonance imaging patterns obtained between 4 and 12 months of age.

  9. Hyperbaric Oxygen Therapy Can Induce Angiogenesis and Regeneration of Nerve Fibers in Traumatic Brain Injury Patients

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    Sigal Tal

    2017-10-01

    Full Text Available Background: Recent clinical studies in stroke and traumatic brain injury (TBI victims suffering chronic neurological injury present evidence that hyperbaric oxygen therapy (HBOT can induce neuroplasticity.Objective: To assess the neurotherapeutic effect of HBOT on prolonged post-concussion syndrome (PPCS due to TBI, using brain microstructure imaging.Methods: Fifteen patients afflicted with PPCS were treated with 60 daily HBOT sessions. Imaging evaluation was performed using Dynamic Susceptibility Contrast-Enhanced (DSC and Diffusion Tensor Imaging (DTI MR sequences. Cognitive evaluation was performed by an objective computerized battery (NeuroTrax.Results: HBOT was initiated 6 months to 27 years (10.3 ± 3.2 years from injury. After HBOT, DTI analysis showed significantly increased fractional anisotropy values and decreased mean diffusivity in both white and gray matter structures. In addition, the cerebral blood flow and volume were increased significantly. Clinically, HBOT induced significant improvement in the memory, executive functions, information processing speed and global cognitive scores.Conclusions: The mechanisms by which HBOT induces brain neuroplasticity can be demonstrated by highly sensitive MRI techniques of DSC and DTI. HBOT can induce cerebral angiogenesis and improve both white and gray microstructures indicating regeneration of nerve fibers. The micro structural changes correlate with the neurocognitive improvements.

  10. Etanercept, an inhibitor of TNF-a, prevents propofol-induced neurotoxicity in the developing brain.

    Science.gov (United States)

    Chen, Bo; Deng, Xiaoyuan; Wang, Bin; Liu, Hongliang

    2016-12-01

    Propofol can induce acute neuronal apoptosis, neuronal loss or long-term cognitive impairment when exposed in neonatal rodents, but the mechanisms by which propofol induces developmental neurotoxicity are unclear. Recent studies have demonstrated that propofol can increase the TNF-α level in the developing brain, but there is a lack of direct evidence to show whether TNF-α is partially or fully involved in propofol-induced neurotoxicity. The present study shows that propofol exposure in neonatal rats induces an increase of TNF-α in the cerebral spinal fluid, hippocampus and prefrontal cortex (PFC). Etanercept, a TNF-α inhibitor, prevents propofol-induced short- or long-term neuronal apoptosis, neuronal loss, synaptic loss and long-term cognitive impairment. Furthermore, mTNF-α (precursor of TNF-α) expression in microglia cells is increased after propofol anaesthesia in either the hippocampus or PFC, but mTNF-α expression in neurons is only increased in the PFC. These findings suggest that TNF-α may mediate propofol-induced developmental neurotoxicity, and etanercept can provide neural protection. Microglia are the main cellular source of TNF-α after propofol exposure, while the synthesis of TNF-α in neurons is brain-region selective. Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.

  11. Cognitive tutoring induces widespread neuroplasticity and remediates brain function in children with mathematical learning disabilities.

    Science.gov (United States)

    Iuculano, Teresa; Rosenberg-Lee, Miriam; Richardson, Jennifer; Tenison, Caitlin; Fuchs, Lynn; Supekar, Kaustubh; Menon, Vinod

    2015-09-30

    Competency with numbers is essential in today's society; yet, up to 20% of children exhibit moderate to severe mathematical learning disabilities (MLD). Behavioural intervention can be effective, but the neurobiological mechanisms underlying successful intervention are unknown. Here we demonstrate that eight weeks of 1:1 cognitive tutoring not only remediates poor performance in children with MLD, but also induces widespread changes in brain activity. Neuroplasticity manifests as normalization of aberrant functional responses in a distributed network of parietal, prefrontal and ventral temporal-occipital areas that support successful numerical problem solving, and is correlated with performance gains. Remarkably, machine learning algorithms show that brain activity patterns in children with MLD are significantly discriminable from neurotypical peers before, but not after, tutoring, suggesting that behavioural gains are not due to compensatory mechanisms. Our study identifies functional brain mechanisms underlying effective intervention in children with MLD and provides novel metrics for assessing response to intervention.

  12. Functional photoacoustic imaging to observe regional brain activation induced by cocaine hydrochloride

    Science.gov (United States)

    Jo, Janggun; Yang, Xinmai

    2011-09-01

    Photoacoustic microscopy (PAM) was used to detect small animal brain activation in response to drug abuse. Cocaine hydrochloride in saline solution was injected into the blood stream of Sprague Dawley rats through tail veins. The rat brain functional change in response to the injection of drug was then monitored by the PAM technique. Images in the coronal view of the rat brain at the locations of 1.2 and 3.4 mm posterior to bregma were obtained. The resulted photoacoustic (PA) images showed the regional changes in the blood volume. Additionally, the regional changes in blood oxygenation were also presented. The results demonstrated that PA imaging is capable of monitoring regional hemodynamic changes induced by drug abuse.

  13. Brain remodelling following endothelin-1 induced stroke in conscious rats.

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    Hima C S Abeysinghe

    Full Text Available The extent of stroke damage in patients affects the range of subsequent pathophysiological responses that influence recovery. Here we investigate the effect of lesion size on development of new blood vessels as well as inflammation and scar formation and cellular responses within the subventricular zone (SVZ following transient focal ischemia in rats (n = 34. Endothelin-1-induced stroke resulted in neurological deficits detected between 1 and 7 days (P<0.001, but significant recovery was observed beyond this time. MCID image analysis revealed varying degrees of damage in the ipsilateral cortex and striatum with infarct volumes ranging from 0.76-77 mm3 after 14 days, where larger infarct volumes correlated with greater functional deficits up to 7 days (r = 0.53, P<0.05. Point counting of blood vessels within consistent sample regions revealed that increased vessel numbers correlated significantly with larger infarct volumes 14 days post-stroke in the core cortical infarct (r = 0.81, P<0.0001, core striatal infarct (r = 0.91, P<0.005 and surrounding border zones (r = 0.66, P<0.005; and r = 0.73, P<0.05. Cell proliferation within the SVZ also increased with infarct size (P<0.01 with a greater number of Nestin/GFAP positive cells observed extending towards the border zone in rats with larger infarcts. Lesion size correlated with both increased microglia and astrocyte activation, with severely diffuse astrocyte transition, the formation of the glial scar being more pronounced in rats with larger infarcts. Thus stroke severity affects cell proliferation within the SVZ in response to injury, which may ultimately make a further contribution to glial scar formation, an important factor to consider when developing treatment strategies that promote neurogenesis.

  14. Seizure-induced brain lesions: A wide spectrum of variably reversible MRI abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    Cianfoni, A., E-mail: acianfoni@hotmail.com [Neuroradiology, Neurocenter of Italian Switzerland–Ospedale regionale Lugano, Via Tesserete 46, Lugano, 6900, CH (Switzerland); Caulo, M., E-mail: caulo@unich.it [Department of Neuroscience and Imaging, University of Chieti, Via dei Vestini 33, 6610 Chieti. Italy (Italy); Cerase, A., E-mail: alfonsocerase@gmail.com [Unit of Neuroimaging and Neurointervention NINT, Department of Neurological and Sensorineural Sciences, Azienda Ospedaliera Universitaria Senese, Policlinico “Santa Maria alle Scotte”, V.le Bracci 16, Siena (Italy); Della Marca, G., E-mail: dellamarca@rm.unicatt.it [Neurology Dept., Catholic University of Rome, L.go F Vito 1, 00100, Rome (Italy); Falcone, C., E-mail: carlo_falc@libero.it [Radiology Dept., Catholic University of Rome, L.go F Vito 1, 00100, Rome (Italy); Di Lella, G.M., E-mail: gdilella@rm.unicatt.it [Radiology Dept., Catholic University of Rome, L.go F Vito 1, 00100, Rome (Italy); Gaudino, S., E-mail: sgaudino@sirm.org [Radiology Dept., Catholic University of Rome, L.go F Vito 1, 00100, Rome (Italy); Edwards, J., E-mail: edwardjc@musc.edu [Neuroscience Dept., Medical University of South Carolina, 96J Lucas st, 29425, Charleston, SC (United States); Colosimo, C., E-mail: colosimo@rm.unicatt.it [Radiology Dept., Catholic University of Rome, L.go F Vito 1, 00100, Rome (Italy)

    2013-11-01

    Introduction MRI abnormalities in the postictal period might represent the effect of the seizure activity, rather than its structural cause. Material and Methods Retrospective review of clinical and neuroimaging charts of 26 patients diagnosed with seizure-related MR-signal changes. All patients underwent brain-MRI (1.5-Tesla, standard pre- and post-contrast brain imaging, including DWI-ADC in 19/26) within 7 days from a seizure and at least one follow-up MRI, showing partial or complete reversibility of the MR-signal changes. Extensive clinical work-up and follow-up, ranging from 3 months to 5 years, ruled out infection or other possible causes of brain damage. Seizure-induced brain-MRI abnormalities remained a diagnosis of exclusion. Site, characteristics and reversibility of MRI changes, and association with characteristics of seizures were determined. Results MRI showed unilateral (13/26) and bilateral abnormalities, with high (24/26) and low (2/26) T2-signal, leptomeningeal contrast-enhancement (2/26), restricted diffusion (9/19). Location of abnormality was cortical/subcortical, basal ganglia, white matter, corpus callosum, cerebellum. Hippocampus was involved in 10/26 patients. Reversibility of MRI changes was complete in 15, and with residual gliosis or focal atrophy in 11 patients. Reversibility was noted between 15 and 150 days (average, 62 days). Partial simple and complex seizures were associated with hippocampal involvement (p = 0.015), status epilepticus with incomplete reversibility of MRI abnormalities (p = 0.041). Conclusions Seizure or epileptic status can induce transient, variably reversible MRI brain abnormalities. Partial seizures are frequently associated with hippocampal involvement and status epilepticus with incompletely reversible lesions. These seizure-induced MRI abnormalities pose a broad differential diagnosis; increased awareness may reduce the risk of misdiagnosis and unnecessary intervention.

  15. Endoplasmic Reticulum Stress Mediates Methamphetamine-Induced Blood-Brain Barrier Damage.

    Science.gov (United States)

    Qie, Xiaojuan; Wen, Di; Guo, Hongyan; Xu, Guanjie; Liu, Shuai; Shen, Qianchao; Liu, Yi; Zhang, Wenfang; Cong, Bin; Ma, Chunling

    2017-01-01

    Methamphetamine (METH) abuse causes serious health problems worldwide, and long-term use of METH disrupts the blood-brain barrier (BBB). Herein, we explored the potential mechanism of endoplasmic reticulum (ER) stress in METH-induced BBB endothelial cell damage in vitro and the therapeutic potential of endoplasmic reticulum stress inhibitors for METH-induced BBB disruption in C57BL/6J mice. Exposure of immortalized BMVEC (bEnd.3) cells to METH significantly decreased cell viability, induced apoptosis, and diminished the tightness of cell monolayers. METH activated ER stress sensor proteins, including PERK, ATF6, and IRE1, and upregulated the pro-apoptotic protein CHOP. The ER stress inhibitors significantly blocked the upregulation of CHOP. Knockdown of CHOP protected bEnd.3 cells from METH-induced cytotoxicity. Furthermore, METH elevated the production of reactive oxygen species (ROS) and induced the dysfunction of mitochondrial characterized by a Bcl2/Bax ratio decrease, mitochondrial membrane potential collapse, and cytochrome c. ER stress release was partially reversed by ROS inhibition, and cytochrome c release was partially blocked by knockdown of CHOP. Finally, PBA significantly attenuated METH-induced sodium fluorescein (NaFluo) and Evans Blue leakage, as well as tight junction protein loss, in C57BL/6J mice. These data suggest that BBB endothelial cell damage was caused by METH-induced endoplasmic reticulum stress, which further induced mitochondrial dysfunction, and that PBA was an effective treatment for METH-induced BBB disruption.

  16. Endoplasmic Reticulum Stress Mediates Methamphetamine-Induced Blood–Brain Barrier Damage

    Directory of Open Access Journals (Sweden)

    Xiaojuan Qie

    2017-09-01

    Full Text Available Methamphetamine (METH abuse causes serious health problems worldwide, and long-term use of METH disrupts the blood–brain barrier (BBB. Herein, we explored the potential mechanism of endoplasmic reticulum (ER stress in METH-induced BBB endothelial cell damage in vitro and the therapeutic potential of endoplasmic reticulum stress inhibitors for METH-induced BBB disruption in C57BL/6J mice. Exposure of immortalized BMVEC (bEnd.3 cells to METH significantly decreased cell viability, induced apoptosis, and diminished the tightness of cell monolayers. METH activated ER stress sensor proteins, including PERK, ATF6, and IRE1, and upregulated the pro-apoptotic protein CHOP. The ER stress inhibitors significantly blocked the upregulation of CHOP. Knockdown of CHOP protected bEnd.3 cells from METH-induced cytotoxicity. Furthermore, METH elevated the production of reactive oxygen species (ROS and induced the dysfunction of mitochondrial characterized by a Bcl2/Bax ratio decrease, mitochondrial membrane potential collapse, and cytochrome c. ER stress release was partially reversed by ROS inhibition, and cytochrome c release was partially blocked by knockdown of CHOP. Finally, PBA significantly attenuated METH-induced sodium fluorescein (NaFluo and Evans Blue leakage, as well as tight junction protein loss, in C57BL/6J mice. These data suggest that BBB endothelial cell damage was caused by METH-induced endoplasmic reticulum stress, which further induced mitochondrial dysfunction, and that PBA was an effective treatment for METH-induced BBB disruption.

  17. Effect of fructose diphosphate combined with large-dose vitamin C therapy on the myocardial oxidative stress injury after neonatal asphyxia

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    Chun-Hua Liang1

    2017-04-01

    Full Text Available Objective: To study the effect of fructose diphosphate combined with large-dose vitamin C therapy on the myocardial oxidative stress injury after neonatal asphyxia. Methods: 40 patients with neonatal asphyxia who were treated in our hospital between June 2013 and April 2016 were collected and divided into the control group (n=20 who received large-dose vitamin C therapy and the observation group (n=20 who received fructose diphosphate combined with large-dose vitamin C therapy according to the double-blind randomized control method, and the treatment lasted for 10 d. Immediately after admission and after 10 d of treatment, RIA method was used to detect the serum levels of oxidative stress indexes, color Doppler diasonograph was used to determine left cardiac function parameters, and the myocardial enzyme spectrum detector was used to determine myocardial enzyme spectrum index levels. Results: Immediately after admission, the differences in the systemic oxidative stress degree, the left cardiac function damage degree and the myocardial enzyme spectrum index levels were not statistically significant between two groups of patients (P>0.05. After 10 d of treatment, serum malondialdehyde (MDA, advanced oxidation protein products (AOPP, creatine kinase isoenzyme (CK-MB, N-terminal pro-brain natriuretic peptide (Nt-proBNP, heart-type fatty acid-binding protein (H-FABP and troponin I (cTnI contents of observation group were lower than those of control group (P<0.05 while superoxide dismutase (SOD content was higher than that of control group (P<0.05, and the left cardiac function parameter ejection time (ET level was higher than that of control group (P<0.05 while left ventricular isovolumetric contraction time (ICT and left ventricular isovolumetric relaxation time (IRT levels were lower than those of control group (P<0.05. Conclusion: Fructose diphosphate combined with large-dose vitamin C can reduce the systemic oxidative stress of neonatal asphyxia

  18. Reduction in radiation-induced brain injury by use of pentobarbital or lidocaine protection

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    Oldfield, E.H.; Friedman, R.; Kinsella, T.; Moquin, R.; Olson, J.J.; Orr, K.; DeLuca, A.M. (National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (USA))

    1990-05-01

    To determine if barbiturates would protect brain at high doses of radiation, survival rates in rats that received whole-brain x-irradiation during pentobarbital- or lidocaine-induced anesthesia were compared with those of control animals that received no medication and of animals anesthetized with ketamine. The animals were shielded so that respiratory and digestive tissues would not be damaged by the radiation. Survival rates in rats that received whole-brain irradiation as a single 7500-rad dose under pentobarbital- or lidocaine-induced anesthesia was increased from between from 0% and 20% to between 45% and 69% over the 40 days of observation compared with the other two groups (p less than 0.007). Ketamine anesthesia provided no protection. There were no notable differential effects upon non-neural tissues, suggesting that pentobarbital afforded protection through modulation of ambient neural activity during radiation exposure. Neural suppression during high-dose cranial irradiation protects brain from acute and early delayed radiation injury. Further development and application of this knowledge may reduce the incidence of radiation toxicity of the central nervous system (CNS) and may permit the safe use of otherwise unsafe doses of radiation in patients with CNS neoplasms.

  19. Glioblastoma cell-secreted interleukin-8 induces brain endothelial cell permeability via CXCR2.

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    Julie Dwyer

    Full Text Available Glioblastoma constitutes the most aggressive and deadly of brain tumors. As yet, both conventional and molecular-based therapies have met with limited success in treatment of this cancer. Among other explanations, the heterogeneity of glioblastoma and the associated microenvironment contribute to its development, as well as resistance and recurrence in response to treatments. Increased vascularity suggests that tumor angiogenesis plays an important role in glioblastoma progression. However, the molecular crosstalk between endothelial and glioblastoma cells requires further investigation. To examine the effects of glioblastoma-derived signals on endothelial homeostasis, glioblastoma cell secretions were collected and used to treat brain endothelial cells. Here, we present evidence that the glioblastoma secretome provides pro-angiogenic signals sufficient to disrupt VE-cadherin-mediated cell-cell junctions and promote endothelial permeability in brain microvascular endothelial cells. An unbiased angiogenesis-specific antibody array screen identified the chemokine, interleukin-8, which was further demonstrated to function as a key factor involved in glioblastoma-induced permeability, mediated through its receptor CXCR2 on brain endothelia. This underappreciated interface between glioblastoma cells and associated endothelium may inspire the development of novel therapeutic strategies to induce tumor regression by preventing vascular permeability and inhibiting angiogenesis.

  20. Detection of electroporation-induced membrane permeabilization states in the brain using diffusion-weighted MRI

    DEFF Research Database (Denmark)

    Mahmood, Faisal; Hansen, Rasmus H; Agerholm-Larsen, Birgit

    2015-01-01

    (DW-MRI) as a quantitative method for detecting EP-induced membrane permeabilization of brain tissue using a rat brain model. MATERIAL AND METHODS: Fifty-four anesthetized Sprague-Dawley male rats were electroporated in the right hemisphere, using different voltage levels to induce no permeabilization...... (NP), transient membrane permeabilization (TMP), and permanent membrane permeabilization (PMP), respectively. DW-MRI was acquired 5 minutes, 2 hours, 24 hours and 48 hours after EP. Histology was performed for validation of the permeabilization states. Tissue content of water, Na+, K+, Ca2......+, and extracellular volume were determined. The Kruskal-Wallis test was used to compare the DW-MRI parameters, apparent diffusion coefficient (ADC) and kurtosis, at different voltage levels. The two-sample Mann- Whitney test with Holm's Bonferroni correction was used to identify pairs of significantly different...

  1. Demethoxycurcumin Retards Cell Growth and Induces Apoptosis in Human Brain Malignant Glioma GBM 8401 Cells

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    Tzuu-Yuan Huang

    2012-01-01

    Full Text Available Demethoxycurcumin (DMC; a curcumin-related demethoxy compound has been recently shown to display antioxidant and antitumor activities. It has also produced a potent chemopreventive action against cancer. In the present study, the antiproliferation (using the MTT assay, DMC was found to have cytotoxic activities against GBM 8401 cell with IC50 values at 22.71 μM and induced apoptosis effects of DMC have been investigated in human brain malignant glioma GBM 8401 cells. We have studied the mitochondrial membrane potential (MMP, DNA fragmentation, caspase activation, and NF-κB transcriptional factor activity. By these approaches, our results indicated that DMC has produced an inhibition of cell proliferation as well as the activation of apoptosis in GBM 8401 cells. Both effects were observed to increase in proportion with the dosage of DMC treatment, and the apoptosis was induced by DMC in human brain malignant glioma GBM 8401 cells via mitochondria- and caspase-dependent pathways.

  2. Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A.

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    Fayçal Guedj

    Full Text Available Individuals with partial HSA21 trisomies and mice with partial MMU16 trisomies containing an extra copy of the DYRK1A gene present various alterations in brain morphogenesis. They present also learning impairments modeling those encountered in Down syndrome. Previous MRI and histological analyses of a transgenic mice generated using a human YAC construct that contains five genes including DYRK1A reveal that DYRK1A is involved, during development, in the control of brain volume and cell density of specific brain regions. Gene dosage correction induces a rescue of the brain volume alterations. DYRK1A is also involved in the control of synaptic plasticity and memory consolidation. Increased gene dosage results in brain morphogenesis defects, low BDNF levels and mnemonic deficits in these mice. Epigallocatechin gallate (EGCG - a member of a natural polyphenols family, found in great amount in green tea leaves - is a specific and safe DYRK1A inhibitor. We maintained control and transgenic mice overexpressing DYRK1A on two different polyphenol-based diets, from gestation to adulthood. The major features of the transgenic phenotype were rescued in these mice.

  3. Motor Learning Induces Plasticity in the Resting Brain-Drumming Up a Connection.

    Science.gov (United States)

    Amad, Ali; Seidman, Jade; Draper, Stephen B; Bruchhage, Muriel M K; Lowry, Ruth G; Wheeler, James; Robertson, Andrew; Williams, Steven C R; Smith, Marcus S

    2017-03-01

    Neuroimaging methods have recently been used to investigate plasticity-induced changes in brain structure. However, little is known about the dynamic interactions between different brain regions after extensive coordinated motor learning such as drumming. In this article, we have compared the resting-state functional connectivity (rs-FC) in 15 novice healthy participants before and after a course of drumming (30-min drumming sessions, 3 days a week for 8 weeks) and 16 age-matched novice comparison participants. To identify brain regions showing significant FC differences before and after drumming, without a priori regions of interest, a multivariate pattern analysis was performed. Drum training was associated with an increased FC between the posterior part of bilateral superior temporal gyri (pSTG) and the rest of the brain (i.e., all other voxels). These regions were then used to perform seed-to-voxel analysis. The pSTG presented an increased FC with the premotor and motor regions, the right parietal lobe and a decreased FC with the cerebellum. Perspectives and the potential for rehabilitation treatments with exercise-based intervention to overcome impairments due to brain diseases are also discussed. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  4. Combined cognitive-psychological-physical intervention induces reorganization of intrinsic functional brain architecture in older adults.

    Science.gov (United States)

    Zheng, Zhiwei; Zhu, Xinyi; Yin, Shufei; Wang, Baoxi; Niu, Yanan; Huang, Xin; Li, Rui; Li, Juan

    2015-01-01

    Mounting evidence suggests that enriched mental, physical, and socially stimulating activities are beneficial for counteracting age-related decreases in brain function and cognition in older adults. Here, we used functional magnetic resonance imaging (fMRI) to demonstrate the functional plasticity of brain activity in response to a combined cognitive-psychological-physical intervention and investigated the contribution of the intervention-related brain changes to individual performance in healthy older adults. The intervention was composed of a 6-week program of combined activities including cognitive training, Tai Chi exercise, and group counseling. The results showed improved cognitive performance and reorganized regional homogeneity of spontaneous fluctuations in the blood oxygen level-dependent (BOLD) signals in the superior and middle temporal gyri, and the posterior lobe of the cerebellum, in the participants who attended the intervention. Intriguingly, the intervention-induced changes in the coherence of local spontaneous activity correlated with the improvements in individual cognitive performance. Taken together with our previous findings of enhanced resting-state functional connectivity between the medial prefrontal cortex and medial temporal lobe regions following a combined intervention program in older adults, we conclude that the functional plasticity of the aging brain is a rather complex process, and an effective cognitive-psychological-physical intervention is helpful for maintaining a healthy brain and comprehensive cognition during old age.

  5. Acute Ethanol-Induced Changes in Edema and Metabolite Concentrations in Rat Brain

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    Huimin Liu

    2014-01-01

    Full Text Available The aim of this study is to describe the acute effects of EtOH on brain edema and cerebral metabolites, using diffusion weight imaging (DWI and proton magnetic resonance spectroscopy (1H-MRS at a 7.0T MR and to define changes in apparent diffusion coefficient (ADC values and the concentration of metabolites in the rat brain after acute EtOH intoxication. ADC values in each ROI decreased significantly at 1 h and 3 h after ethanol administration. ADC values in frontal lobe were decreased significantly compared with other regions at 3 h. For EtOH/Cr+PCr and cerebral metabolites (Cho, Tau, and Glu differing over time, no significant differences for Ins, NAA, and Cr were observed in frontal lobes. Regression analysis revealed a significant association between TSEtOH/Cr+PCr and TSCho, TSTau, TSGlu, and TSADC. The changes of ADC values in different brain regions reflect the process of the cytotoxic edema in vivo. The characterization of frontal lobes metabolites changes and the correlations between TSEtOH/Cr+PCr and TSCho, TSTau, and TSGlu provide a better understanding for the biological mechanisms in neurotoxic effects of EtOH on the brain. In addition, the correlations between TSEtOH/Cr+PCr and TSADC will help us to understand development of the ethanol-induced brain cytotoxic edema.

  6. Diet-Induced Weight Loss Alters Functional Brain Responses during an Episodic Memory Task

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    Carl-Johan Boraxbekk

    2015-07-01

    Full Text Available Objective: It has been suggested that overweight is negatively associated with cognitive functions. The aim of this study was to investigate whether a reduction in body weight by dietary interventions could improve episodic memory performance and alter associated functional brain responses in overweight and obese women. Methods: 20 overweight postmenopausal women were randomized to either a modified paleolithic diet or a standard diet adhering to the Nordic Nutrition Recommendations for 6 months. We used functional magnetic resonance imaging to examine brain function during an episodic memory task as well as anthropometric and biochemical data before and after the interventions. Results: Episodic memory performance improved significantly (p = 0.010 after the dietary interventions. Concomitantly, brain activity increased in the anterior part of the right hippocampus during memory encoding, without differences between diets. This was associated with decreased levels of plasma free fatty acids (FFA. Brain activity increased in pre-frontal cortex and superior/middle temporal gyri. The magnitude of increase correlated with waist circumference reduction. During episodic retrieval, brain activity decreased in inferior and middle frontal gyri, and increased in middle/superior temporal gyri. Conclusions: Diet-induced weight loss, associated with decreased levels of plasma FFA, improves episodic memory linked to increased hippocampal activity.

  7. Immunomodulation by poly-YE reduces organophosphate-induced brain damage.

    Science.gov (United States)

    Finkelstein, Arseny; Kunis, Gilad; Berkutzki, Tamara; Ronen, Ayal; Krivoy, Amir; Yoles, Eti; Last, David; Mardor, Yael; Van Shura, Kerry; McFarland, Emylee; Capacio, Benedict A; Eisner, Claire; Gonzales, Mary; Gregorowicz, Danise; Eisenkraft, Arik; McDonough, John H; Schwartz, Michal

    2012-01-01

    Accidental organophosphate poisoning resulting from environmental or occupational exposure, as well as the deliberate use of nerve agents on the battlefield or by terrorists, remain major threats for multi-casualty events, with no effective therapies yet available. Even transient exposure to organophosphorous compounds may lead to brain damage associated with microglial activation and to long-lasting neurological and psychological deficits. Regulation of the microglial response by adaptive immunity was previously shown to reduce the consequences of acute insult to the central nervous system (CNS). Here, we tested whether an immunization-based treatment that affects the properties of T regulatory cells (Tregs) can reduce brain damage following organophosphate intoxication, as a supplement to the standard antidotal protocol. Rats were intoxicated by acute exposure to the nerve agent soman, or the organophosphate pesticide, paraoxon, and after 24 h were treated with the immunomodulator, poly-YE. A single injection of poly-YE resulted in a significant increase in neuronal survival and tissue preservation. The beneficial effect of poly-YE treatment was associated with specific recruitment of CD4(+) T cells into the brain, reduced microglial activation, and an increase in the levels of brain derived neurotrophic factor (BDNF) in the piriform cortex. These results suggest therapeutic intervention with poly-YE as an immunomodulatory supplementary approach against consequences of organophosphate-induced brain damage. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. Combined Cognitive-Psychological-Physical Intervention Induces Reorganization of Intrinsic Functional Brain Architecture in Older Adults

    Directory of Open Access Journals (Sweden)

    Zhiwei Zheng

    2015-01-01

    Full Text Available Mounting evidence suggests that enriched mental, physical, and socially stimulating activities are beneficial for counteracting age-related decreases in brain function and cognition in older adults. Here, we used functional magnetic resonance imaging (fMRI to demonstrate the functional plasticity of brain activity in response to a combined cognitive-psychological-physical intervention and investigated the contribution of the intervention-related brain changes to individual performance in healthy older adults. The intervention was composed of a 6-week program of combined activities including cognitive training, Tai Chi exercise, and group counseling. The results showed improved cognitive performance and reorganized regional homogeneity of spontaneous fluctuations in the blood oxygen level-dependent (BOLD signals in the superior and middle temporal gyri, and the posterior lobe of the cerebellum, in the participants who attended the intervention. Intriguingly, the intervention-induced changes in the coherence of local spontaneous activity correlated with the improvements in individual cognitive performance. Taken together with our previous findings of enhanced resting-state functional connectivity between the medial prefrontal cortex and medial temporal lobe regions following a combined intervention program in older adults, we conclude that the functional plasticity of the aging brain is a rather complex process, and an effective cognitive-psychological-physical intervention is helpful for maintaining a healthy brain and comprehensive cognition during old age.

  9. Hyperbaric oxygen can induce neuroplasticity and improve cognitive functions of patients suffering from anoxic brain damage.

    Science.gov (United States)

    Hadanny, A; Golan, H; Fishlev, G; Bechor, Y; Volkov, O; Suzin, G; Ben-Jacob, E; Efrati, S

    2015-01-01

    Cognitive impairment may occur in 42-50% of cardiac arrest survivors. Hyperbaric oxygen therapy (HBO2) has recently been shown to have neurotherapeutic effects in patients suffering from chronic cognitive impairments (CCI) consequent to stroke and mild traumatic brain injury.The objective of this study was to assess the neurotherapeutic effect of HBO2 in patients suffering from CCI due to cardiac arrest. Retrospective analysis of patients with CCI caused by cardiac arrest, treated with 60 daily sessions of HBO2. Evaluation included objective computerized cognitive tests (NeuroTrax), Activity of Daily Living (ADL) and Quality of life questionnaires. The results of these tests were compared with changes in brain activity as assessed by single photon emission computed tomography (SPECT) brain imaging. The study included 11 cases of CCI patients. Patients were treated with HBO2, 0.5-7.5 years (mean 2.6 ± 0.6 years) after the cardiac arrest. HBO2 was found to induce modest, but statistically significant improvement in memory, attention and executive function (mean scores) of 12% , 20% and 24% respectively. The clinical improvements were found to be well correlated with increased brain activity in relevant brain areas as assessed by computerized analysis of the SPECT imaging. Although further research is needed, the results demonstrate the beneficial effects of HBO2 on CCI in patients after cardiac arrest, even months to years after the acute event.

  10. Physical exercise in overweight to obese individuals induces metabolic- and neurotrophic-related structural brain plasticity

    Directory of Open Access Journals (Sweden)

    Karsten eMueller

    2015-07-01

    Full Text Available Previous cross-sectional studies on body-weight-related alterations in brain structure revealed profound changes in the gray matter (GM and white matter (WM that resemble findings obtained from individuals with advancing age. This suggests that obesity may lead to structural brain changes that are comparable with brain aging. Here, we asked whether weight-loss-dependent improved metabolic and neurotrophic functioning parallels the reversal of obesity-related alterations in brain structure. To this end we applied magnetic resonance imaging together with voxel-based morphometry and diffusion-tensor imaging in overweight to obese individuals who participated in a fitness course with intensive physical training three days per week over a period of three months. After the fitness course, participants presented, with inter-individual heterogeneity, a reduced body mass index (BMI, reduced serum leptin concentrations, elevated high-density lipoprotein-cholesterol (HDL-C, and alterations of serum brain-derived neurotrophic factor (BDNF concentrations suggesting changes of metabolic and neurotrophic function. Exercise-dependent changes in BMI and serum concentration of BDNF, leptin, and HDL-C were related to an increase in GM density in the left hippocampus, the insular cortex, and the left cerebellar lobule. We also observed exercise-dependent changes of diffusivity parameters in surrounding WM structures as well as in the corpus callosum. These findings suggest that weight-loss due to physical exercise in overweight to obese participants induces profound structural brain plasticity, not primarily of sensorimotor brain regions involved in physical exercise, but of regions previously reported to be structurally affected by an increased body weight and functionally implemented in gustation and cognitive processing.

  11. Physical exercise in overweight to obese individuals induces metabolic- and neurotrophic-related structural brain plasticity.

    Science.gov (United States)

    Mueller, Karsten; Möller, Harald E; Horstmann, Annette; Busse, Franziska; Lepsien, Jöran; Blüher, Matthias; Stumvoll, Michael; Villringer, Arno; Pleger, Burkhard

    2015-01-01

    Previous cross-sectional studies on body-weight-related alterations in brain structure revealed profound changes in the gray matter (GM) and white matter (WM) that resemble findings obtained from individuals with advancing age. This suggests that obesity may lead to structural brain changes that are comparable with brain aging. Here, we asked whether weight-loss-dependent improved metabolic and neurotrophic functioning parallels the reversal of obesity-related alterations in brain structure. To this end we applied magnetic resonance imaging (MRI) together with voxel-based morphometry and diffusion-tensor imaging in overweight to obese individuals who participated in a fitness course with intensive physical training twice a week over a period of 3 months. After the fitness course, participants presented, with inter-individual heterogeneity, a reduced body mass index (BMI), reduced serum leptin concentrations, elevated high-density lipoprotein-cholesterol (HDL-C), and alterations of serum brain-derived neurotrophic factor (BDNF) concentrations suggesting changes of metabolic and neurotrophic function. Exercise-dependent changes in BMI and serum concentration of BDNF, leptin, and HDL-C were related to an increase in GM density in the left hippocampus, the insular cortex, and the left cerebellar lobule. We also observed exercise-dependent changes of diffusivity parameters in surrounding WM structures as well as in the corpus callosum. These findings suggest that weight-loss due to physical exercise in overweight to obese participants induces profound structural brain plasticity, not primarily of sensorimotor brain regions involved in physical exercise, but of regions previously reported to be structurally affected by an increased body weight and functionally implemented in gustation and cognitive processing.

  12. Non-verbal emotion communication training induces specific changes in brain function and structure

    Science.gov (United States)

    Kreifelts, Benjamin; Jacob, Heike; Brück, Carolin; Erb, Michael; Ethofer, Thomas; Wildgruber, Dirk

    2013-01-01

    The perception of emotional cues from voice and face is essential for social interaction. However, this process is altered in various psychiatric conditions along with impaired social functioning. Emotion communication trainings have been demonstrated to improve social interaction in healthy individuals and to reduce emotional communication deficits in psychiatric patients. Here, we investigated the impact of a non-verbal emotion communication training (NECT) on cerebral activation and brain structure in a controlled and combined functional magnetic resonance imaging (fMRI) and voxel-based morphometry study. NECT-specific reductions in brain activity occurred in a distributed set of brain regions including face and voice processing regions as well as emotion processing- and motor-related regions presumably reflecting training-induced familiarization with the evaluation of face/voice stimuli. Training-induced changes in non-verbal emotion sensitivity at the behavioral level and the respective cerebral activation patterns were correlated in the face-selective cortical areas in the posterior superior temporal sulcus and fusiform gyrus for valence ratings and in the temporal pole, lateral prefrontal cortex and midbrain/thalamus for the response times. A NECT-induced increase in gray matter (GM) volume was observed in the fusiform face area. Thus, NECT induces both functional and structural plasticity in the face processing system as well as functional plasticity in the emotion perception and evaluation system. We propose that functional alterations are presumably related to changes in sensory tuning in the decoding of emotional expressions. Taken together, these findings highlight that the present experimental design may serve as a valuable tool to investigate the altered behavioral and neuronal processing of emotional cues in psychiatric disorders as well as the impact of therapeutic interventions on brain function and structure. PMID:24146641

  13. Nonverbal emotion communication training induces specific changes in brain function and structure

    Directory of Open Access Journals (Sweden)

    Benjamin eKreifelts

    2013-10-01

    Full Text Available The perception of emotional cues from voice and face is essential for social interaction. However, this process is altered in various psychiatric conditions along with impaired social functioning. Emotion communication trainings have been demonstrated to improve social interaction in healthy individuals and to reduce emotional communication deficits in psychiatric patients. Here, we investigated the impact of a nonverbal emotion communication training (NECT on cerebral activation and brain structure in a controlled and combined functional magnetic resonance imaging and voxel-based morphometry study. NECT-specific reductions in brain activity occurred in a distributed set of brain regions including face- and voice processing regions as well as emotion processing- and motor-related regions presumably reflecting training-induced familiarization with the evaluation of face/voice stimuli. Training-induced changes in nonverbal emotion sensitivity at the behavioral level and the respective cerebral activation patterns were correlated in the face-selective cortical areas in the posterior superior temporal sulcus and fusiform gyrus for valence ratings and in the temporal pole, lateral prefrontal cortex and midbrain/thalamus for the response times. A NECT-induced increase in grey matter volume was observed in the fusiform face area. Thus, NECT induces both functional and structural plasticity in the face processing system as well as functional plasticity in the emotion perception and evaluation system. We propose that functional alterations are presumably related to changes in sensory tuning in the decoding of emotional expressions. Taken together, these findings highlight that the present experimental design may serve as a valuable tool to investigate the altered behavioral and neuronal processing of emotional cues in psychiatric disorders as well as the impact of therapeutic interventions on brain function and structure.

  14. Placement of field probes for stabilization of breathing-induced B0-fluctuations in the brain

    DEFF Research Database (Denmark)

    Andersen, Mads; Madsen, Kristoffer H; Hanson, L.G.

    2015-01-01

    Introduction: B0-fluctuations induced by breathing and body motion lead to artifacts for certain brain imaging sequences at ultra-high field (7T). A promising solution is to monitor the B0-fluctuations during the scan using external field probes, and update the shim currents in real-time (1). It ...... SNR. Here, we provide a simulation of breathing-induced B0-fluctuations inside and around the head and use this simulated field to test different sets of probe positions. We also formulate two optimization problems to guide placement of the field probes....

  15. Neuroprotective Effects of Alpha Lipoic Acid on Haloperidol-Induced Oxidative Stress in the Rat Brain

    Directory of Open Access Journals (Sweden)

    Perera Joachim

    2011-03-01

    Full Text Available Abstract Haloperidol is an antipsychotic drug that exerts its' antipsychotic effects by inhibiting dopaminergic neurons. Although the exact pathophysiology of haloperidol extrapyramidal symptoms are not known, the role of reactive oxygen species in inducing oxidative stress has been proposed as one of the mechanisms of prolonged haloperidol-induced neurotoxicity. In the present study, we evaluate the protective effect of alpha lipoic acid against haloperidol-induced oxidative stress in the rat brain. Sprague Dawley rats were divided into control, alpha lipoic acid alone (100 mg/kg p.o for 21 days, haloperidol alone (2 mg/kg i.p for 21 days, and haloperidol with alpha lipoic acid groups (for 21 days. Haloperidol treatment significantly decreased levels of the brain antioxidant enzymes super oxide dismutase and glutathione peroxidase and concurrent treatment with alpha lipoic acid significantly reversed the oxidative effects of haloperidol. Histopathological changes revealed significant haloperidol-induced damage in the cerebral cortex, internal capsule, and substantia nigra. Alpha lipoic acid significantly reduced this damage and there were very little neuronal atrophy. Areas of angiogenesis were also seen in the alpha lipoic acid-treated group. In conclusion, the study proves that alpha lipoic acid treatment significantly reduces haloperidol-induced neuronal damage.

  16. Sodium butyrate reverses the inhibition of Krebs cycle enzymes induced by amphetamine in the rat brain.

    Science.gov (United States)

    Valvassori, Samira S; Calixto, Karen V; Budni, Josiane; Resende, Wilson R; Varela, Roger B; de Freitas, Karolina V; Gonçalves, Cinara L; Streck, Emilio L; Quevedo, João

    2013-12-01

    There is increasing interest in the possibility that mitochondrial impairment may play an important role in bipolar disorder (BD). The Krebs cycle is the central point of oxidative metabolism, providing carbon for biosynthesis and reducing agents for generation of ATP. Recently, studies have suggested that histone deacetylase (HDAC) inhibitors may have antimanic effects. The present study aims to investigate the effects of sodium butyrate (SB), a HDAC inhibitor, on Krebs cycle enzymes activity in the brain of rats subjected to an animal model of mania induced by D-amphetamine (D-AMPH). Wistar rats were first given D-AMPH or saline (Sal) for 14 days, and then, between days 8 and 14, rats were treated with SB or Sal. The citrate synthase (CS), succinate dehydrogenase (SDH), and malate dehydrogenase (MDH) were evaluated in the prefrontal cortex, hippocampus, and striatum of rats. The D-AMPH administration inhibited Krebs cycle enzymes activity in all analyzed brain structures and SB reversed D-AMPH-induced dysfunction analyzed in all brain regions. These findings suggest that Krebs cycle enzymes' inhibition can be an important link for the mitochondrial dysfunction seen in BD and SB exerts protective effects against the D-AMPH-induced Krebs cycle enzymes' dysfunction.

  17. Neural correlates of training-induced improvements of calculation skills in patients with brain lesions.

    Science.gov (United States)

    Claros-Salinas, Dolores; Greitemann, Georg; Hassa, Thomas; Nedelko, Violetta; Steppacher, Inga; Harris, Joseph Allen; Schoenfeld, Mircea Ariel

    2014-01-01

    The loss of calculation skills due to brain lesions leads to a major reduction in the quality of life and is often associated with difficulties of returning to work and a normal life. Very little is known about the neural mechanisms underlying performance improvement due to calculation training during rehabilitation. The current study investigates the neural basis of training-induced changes in patients with acalculia following ischemic stroke or traumatic brain lesions. Functional hemodynamic responses (fMRI) were recorded in seven patients during calculation and perceptual tasks both before and after acalculia training. Despite the heterogeneity of brain lesions associated with acalculia in our patient sample, a common pattern of training-induced changes emerged. Performance improvements were associated with widespread deactivations in the prefrontal cortex. These deactivations were calculation-specific and only observed in patients exhibiting a considerable improvement after training. These findings suggest that the training-induced changes in our patients rely on an increase of frontal processing efficiency.

  18. Curcumin Mediated Attenuation of Carbofuran Induced Oxidative Stress in Rat Brain

    Directory of Open Access Journals (Sweden)

    Sunil Kumar Jaiswal

    2016-01-01

    Full Text Available The indiscriminate use of carbofuran to improve crop productivity causes adverse effects in nontargets including mammalian systems. The objective of this study was to evaluate carbofuran induced oxidative stress in rat brain stem and its attenuation by curcumin, a herbal product. Out of 6 groups of rats, 2 groups received two different doses of carbofuran, that is, 15 and 30% of LD50, respectively, for 30 days. Out of these, 2 groups receiving same doses of carbofuran were pretreated with curcumin (100 mg/kg body weight. The levels of antioxidants, TBARS, GSH, SOD, catalase, and GST were determined in rat brain stem. The 2 remaining groups served as placebo and curcumin treated, respectively. The data suggested that carbofuran at different doses caused significant alterations in the levels of TBARS and GSH in dose dependent manner. The TBARS and GSH contents were elevated. The activities of SOD, catalase, and GST were significantly inhibited at both doses of carbofuran. The ratio of P/A was also found to be sharply increased. The pretreatment of curcumin exhibited significant protection from carbofuran induced toxicity. The results suggested that carbofuran at sublethal doses was able to induce oxidative stress in rat brain which could be attenuated by curcumin.

  19. In vivo evidence of methamphetamine induced attenuation of brain tissue oxygenation as measured by EPR oximetry

    Energy Technology Data Exchange (ETDEWEB)

    Weaver, John, E-mail: jmweaver@salud.unm.edu [Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Yang, Yirong [Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Purvis, Rebecca [Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Weatherwax, Theodore [Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Rosen, Gerald M. [Center for Biomedical Engineering and Technology, University of Maryland, Baltimore, MD 21201 (United States); Center for EPR Imaging In Vivo Physiology, University of Maryland, Baltimore, MD 21201 (United States); Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201 (United States); Liu, Ke Jian [Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States)

    2014-03-01

    Abuse of methamphetamine (METH) is a major and significant societal problem in the US, as a number of studies have suggested that METH is associated with increased cerebrovascular events, hemorrhage or vasospasm. Although cellular and molecular mechanisms involved in METH-induced toxicity are not completely understood, changes in brain O{sub 2} may play an important role and contribute to METH-induced neurotoxicity including dopaminergic receptor degradation. Given that O{sub 2} is the terminal electron acceptor for many enzymes that are important in brain function, the impact of METH on brain tissue pO{sub 2}in vivo remains largely uncharacterized. This study investigated striatal tissue pO{sub 2} changes in male C57BL/6 mice (16–20 g) following METH administration using EPR oximetry, a highly sensitive modality to measure pO{sub 2}in vivo, in situ and in real time. We demonstrate that 20 min after a single injection of METH (8 mg/kg i.v.), the striatal pO{sub 2} was reduced to 81% of the pretreatment level and exposure to METH for 3 consecutive days further attenuated striatal pO{sub 2} to 64%. More importantly, pO{sub 2} did not recover fully to control levels even 24 h after administration of a single dose of METH and continual exposure to METH exacerbates the condition. We also show a reduction in cerebral blood flow associated with a decreased brain pO{sub 2} indicating an ischemic condition. Our findings suggests that administration of METH can attenuate brain tissue pO{sub 2}, which may lead to hypoxic insult, thus a risk factor for METH-induced brain injury and the development of stroke in young adults. - Highlights: • Explored striatal tissue pO{sub 2}in vivo after METH administration by EPR oximetry. • pO{sub 2} was reduced by 81% after a single dose and 64% after 3 consecutive daily doses. • pO{sub 2} did not recover fully to control levels even 24 h after a single dose. • Decrease in brain tissue pO{sub 2} may be associated with a decrease in

  20. Brain injury induces specific changes in the caecal microbiota of mice via altered autonomic activity and mucoprotein production

    OpenAIRE

    Houlden, A.; Goldrick, M.; Brough, D; Vizi, E. S.; Lénárt, N.; Martinecz, B.; Roberts, I. S.; A.; Denes

    2016-01-01

    Intestinal microbiota are critical for health with changes associated with diverse human diseases. Research suggests that altered intestinal microbiota can profoundly affect brain function. However, whether altering brain function directly affects the microbiota is unknown. Since it is currently unclear how brain injury induces clinical complications such as infections or paralytic ileus, key contributors to prolonged hospitalization and death post-stroke, we tested in mice the hypothesis tha...

  1. Herpes zoster chronification to postherpetic neuralgia induces brain activity and grey matter volume change

    Science.gov (United States)

    Cao, Song; Qin, Bangyong; Zhang, Yi; Yuan, Jie; Fu, Bao; Xie, Peng; Song, Ganjun; Li, Ying; Yu, Tian

    2018-01-01

    Objective: Herpes zoster (HZ) can develop into postherpetic neuralgia (PHN), which is a chronic neuropathic pain (NP). Whether the chronification from HZ to PHN induced brain functional or structural change is unknown and no study compared the changes of the same brains of patients who transited from HZ to PHN. We minimized individual differences and observed whether the chronification of HZ to PHN induces functional and pain duration dependent grey matter volume (GMV) change in HZ-PHN patients. Methods: To minimize individual differences induced error, we enrolled 12 patients with a transition from HZ to PHN. The functional and structural changes of their brains between the two states were identified with resting-state functional MRI (rs-fMRI) technique (i.e., the regional homogeneity (ReHo) and fractional aptitude of low-frequency fluctuation (fALFF) method) and the voxel based morphometry (VBM) technology respectively. The correlations between MRI parameters (i.e., ΔReHo, ΔfALFF and ΔVBM) and Δpain duration were analyzed too. Results: Compared with HZ brains, PHN brains exhibited abnormal ReHo, fALFF and VBM values in pain matrix (the frontal lobe, parietal lobe, thalamus, limbic lobe and cerebellum) as well as the occipital lobe and temporal lobe. Nevertheless, the activity of vast area of cerebellum and frontal lobe significantly increased while that of occipital lobe and limbic lobe showed apparent decrease when HZ developed to PHN. In addition, PHN brain showed decreased GMV in the frontal lobe, the parietal lobe and the occipital lobe but increased in the cerebellum and the temporal lobe. Correlation analyses showed that some of the ReHo, fALFF and VBM differential areas (such as the cerebellum posterior lobe, the thalamus extra-nuclear and the middle temporal gyrus) correlated well with Δpain duration. Conclusions: HZ chronification induced functional and structural change in cerebellum, occipital lobe, temporal lobe, parietal lobe and limbic lobe

  2. Inhibition of miRNA-210 reverses nicotine-induced brain hypoxic-ischemic injury in neonatal rats.

    Science.gov (United States)

    Wang, Lei; Ke, Jun; Li, Yong; Ma, Qinyi; Dasgupta, Chiranjib; Huang, Xiaohui; Zhang, Lubo; Xiao, DaLiao

    2017-01-01

    Maternal tobacco use in pregnancy increases the risk of neurodevelopmental disorders and neurobehavioral deficits in postnatal life. The present study tested the hypothesis that perinatal nicotine exposure exacerbated brain vulnerability to hypoxic-ischemic (HI) injury in neonatal rats through up-regulation of miR-210 expression in the developing brain. Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps. Experiments of HI brain injury were performed in 10-day-old pups. Perinatal nicotine treatment significantly decreased neonatal body and brain weights, but increased the brain to body weight ratio. Perinatal nicotine exposure caused a significant increase in HI brain infarct size in the neonates. In addition, nicotine enhanced miR-210 expression and significantly attenuated brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase isoform B (TrkB) protein abundance in the brain. Of importance, intracerebroventricular administration of a miR-210 inhibitor (miR-210-LNA) significantly decreased HI-induced brain infarct size and reversed the nicotine-increased vulnerability to brain HI injury in the neonate. Furthermore, miR-210-LNA treatment also reversed nicotine-mediated down-regulation of BDNF and TrkB protein expression in the neonatal brains. These findings provide novel evidence that the increased miR-210 plays a causal role in perinatal nicotine-induced developmental programming of ischemic sensitive phenotype in the brain. It represents a potential novel therapeutic approach for treatment of brain hypoxic-ischemic encephalopathy in the neonate-induced by fetal stress.

  3. Disruption of the blood-brain interface in neonatal rat neocortex induces a transient expression of metallothionein in reactive astrocytes

    DEFF Research Database (Denmark)

    Penkowa, M; Moos, T

    1995-01-01

    rats were subjected to a localized freeze lesion of the neocortex of the right temporal cortex. This lesion results in a disrupted blood-brain interface, leading to extravasation of plasma proteins. From 16 h, reactive astrocytosis, defined as an increase in the number and size of cells expressing GFAP......Exposure of the adult rat brain parenchyma to zinc induces an increase in the intracerebral expression of the metal-binding protein, metallothionein, which is normally confined to astrocytes, ependymal cells, choroid plexus epithelial cells, and brain endothelial cells. Metallothionein is expressed...... only in diminutive amounts in astrocytes of the neonatal rat brain, which could imply that neonatal rats are devoid of the capacity to detoxify free metals released from a brain wound. In order to examine the influence of a brain injury on the expression of metallothionein in the neonatal brain, PO...

  4. Regulatory T cells ameliorate tissue plasminogen activator-induced brain haemorrhage after stroke.

    Science.gov (United States)

    Mao, Leilei; Li, Peiying; Zhu, Wen; Cai, Wei; Liu, Zongjian; Wang, Yanling; Luo, Wenli; Stetler, Ruth A; Leak, Rehana K; Yu, Weifeng; Gao, Yanqin; Chen, Jun; Chen, Gang; Hu, Xiaoming

    2017-07-01

    Delayed thrombolytic treatment with recombinant tissue plasminogen activator (tPA) may exacerbate blood-brain barrier breakdown after ischaemic stroke and lead to lethal haemorrhagic transformation. The immune system is a dynamic modulator of stroke response, and excessive immune cell accumulation in the cerebral vasculature is associated with compromised integrity of the blood-brain barrier. We previously reported that regulatory T cells, which function to suppress excessive immune responses, ameliorated blood-brain barrier damage after cerebral ischaemia. This study assessed the impact of regulatory T cells in the context of tPA-induced brain haemorrhage and investigated the underlying mechanisms of action. The number of circulating regulatory T cells in stroke patients was dramatically reduced soon after stroke onset (84 acute ischaemic stroke patients with or without intravenous tPA treatment, compared to 115 age and gender-matched healthy controls). Although stroke patients without tPA treatment gradually repopulated the numbers of circulating regulatory T cells within the first 7 days after stroke, post-ischaemic tPA treatment led to sustained suppression of regulatory T cells in the blood. We then used the murine suture and embolic middle cerebral artery occlusion models of stroke to investigate the therapeutic potential of adoptive regulatory T cell transfer against tPA-induced haemorrhagic transformation. Delayed administration of tPA (10 mg/kg) resulted in haemorrhagic transformation in the ischaemic territory 1 day after ischaemia. When regulatory T cells (2 × 106/mouse) were intravenously administered immediately after delayed tPA treatment in ischaemic mice, haemorrhagic transformation was significantly decreased, and this was associated with improved sensorimotor functions. Blood-brain barrier disruption and tight junction damages were observed in the presence of delayed tPA after stroke, but were mitigated by regulatory T cell transfer. Mechanistic

  5. Not Just the Brain: Methamphetamine Disrupts Blood-Spinal Cord Barrier and Induces Acute Glial Activation and Structural Damage of Spinal Cord Cells

    OpenAIRE

    Eugene A Kiyatkin; Sharma, Hari S.

    2015-01-01

    Acute methamphetamine (METH) intoxication induces metabolic brain activation as well as multiple physiological and behavioral responses that could result in life-threatening health complications. Previously, we showed that METH (9 mg/kg) used in freely moving rats induces robust leakage of blood-brain barrier (BBB), acute glial activation, vasogenic edema, and structural abnormalities of brain cells. These changes tightly correlated with drug-induced brain hyperthermia and were greatly potent...

  6. Comparison of the four proposed Apgar scoring systems in the assessment of birth asphyxia and adverse early neurologic outcomes.

    Science.gov (United States)

    Dalili, Hosein; Nili, Firouzeh; Sheikh, Mahdi; Hardani, Amir Kamal; Shariat, Mamak; Nayeri, Fatemeh

    2015-01-01

    To compare the Conventional, Specified, Expanded and Combined Apgar scoring systems in predicting birth asphyxia and the adverse early neurologic outcomes. This prospective cohort study was conducted on 464 admitted neonates. In the delivery room, after delivery the umbilical cord was double clamped and a blood samples was obtained from the umbilical artery for blood gas analysis, meanwhile on the 1- , 5- and 10- minutes Conventional, Specified, Expanded, and Combined Apgar scores were recorded. Then the neonates were followed and intracranial ultrasound imaging was performed, and the following information were recorded: the occurrence of birth asphyxia, hypoxic Ischemic Encephalopathy (HIE), intraventricular hemorrhage (IVH), and neonatal seizure. The Combined-Apgar score had the highest sensitivity (97%) and specificity (99%) in predicting birth asphyxia, followed by the Specified-Apgar score that was also highly sensitive (95%) and specific (97%). The Expanded-Apgar score was highly specific (95%) but not sensitive (67%) and the Conventional-Apgar score had the lowest sensitivity (81%) and low specificity (81%) in predicting birth asphyxia. When adjusted for gestational age, only the low 5-minute Combined-Apgar score was independently associated with the occurrence of HIE (B = 1.61, P = 0.02) and IVH (B = 2.8, P = 0.01). The newly proposed Combined-Apgar score is highly sensitive and specific in predicting birth asphyxia and also is a good predictor of the occurrence of HIE and IVH in asphyxiated neonates.

  7. Expression of manganese superoxide dismutase in rat blood, heart and brain during induced systemic hypoxia

    Directory of Open Access Journals (Sweden)

    Septelia I. Wanandi

    2011-02-01

    Full Text Available Background: Hypoxia results in an increased generation of ROS. Until now, little is known about the role of MnSOD - a major endogenous antioxidant enzyme - on the cell adaptation response against hypoxia. The aim of this study was to  determine the MnSOD mRNA expression and levels of specific activity in blood, heart and brain of rats during induced systemic hypoxia.Methods: Twenty-five male Sprague Dawley rats were subjected to systemic hypoxia in an hypoxic chamber (at 8-10% O2 for 0, 1, 7, 14 and 21 days, respectively. The mRNA relative expression of MnSOD was analyzed using Real Time RT-PCR. MnSOD specific activity was determined using xanthine oxidase inhibition assay.Results: The MnSOD mRNA relative expression in rat blood and heart was decreased during early induced systemic hypoxia (day 1 and increased as hypoxia continued, whereas the mRNA expression in brain was increased since day 1 and reached its maximum level at day 7. The result of MnSOD specific activity during early systemic hypoxia was similar to the mRNA expression. Under very late hypoxic condition (day 21, MnSOD specific activity in blood, heart and brain was significantly decreased. We demonstrate a positive correlation between MnSOD mRNA expression and specific activity in these 3 tissues during day 0-14 of induced systemic hypoxia. Furthermore, mRNA expression and specific activity levels in heart strongly correlate with those in blood.Conclusion: The MnSOD expression at early and late phases of induced systemic hypoxia is distinctly regulated. The MnSOD expression in brain differs from that in blood and heart revealing that brain tissue can  possibly survive better from induced systemic hypoxia than heart and blood. The determination of MnSOD expression in blood can be used to describe its expression in heart under systemic hypoxic condition. (Med J Indones 2011; 20:27-33Keywords: MnSOD, mRNA expression, ROS, specific activity, systemic hypoxia

  8. Using MRI for the assessment of paraoxon-induced brain damage and efficacy of antidotal treatment.

    Science.gov (United States)

    Rosman, Yossi; Eisenkraft, Arik; Krivoy, Amir; Schein, Ophir; Makarovski, Igor; Shrot, Shai; Ramaty, Erez; Shilderman, Eugenia Bloch; Kapon, Joseph; Gilat, Eran; Kadar, Tamar; Maier, Stephan; Daniels, Dianne; Shneor, Ran; Salomon, Sharona; Tamar, Gregori; Last, David; Mardor, Yael

    2012-06-01

    Organophosphate intoxication induces neural toxicity as demonstrated in histological analysis of poisoned animals. Diffusion-weighted magnetic resonance imaging (DWMRI) enables early noninvasive characterization of biological tissues based on their water diffusion characteristics. Our objectives were to study the application of MRI for assessment of paraoxon-induced brain damage and the efficacy of antidotal treatments. Seventy-six rats were poisoned with paraoxon followed by treatment with atropine and obidoxime. The rats were then divided into five treatment groups consisting of midazolam after 1 or 30 min, scopolamine after 1 or 30 min and a no anticonvulsant treatment group. Five untreated rats served as controls. Animals underwent MRI on days 1, 8, 15, 29 and 50 post poisoning. Histological evaluation was performed on representative rat brains. Acute DWMRI effects, such as enhancement of temporal brain regions, and chronic effects such as ventricular enlargement and brain atrophy, depicted on T₂-weighted MRI, were significantly more prominent in late anticonvulsant treatment groups. There was no significant difference between the neuroprotective effects of midazolam and scopolamine as shown by DWMRI. Early MRI abnormalities were found to correlate significantly with histological analysis of samples obtained 15 days post treatment. In conclusion, our results demonstrate the feasibility of using DWMRI for depiction of early cytotoxic response to paraoxon and T₂-weighted MRI for later changes, thus enabling assessment of early/late brain damage as well as treatment efficacy in rats. The ability to depict these changes early and noninvasively may be applied clinically in the acute phase of organophosphate poisoning. Copyright © 2011 John Wiley & Sons, Ltd.

  9. Ethanol-induced alterations in sup 14 C-glucose utilization: Modulation by brain adenosine in mice

    Energy Technology Data Exchange (ETDEWEB)

    Anwer, J.; Dar, M.S. (East Carolina Univ., Greenville, NC (United States))

    1992-02-26

    The possible role of brain adenosine (Ado) in acute ethanol-induced alteration in glucose utilization in the cerebellum and brain stem was investigated. The slices were incubated for 100 min in a glucose medium in Warburg flasks using {sup 14}C-glucose as a tracer. Trapped {sup 14}CO{sub 2} was counted to estimate glucose utilization. Ethanol markedly increased the glucose utilization in both areas of brain. Theophylline, an Ado antagonist, significantly reduced ethanol-induced increase in glucose utilization in both brain areas. Ado agonist CHA significantly accentuated ethanol-induced increase in glucose utilization in both motor areas. Ado agonist CHA significantly accentuated ethanol-induced increase in glucose utilization in both motor areas. Ethanol was still able to produce a smaller but significant increase in glucose utilization in both brain areas when theophylline and CHA were given together, suggesting an additional mechanism. Collectively, the data indicate that ethanol-induced glucose utilization in the cerebellum and brain stem is modulated by brain Ado receptor and by non-adenosinergic mechanism.

  10. Chronic noise stress-induced alterations of glutamate and gamma-aminobutyric acid and their metabolism in the rat brain

    OpenAIRE

    Amajad Iqbal Kazi; Anna Oommen

    2014-01-01

    Chronic stress induces neurochemical changes that include neurotransmitter imbalance in the brain. Noise is an environmental factor inducing stress. Chronic noise stress affects monoamine neurotransmitter systems in the central nervous system. The effect on other excitatory and inhibitory neurotransmitter systems is not known. The aim was to study the role of chronic noise stress on the glutamatergic and gamma-aminobutyric acid (GABA)ergic systems of the brain. Female Wistar rats (155 ± 5 g) ...

  11. Mesenchymal stem cell-derived extracellular vesicles ameliorate inflammation-induced preterm brain injury.

    Science.gov (United States)

    Drommelschmidt, Karla; Serdar, Meray; Bendix, Ivo; Herz, Josephine; Bertling, Frederik; Prager, Sebastian; Keller, Matthias; Ludwig, Anna-Kristin; Duhan, Vikas; Radtke, Stefan; de Miroschedji, Kyra; Horn, Peter A; van de Looij, Yohan; Giebel, Bernd; Felderhoff-Müser, Ursula

    2017-02-01

    Preterm brain injury is a major cause of disability in later life, and may result in motor, cognitive and behavioural impairment for which no treatment is currently available. The aetiology is considered as multifactorial, and one underlying key player is inflammation leading to white and grey matter injury. Extracellular vesicles secreted by mesenchymal stem/stromal cells (MSC-EVs) have shown therapeutic potential in regenerative medicine. Here, we investigated the effects of MSC-EV treatment on brain microstructure and maturation, inflammatory processes and long-time outcome in a rodent model of inflammation-induced brain injury. 3-Day-old Wistar rats (P3) were intraperitoneally injected with 0.25mg/kg lipopolysaccharide or saline and treated with two repetitive doses of 1×10 8 cell equivalents of MSC-EVs per kg bodyweight. Cellular degeneration and reactive gliosis at P5 and myelination at P11 were evaluated by immunohistochemistry and western blot. Long-term cognitive and motor function was assessed by behavioural testing. Diffusion tensor imaging at P125 evaluated long-term microstructural white matter alterations. MSC-EV treatment significantly ameliorated inflammation-induced neuronal cellular degeneration reduced microgliosis and prevented reactive astrogliosis. Short-term myelination deficits and long-term microstructural abnormalities of the white matter were restored by MSC-EV administration. Morphological effects of MSC-EV treatment resulted in improved long-lasting cognitive functions INTERPRETATION: MSC-EVs ameliorate inflammation-induced cellular damage in a rat model of preterm brain injury. MSC-EVs may serve as a novel therapeutic option by prevention of neuronal cell death, restoration of white matter microstructure, reduction of gliosis and long-term functional improvement. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Optical monitoring of shock wave-induced spreading depolarization and concomitant hypoxemia in rat brain

    Science.gov (United States)

    Okuda, Wataru; Kawauchi, Satoko; Ashida, Hiroshi; Sato, Shunichi; Nishidate, Izumi

    2014-03-01

    Blast-induced traumatic brain injury is a growing concern, but its underlying pathophysiology and mechanism are still unknown. Thus, study using an animal model is needed. We have been proposing the use of a laser-induced shock wave (LISW), whose energy is highly controllable and reproducible, to mimic blast-related injury. We previously observed the occurrence of spreading depolarization (SD) and prolonged hypoxemia in the rat brain exposed to an LISW. However, the relationship between these two events is unclear. In this study, we investigated the spatiotemporal characteristics of hypoxemia and SD to examine their correlation, for which multichannel fiber measurement and multispectral imaging of the diffuse reflectance were performed for the rat brain exposed to an LISW. We also quantified tissue oxygen saturation (StO2) in the hypoxemic phase, which is associated with possible neuronal cell death, based on an inverse Monte Carlo simulation. Fiber measurement showed that the region of hypoxemia was expanding from the site of LISW application to the distant region over the brain; the speed of expansion was similar to that of the propagation speed of SD. Simulation showed that oxygen saturation was decreased by ~40%. Multispectral imaging showed that after LISW application, a vasodilatation occurred for ~1 min, which was followed by a long-lasting vasoconstriction. In the phase of vasoconstriction, StO2 declined all over the field of view. These results indicate a strong correlation between SD and hypoxemia; the estimated StO2 seems to be low enough to induce neuronal cell death.

  13. Aging-induced changes in brain regional serotonin receptor binding: Effect of Carnosine.

    Science.gov (United States)

    Banerjee, S; Poddar, M K

    2016-04-05

    Monoamine neurotransmitter, serotonin (5-HT) has its own specific receptors in both pre- and post-synapse. In the present study the role of carnosine on aging-induced changes of [(3)H]-5-HT receptor binding in different brain regions in a rat model was studied. The results showed that during aging (18 and 24 months) the [(3)H]-5-HT receptor binding was reduced in hippocampus, hypothalamus and pons-medulla with a decrease in their both Bmax and KD but in cerebral cortex the [(3)H]-5-HT binding was increased with the increase of its only Bmax. The aging-induced changes in [(3)H]-5-HT receptor binding with carnosine (2.0 μg/kg/day, intrathecally, for 21 consecutive days) attenuated in (a) 24-month-aged rats irrespective of the brain regions with the attenuation of its Bmax except hypothalamus where both Bmax and KD were significantly attenuated, (b) hippocampus and hypothalamus of 18-month-aged rats with the attenuation of its Bmax, and restored toward the [(3)H]-5-HT receptor binding that observed in 4-month-young rats. The decrease in pons-medullary [(3)H]-5-HT binding including its Bmax of 18-month-aged rats was promoted with carnosine without any significant change in its cerebral cortex. The [(3)H]-5-HT receptor binding with the same dosages of carnosine in 4-month-young rats (a) increased in the cerebral cortex and hippocampus with the increase in their only Bmax whereas (b) decreased in hypothalamus and pons-medulla with a decrease in their both Bmax and KD. These results suggest that carnosine treatment may (a) play a preventive role in aging-induced brain region-specific changes in serotonergic activity (b) not be worthy in 4-month-young rats in relation to the brain regional serotonergic activity. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  14. The Ketogenic Diet Suppresses the Cathepsin E Expression Induced by Kainic Acid in the Rat Brain

    Science.gov (United States)

    Jeong, Hyun Jeong; Kim, Hojeong; Kim, Yoon-Kyoung; Park, Sang-Kyu; Kang, Dong-Won

    2010-01-01

    Purpose The ketogenic diet has long been used to treat epilepsy, but its mechanism is not yet clearly understood. To explore the potential mechanism, we analyzed the changes in gene expression induced by the ketogenic diet in the rat kainic acid (KA) epilepsy model. Materials and Methods KA-administered rats were fed the ketogenic diet or a normal diet for 4 weeks, and microarray analysis was performed with their brain tissues. The effects of the ketogenic diet on cathepsin E messenger ribonucleic acid (mRNA) expression were analyzed in KA-administered and normal saline-administered groups with semi-quantitative and real-time reverse transcription polymerase chain reaction (RT-PCR). Brain tissues were dissected into 8 regions to compare differential effects of the ketogenic diet on cathepsin E mRNA expression. Immunohistochemistry with an anti-cathepsin E antibody was performed on slides of hippocampus obtained from whole brain paraffin blocks. Results The microarray data and subsequent RT-PCR experiments showed that KA increased the mRNA expression of cathepsin E, known to be related to neuronal cell death, in most brain areas except the brain stem, and these increases of cathepsin E mRNA expression were suppressed by the ketogenic diet. The expression of cathepsin E mRNA in the control group, however, was not significantly affected by the ketogenic diet. The change in cathepsin E mRNA expression was greatest in the hippocampus. The protein level of cathepsin E in the hippocampus of KA-administered rat was elevated in immunohistochemistry and the ketogenic diet suppressed this increase. Conclusion Our results showed that KA administration increased cathepsin E expression in the rat brain and its increase was suppressed by the ketogenic diet. PMID:20635438

  15. Novel application of brain-targeting polyphenol compounds in sleep deprivation-induced cognitive dysfunction.

    Science.gov (United States)

    Zhao, Wei; Wang, Jun; Bi, Weina; Ferruzzi, Mario; Yemul, Shrishailam; Freire, Daniel; Mazzola, Paolo; Ho, Lap; Dubner, Lauren; Pasinetti, Giulio Maria

    2015-10-01

    Sleep deprivation produces deficits in hippocampal synaptic plasticity and hippocampal-dependent memory storage. Recent evidence suggests that sleep deprivation disrupts memory consolidation through multiple mechanisms, including the down-regulation of the cAMP-response element-binding protein (CREB) and of mammalian target of rapamycin (mTOR) signaling. In this study, we tested the effects of a Bioactive Dietary Polyphenol Preparation (BDPP), comprised of grape seed polyphenol extract, Concord grape juice, and resveratrol, on the attenuation of sleep deprivation-induced cognitive impairment. We found that BDPP significantly improves sleep deprivation-induced contextual memory deficits, possibly through the activation of CREB and mTOR signaling pathways. We also identified brain-available polyphenol metabolites from BDPP, among which quercetin-3-O-glucuronide activates CREB signaling and malvidin-3-O-glucoside activates mTOR signaling. In combination, quercetin and malvidin-glucoside significantly attenuated sleep deprivation-induced cognitive impairment in -a mouse model of acute sleep deprivation. Our data suggests the feasibility of using select brain-targeting polyphenol compounds derived from BDPP as potential therapeutic agents in promoting resilience against sleep deprivation-induced cognitive dysfunction. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Administration of Protocatechuic Acid Reduces Traumatic Brain Injury-Induced Neuronal Death

    Directory of Open Access Journals (Sweden)

    Sang Hwon Lee

    2017-11-01

    Full Text Available Protocatechuic acid (PCA was first purified from green tea and has shown numerous biological activities, including anti-apoptotic, anti-inflammatory, and anti-atherosclerotic effects. The effect of PCA on traumatic brain injury (TBI-induced neuronal death has not previously been evaluated. TBI is defined as damage to the brain resulting from external mechanical force, such as rapid acceleration or deceleration, impact, blast waves, or penetration by a projectile. TBI causes neuronal death in the hippocampus and cerebral cortex. The present study aimed to evaluate the therapeutic potential of PCA on TBI-induced neuronal death. Here, TBI was induced by a controlled cortical impact model using rats. PCA (30 mg/kg was injected into the intraperitoneal (ip space immediately after TBI. Neuronal death was evaluated with Fluoro Jade-B (FJB staining at 24 h after TBI. Oxidative injury was detected by 4-hydroxy-2-nonenal (4HNE, glutathione (GSH concentration was analyzed by glutathione adduct with N-ethylmaleimide (GS-NEM staining at 24 h after TBI, and microglial activation in the hippocampus was detected by CD11b immunohistochemistry at one week after TBI. We found that the proportion of degenerating neurons, oxidative injury, GSH depletion, and microglia activation in the hippocampus and cortex were all reduced by PCA treatment following TBI. Therefore, our study suggests that PCA may have therapeutic potential in preventing TBI-induced neuronal death.

  17. Music-induced emotions can be predicted from a combination of brain activity and acoustic features.

    Science.gov (United States)

    Daly, Ian; Williams, Duncan; Hallowell, James; Hwang, Faustina; Kirke, Alexis; Malik, Asad; Weaver, James; Miranda, Eduardo; Nasuto, Slawomir J

    2015-12-01

    It is widely acknowledged that music can communicate and induce a wide range of emotions in the listener. However, music is a highly-complex audio signal composed of a wide range of complex time- and frequency-varying components. Additionally, music-induced emotions are known to differ greatly between listeners. Therefore, it is not immediately clear what emotions will be induced in a given individual by a piece of music. We attempt to predict the music-induced emotional response in a listener by measuring the activity in the listeners electroencephalogram (EEG). We combine these measures with acoustic descriptors of the music, an approach that allows us to consider music as a complex set of time-varying acoustic features, independently of any specific music theory. Regression models are found which allow us to predict the music-induced emotions of our participants with a correlation between the actual and predicted responses of up to r=0.234,pmusic induced emotions can be predicted by their neural activity and the properties of the music. Given the large amount of noise, non-stationarity, and non-linearity in both EEG and music, this is an encouraging result. Additionally, the combination of measures of brain activity and acoustic features describing the music played to our participants allows us to predict music-induced emotions with significantly higher accuracies than either feature type alone (p<0.01). Copyright © 2015 Elsevier Inc. All rights reserved.

  18. [Care of the newborn with perinatal asphyxia candidate for therapeutic hypothermia during the first six hours of life in Spain].

    Science.gov (United States)

    Arnaez, Juan; Garcia-Alix, Alfredo; Calvo, Sara; Lubián-López, Simón

    2017-12-11

    The process of care and assistance from birth to the starting of therapeutic hypothermia (TH) is crucial in order to improve its effectiveness and prevent the worsening of hypoxic-ischaemic injury. A national cross-sectional study carried out in 2015 by use of a questionnaire sent to all level iii units on the care of the newborn≥35 weeks gestation within the first hours of life after a perinatal asphyxia event. According to clinical practice guidelines, the quality of care was compared between the hospitals that carried out or did not carry out TH, and according to the level of care. A total of 89/90 hospitals participated, of which 57/90 performed TH. They all used resuscitation protocols and turned off the radiant warmer after stabilisation. All of them performed glucose and blood gas analysis, monitored the central temperature, put the newborn on a diet, and performed at least two examinations for the diagnosis of hypoxic-ischaemic encephalopathy. Greater than one-third (35%) of hospitals did not have amplitude-integrated electroencephalogram, and 6/57 were TH-hospitals. The quality of care among hospitals with and without TH was similar, childbirth being better in those that performed TH, and those with a higher level of care. Level IIIc hospitals had higher scores than the others. The TH-hospitals mentioned not always having neonatologists with experience in neurological assessment and interpretation of amplitude-integrated electroencephalogram (25%), or in brain ultrasound (62%). In response to the recommendations of the asphyxiated newborn, there is a proper national health care standard with differences according to the level of care and whether TH is offered. More amplitude-integrated electroencephalogram devices are necessary, as well as more neonatologists trained in the evaluations that will be require by the newborn with hypoxic-ischaemic encephalopathy. Copyright © 2017. Publicado por Elsevier España, S.L.U.

  19. C5a induces caspase-dependent apoptosis in brain vascular endothelial cells in experimental lupus.

    Science.gov (United States)

    Mahajan, Supriya D; Tutino, Vincent M; Redae, Yonas; Meng, Hui; Siddiqui, Adnan; Woodruff, Trent M; Jarvis, James N; Hennon, Teresa; Schwartz, Stanley; Quigg, Richard J; Alexander, Jessy J

    2016-08-01

    Blood-brain barrier (BBB) dysfunction complicates central nervous system lupus, an important aspect of systemic lupus erythematosus. To gain insight into the underlying mechanism, vascular corrosion casts of brain were generated from the lupus mouse model, MRL/lpr mice and the MRL/MpJ congenic controls. Scanning electron microscopy of the casts showed loss of vascular endothelial cells in lupus mice compared with controls. Immunostaining revealed a significant increase in caspase 3 expression in the brain vascular endothelial cells, which suggests that apoptosis could be an important mechanism causing cell loss, and thereby loss of BBB integrity. Complement activation occurs in lupus resulting in increased generation of circulating C5a, which caused the endothelial layer to become 'leaky'. In this study, we show that C5a and lupus serum induced apoptosis in cultured human brain microvascular endothelial cells (HBMVECs), whereas selective C5a receptor 1 (C5aR1) antagonist reduced apoptosis in these cells, demonstrating C5a/C5aR1-dependence. Gene expression of initiator caspases, caspase 1 and caspase 8, and pro-apoptotic proteins death-associated protein kinase 1, Fas-associated protein (FADD), cell death-inducing DNA fragmentation factor 45 000 MW subunit A-like effector B (CIDEB) and BCL2-associated X protein were increased in HBMVECs treated with lupus serum or C5a, indicating that both the intrinsic and extrinsic apoptotic pathways could be critical mediators of brain endothelial cell apoptosis in this setting. Overall, our findings suggest that C5a/C5aR1 signalling induces apoptosis through activation of FADD, caspase 8/3 and CIDEB in brain endothelial cells in lupus. Further elucidation of the underlying apoptotic mechanisms mediating the reduced endothelial cell number is important in establishing the potential therapeutic effectiveness of C5aR1 inhibition that could prevent and/or reduce BBB alterations and preserve the physiological function of BBB in

  20. Up-regulation of heme oxygenase-1 protects against cold injury-induced brain damage: a laboratory-based study.

    Science.gov (United States)

    Shih, Ruey-Horng; Cheng, Shin-Ei; Tung, Wei-Hsuan; Yang, Chuen-Mao

    2010-08-01

    Heme oxygenase-1 (HO-1), a kind of stress protein, is critical for the protection against ischemic stroke and cerebrovascular endothelium damage. However, the effects of HO-1 on trauma-induced brain injury are still unknown. Hence, we attempted to use a cold injury-induced brain trauma (CIBT) model in mice, which provides for a well-established approach for assessing brain edema and blood-brain barrier breakdown. Additionally, we explored cultured mouse brain endothelial cells (bEnd.3) to investigate the protective effects of HO-1. HO-1 was induced by infection with a recombinant adenovirus carrying the human HO-1 gene or an inducer of HO-1 activity, cobalt protoporphyrin IX (CoPP). The recombinant adenovirus (3.5 x 10(7) PFU/mouse, i.v.) or CoPP (10 mg/kg, i.v.) significantly increased HO-1 protein expression and HO-1 enzyme activity in the cerebral cortex of the mice. We found that overexpression of HO-1 protected against cold injury-induced secondary damage and behavioral impairment. Up-regulation of HO-1 decreased brain edema and neutrophil infiltration induced by cold injury. These HO-1-dependent protecting effects were abrogated by pretreatment with the HO-1 inhibitor, zinc protoporphyrin IX (ZnPP; 3 mg/kg, i.v.). HO-1 expression in the cerebral endothelium was observed by immunofluorescent staining. CoPP-induced (1 muM, 24 h) HO-1 protein expression was determined by western blotting in bEnd.3 cells. Enhanced HO-1 also protected against cold injury-induced cell loss and damage, which were respectively determined by GAPDH leakage into the cell medium and XTT assay in bEnd.3 cells. In summary, HO-1 overexpression appears to offer an effective neuroprotection against cold-induced secondary brain injury.

  1. Melatonin and the newborn brain.

    Science.gov (United States)

    Colella, Marina; Biran, Valérie; Baud, Olivier

    2016-11-01

    Brain injury related to preterm birth and neonatal asphyxia is a leading cause of childhood neuromotor and cognitive disabilities. Unfortunately, the strategies to prevent perinatal brain damages remain limited. Among the candidate molecules, melatonin appears to be one of the most promising agents for its antioxidant and neuromodulatory action. Robust preclinical evidences and few clinical studies have suggested a neuroprotective benefit conferred by neonatal exposure to melatonin. This review recapitulates current basic research, safety and pharmacokinetic data and ongoing clinical trials on the use of melatonin as a neuroprotective agent in the newborn. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. Cerebrospinal fluid control of neurogenesis induced by retinoic acid during early brain development.

    Science.gov (United States)

    Alonso, M I; Martín, C; Carnicero, E; Bueno, D; Gato, A

    2011-07-01

    Embryonic-cerebrospinal fluid (E-CSF) plays crucial roles in early brain development including the control of neurogenesis. Although FGF2 and lipoproteins present in the E-CSF have previously been shown to be involved in neurogenesis, the main factor triggering this process remains unknown. E-CSF contains all-trans-retinol and retinol-binding protein involved in the synthesis of retinoic acid (RA), a neurogenesis inducer. In early chick embryo brain, only the mesencephalic-rombencephalic isthmus (IsO) is able to synthesize RA. Here we show that in chick embryo brain development: (1) E-CSF helps to control RA synthesis in the IsO by means of the RBP and all-trans-retinol it contains; (2) E-CSF has retinoic acid activity, which suggests it may act as a diffusion pathway for RA; and (3) the influence of E-CSF on embryonic brain neurogenesis is to a large extent due to its involvement in RA synthesis. These data help to understand neurogenesis from neural progenitor cells. Copyright © 2011 Wiley-Liss, Inc.

  3. An introduction to alcohol-induced brain damage and its causes.

    Science.gov (United States)

    Harper, C; Kril, J

    1994-01-01

    The aim of the symposium on alcohol-induced brain damage is to review current opinion and recent advances concerning factors which are thought to play a significant role in this disorder. The three principal factors are: alcohol specific neurotoxicity, associated vitamin B1 (thiamine) deficiency (the Wernicke-Korsakoff syndrome) and liver failure secondary to alcoholic cirrhosis. There is a complex interaction of these and other factors and it is difficult to dissect out the relative importance of each in the pathogenesis of alcohol-related brain damage. Moreover recent molecular and biochemical studies suggest that several of these factors may have pathogenetic mechanisms in common-for example, excitotoxicity, mitric oxide and free radicals. The application of new technologies in neuropathological studies of carefully selected groups of alcoholic cases is beginning to reveal a far more complex pattern of damage than current view holds. Quantitative morphometry and immunohistochemistry can be combined to create three dimensional images of various anatomical regions of the brain together with detailed analyses of neuronal counts, sizes and neurochemical type. In the Wernicke-Korsakoff syndrome (WKS) there is good evidence (in support of neuropsychological and neuroradiological data) to suggest that specific populations of neurons are damaged in cortical and subcortical regions. In those cases with the WKS there is also evidence of pathological damage in cortical and subcortical regions other than the well described periventricular distributions. These more detailed studies provide us with a more comprehensive understanding of alcohol-related brain damage.

  4. Radiation-induced brain injury: retrospective analysis of twelve pathologically proven cases

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Dong Soo; Yu, Mi Na; Jang, Hong Seok [The Cancer Center of Seoul St. Mary' s Hospital, The Catholic University of Korea, Seoul (Korea, Republic of); and others

    2011-09-15

    This study was designed to determine the influencing factors and clinical course of pathologically proven cases of radiation-induced brain injury (RIBI). The pathologic records of twelve patients were reviewed; these patients underwent surgery following radiotherapy due to disease progression found by follow-up imaging. However, they were finally diagnosed with RIBI. All patients had been treated with 3-dimensional conventional fractionated radiotherapy and/or radiosurgery for primary or metastatic brain tumors with or without chemotherapy. The histological distribution was as follows: two falx meningioma, six glioblastoma multiform (GBM), two anaplastic oligodendroglioma, one low grade oligodendroglioma, and one small cell lung cancer with brain metastasis. Radiation necrosis was noted in eight patients and the remaining four were diagnosed with radiation change. Gender (p 0.061) and biologically equivalent dose (BED){sub 3} (p = 0.084) were the only marginally influencing factors of radiation necrosis. Median time to RIBI was 7.3 months (range, 0.5 to 61 months). Three prolonged survivors with GBM were observed. In the subgroup analysis of high grade gliomas, RIBI that developed <6 months after radiotherapy was associated with inferior overall survival rates compared to cases of RIBI that occurred {>=}6 months (p = 0.085). Our study demonstrated that RIBI could occur in early periods after conventional fractionated brain radiotherapy within normal tolerable dose ranges. Studies with a larger number of patients are required to identify the strong influencing factors for RIBI development.

  5. MRI-detectable changes in mouse brain structure induced by voluntary exercise.

    Science.gov (United States)

    Cahill, Lindsay S; Steadman, Patrick E; Jones, Carly E; Laliberté, Christine L; Dazai, Jun; Lerch, Jason P; Stefanovic, Bojana; Sled, John G

    2015-06-01

    Physical exercise, besides improving cognitive and mental health, is known to cause structural changes in the brain. Understanding the structural changes that occur with exercise as well as the neuroanatomical correlates of a predisposition for exercise is important for understanding human health. This study used high-resolution 3D MR imaging, in combination with deformation-based morphometry, to investigate the macroscopic changes in brain structure that occur in healthy adult mice following four weeks of voluntary exercise. We found that exercise induced changes in multiple brain structures that are involved in motor function and learning and memory including the hippocampus, dentate gyrus, stratum granulosum of the dentate gyrus, cingulate cortex, olivary complex, inferior cerebellar peduncle and regions of the cerebellum. In addition, a number of brain structures, including the hippocampus, striatum and pons, when measured on MRI prior to the start of exercise were highly predictive of subsequent exercise activity. Exercise tended to normalize these pre-existing differences between mice. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Brain aging and AD-like pathology in streptozotocin-induced diabetic rats.

    Science.gov (United States)

    Wang, Jian-Qin; Yin, Jie; Song, Yan-Feng; Zhang, Lang; Ren, Ying-Xiang; Wang, De-Gui; Gao, Li-Ping; Jing, Yu-Hong

    2014-01-01

    Numerous epidemiological studies have linked diabetes mellitus (DM) with an increased risk of developing Alzheimer's disease (AD). However, whether or not diabetic encephalopathy shows AD-like pathology remains unclear. Forebrain and hippocampal volumes were measured using stereology in serial coronal sections of the brain in streptozotocin- (STZ-) induced rats. Neurodegeneration in the frontal cortex, hypothalamus, and hippocampus was evaluated using Fluoro-Jade C (FJC). Aβ aggregation in the frontal cortex and hippocampus was tested using immunohistochemistry and ELISA. Dendritic spine density in the frontal cortex and hippocampus was measured using Golgi staining, and western blot was conducted to detect the levels of synaptophysin. Cognitive ability was evaluated through the Morris water maze and inhibitory avoidant box. Rats are characterized by insulin deficiency accompanied with polydipsia, polyphagia, polyuria, and weight loss after STZ injection. The number of FJC-positive cells significantly increased in discrete brain regions of the diabetic rats compared with the age-matched control rats. Hippocampal atrophy, Aβ aggregation, and synapse loss were observed in the diabetic rats compared with the control rats. The learning and memory of the diabetic rats decreased compared with those of the age-matched control rats. Our results suggested that aberrant metabolism induced brain aging as characterized by AD-like pathologies.

  7. Brain Aging and AD-Like Pathology in Streptozotocin-Induced Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Jian-Qin Wang

    2014-01-01

    Full Text Available Objective. Numerous epidemiological studies have linked diabetes mellitus (DM with an increased risk of developing Alzheimer’s disease (AD. However, whether or not diabetic encephalopathy shows AD-like pathology remains unclear. Research Design and Methods. Forebrain and hippocampal volumes were measured using stereology in serial coronal sections of the brain in streptozotocin- (STZ- induced rats. Neurodegeneration in the frontal cortex, hypothalamus, and hippocampus was evaluated using Fluoro-Jade C (FJC. Aβ aggregation in the frontal cortex and hippocampus was tested using immunohistochemistry and ELISA. Dendritic spine density in the frontal cortex and hippocampus was measured using Golgi staining, and western blot was conducted to detect the levels of synaptophysin. Cognitive ability was evaluated through the Morris water maze and inhibitory avoidant box. Results. Rats are characterized by insulin deficiency accompanied with polydipsia, polyphagia, polyuria, and weight loss after STZ injection. The number of FJC-positive cells significantly increased in discrete brain regions of the diabetic rats compared with the age-matched control rats. Hippocampal atrophy, Aβ aggregation, and synapse loss were observed in the diabetic rats compared with the control rats. The learning and memory of the diabetic rats decreased compared with those of the age-matched control rats. Conclusions. Our results suggested that aberrant metabolism induced brain aging as characterized by AD-like pathologies.

  8. Behavioral consequences of NMDA antagonist-induced neuroapoptosis in the infant mouse brain.

    Directory of Open Access Journals (Sweden)

    Carla M Yuede

    2010-06-01

    Full Text Available Exposure to NMDA glutamate antagonists during the brain growth spurt period causes widespread neuroapoptosis in the rodent brain. This period in rodents occurs during the first two weeks after birth, and corresponds to the third trimester of pregnancy and several years after birth in humans. The developing human brain may be exposed to NMDA antagonists through drug-abusing mothers or through anesthesia.We evaluated the long-term neurobehavioral effects of mice exposed to a single dose of the NMDA antagonist, phencyclidine (PCP, or saline, on postnatal day 2 (P2 or P7, or on both P2 and P7. PCP treatment on P2 + P7 caused more severe cognitive impairments than either single treatment. Histological examination of acute neuroapoptosis resulting from exposure to PCP indicated that the regional pattern of degeneration induced by PCP in P2 pups was different from that in P7 pups. The extent of damage when evaluated quantitatively on P7 was greater for pups previously treated on P2 compared to pups treated only on P7.These findings signify that PCP induces different patterns of neuroapoptosis depending on the developmental age at the time of exposure, and that exposure at two separate developmental ages causes more severe neuropathological and neurobehavioral consequences than a single treatment.

  9. Intracerebroventricular galanin-like peptide induces different brain activation compared with galanin.

    Science.gov (United States)

    Lawrence, Catherine B; Williams, Torrie; Luckman, Simon M

    2003-09-01

    Like galanin, the 60-amino-acid peptide, galanin-like peptide (GALP), has orexigenic actions, demonstrated by an acute increase in feeding after central injection in rodents. However, in contrast to galanin, GALP causes a prolonged rise in core body temperature and a reduction in body weight over 24 h. In an attempt to identify potential explanations for the observed differences between GALP and galanin, this study examined which brain areas were activated by these peptides. Intracerebroventricular injection of GALP into conscious rats significantly stimulated feeding over 0-1 h, increased core body temperature, but reduced body weight gain over 24 h. Immunohistochemistry to detect c-fos demonstrated that intracerebroventricular injection of GALP or galanin activated several brain regions in common, including the dorsomedial nucleus of the hypothalamus, lateral hypothalamus, and nucleus tractus solitarius of the brainstem. However, GALP also induced c-fos expression in the periventricular hypothalamic region and supraoptic hypothalamic nucleus. Cell activation induced by GALP in the supraoptic hypothalamic nucleus and nucleus tractus solitarius was dependent on food intake but independent of food consumption in all other brain regions. Double immunohistochemistry indicated that small cells expressing c-fos in the periventricular hypothalamic region after GALP were astrocytes and not microglia.

  10. Blood-brain barrier dysfunction in mice induced by lipopolysaccharide is attenuated by dapsone.

    Science.gov (United States)

    Zhou, Ting; Zhao, Lei; Zhan, Rui; He, Qihua; Tong, Yawei; Tian, Xiaosheng; Wang, Hecheng; Zhang, Tao; Fu, Yaoyun; Sun, Yang; Xu, Feng; Guo, Xiangyang; Fan, Dongsheng; Han, Hongbin; Chui, Dehua

    2014-10-24

    Blood-brain barrier (BBB) dysfunction is a key event in the development of many central nervous system (CNS) diseases, such as septic encephalopathy and stroke. 4,4'-Diaminodiphenylsulfone (DDS, Dapsone) has displayed neuroprotective effect, but whether DDS has protective role on BBB integrity is not clear. This study was designed to examine the effect of DDS on lipopolysaccharide (LPS)-induced BBB disruption and oxidative stress in brain vessels. Using in vivo multiphoton imaging, we found that DDS administration significantly restored BBB integrity compromised by LPS. DDS also increased the expression of tight junction proteins occludin, zona occludens-1 (ZO-1) and claudin-5 in brain vessels. Level of reactive oxygen species (ROS) was reduced by DDS treatment, which may due to decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and NOX2 expression. Our results showed that LPS-induced BBB dysfunction could be attenuated by DDS, indicated that DDS has a therapeutic potential for treating CNS infection and other BBB related diseases. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Candesartan improves ischemia-induced impairment of the blood-brain barrier in vitro.

    Science.gov (United States)

    So, Gohei; Nakagawa, Shinsuke; Morofuji, Yoichi; Hiu, Takeshi; Hayashi, Kentaro; Tanaka, Kunihiko; Suyama, Kazuhiko; Deli, Maria A; Nagata, Izumi; Matsuo, Takayuki; Niwa, Masami

    2015-05-01

    Candesartan has been reported to have a protective effect on cerebral ischemia in vivo and in human ischemic stroke. We studied the direct effects of candesartan on blood-brain barrier (BBB) function with our in vitro monolayer model generated using rat brain capillary endothelial cells (RBECs). The in vitro BBB model was subjected to normoxia or 6-h oxygen glucose deprivation (OGD)/24-h reoxygenation, with or without candesartan. 6-h OGD/24-h reoxygenation decreased transendothelial electrical resistance and increased the endothelial permeability for sodium fluorescein in RBEC monolayers. Candesartan (10 nM) improved RBEC barrier dysfunction induced by 6-h OGD/24-h reoxygenation. Immunostaining and immunoblotting analysis indicated that the effect of candesartan on barrier function under 6-h OGD/24-h reoxygenation was not related to the expression levels of tight junction proteins. However, candesartan affected RBEC morphological changes induced by 6-h OGD/24-h reoxygenation. We analyzed oxidative stress and cell viability using chemical reagents. Candesartan improved cell viability following 6-h OGD/24-h reoxygenation, whereas candesartan had no effect on oxidative stress. These results show that candesartan directly improves cell function and viability of brain capillary endothelial cells under OGD/reoxygenation, suggesting that the protective effects of candesartan on ischemic stroke are related to protection of the BBB.

  12. A Brain-Machine Interface for Control of Medically-Induced Coma

    Science.gov (United States)

    Liberman, Max; Solt, Ken; Brown, Emery N.

    2013-01-01

    Medically-induced coma is a drug-induced state of profound brain inactivation and unconsciousness used to treat refractory intracranial hypertension and to manage treatment-resistant epilepsy. The state of coma is achieved by continually monitoring the patient's brain activity with an electroencephalogram (EEG) and manually titrating the anesthetic infusion rate to maintain a specified level of burst suppression, an EEG marker of profound brain inactivation in which bursts of electrical activity alternate with periods of quiescence or suppression. The medical coma is often required for several days. A more rational approach would be to implement a brain-machine interface (BMI) that monitors the EEG and adjusts the anesthetic infusion rate in real time to maintain the specified target level of burst suppression. We used a stochastic control framework to develop a BMI to control medically-induced coma in a rodent model. The BMI controlled an EEG-guided closed-loop infusion of the anesthetic propofol to maintain precisely specified dynamic target levels of burst suppression. We used as the control signal the burst suppression probability (BSP), the brain's instantaneous probability of being in the suppressed state. We characterized the EEG response to propofol using a two-dimensional linear compartment model and estimated the model parameters specific to each animal prior to initiating control. We derived a recursive Bayesian binary filter algorithm to compute the BSP from the EEG and controllers using a linear-quadratic-regulator and a model-predictive control strategy. Both controllers used the estimated BSP as feedback. The BMI accurately controlled burst suppression in individual rodents across dynamic target trajectories, and enabled prompt transitions between target levels while avoiding both undershoot and overshoot. The median performance error for the BMI was 3.6%, the median bias was -1.4% and the overall posterior probability of reliable control was 1 (95

  13. Oxidative stress induces the decline of brain EPO expression in aging rats.

    Science.gov (United States)

    Li, Xu; Chen, Yubao; Shao, Siying; Tang, Qing; Chen, Weihai; Chen, Yi; Xu, Xiaoyu

    2016-10-01

    Brain Erythropoietin (EPO), an important neurotrophic factor and neuroprotective factor, was found to be associated with aging. Studies found EPO expression was significantly decreased in the hippocampus of aging rat compared with that of the youth. But mechanisms of the decline of the brain EPO during aging remain unclear. The present study utilized a d-galactose (d-gal)-induced aging model in which the inducement of aging was mainly oxidative injury, to explore underlying mechanisms for the decline of brain EPO in aging rats. d-gal-induced aging rats (2months) were simulated by subcutaneously injecting with d-gal at doses of 50mg·kg(-1), 150mg·kg(-1) and 250mg·kg(-1) daily for 8weeks while the control group received vehicle only. These groups were all compared with the aging rats (24months) which had received no other treatment. The cognitive impairment was assessed using Morris water maze (MWM) in the prepared models, and the amount of β-galactosidase, the lipid peroxidation product malondialdehyde (MDA) level and the superoxide dismutase (SOD) activity in the hippocampus was examined by assay kits. The levels of EPO, EPOR, p-JAK2 and hypoxia-inducible factor-2α (HIF-2α) in the hippocampus were detected by western blot. Additionally, the correlation coefficient between EPO/EPOR expression and MDA level was analyzed. The MWM test showed that compared to control group, the escape latency was significantly extended and the times of crossing the platform was decreased at the doses of 150mg·kg(-1) and 250mg·kg(-1) (paging rats, the expressions of EPO, EPOR, p-JAK2, and HIF-2αin the brain of d-gal-treated rats were significantly decreased (paging could result in the decline of EPO in the hippocampus and oxidative stress might be the main reason for the decline of brain EPO in aging rats, involved with the decrease of HIF-2α stability. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Oenothein B Suppresses Lipopolysaccharide (LPS-Induced Inflammation in the Mouse Brain

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    Yoshiko Furukawa

    2013-05-01

    Full Text Available Oenothein B has been recently evaluated for its ability to affect inflammatory responses in peripheral tissues. In this study, we examined its effect on the damage to the central nervous system due to systemic inflammation. For this purpose, ICR mice were injected with an intraperitoneal (i.p. dose of lipopolysaccharide (LPS; 1 mg/kg mouse. When oenothein B was administered per os (p.o., it suppressed (1 LPS-induced abnormal behavior in open field; (2 LPS-induced microglial activation in the hippocampus and striatum; and (3 LPS-induced cyclooxygenase (COX-2 production in the hippocampus and striatum of these mice. These results suggest that oenothein B had the ability to reduce neuroinflammation in the brain during systemic inflammation.

  15. Brain Injury-Induced Synaptic Reorganization in Hilar Inhibitory Neurons Is Differentially Suppressed by Rapamycin.

    Science.gov (United States)

    Butler, Corwin R; Boychuk, Jeffery A; Smith, Bret N

    2017-01-01

    Following traumatic brain injury (TBI), treatment with rapamycin suppresses mammalian (mechanistic) target of rapamycin (mTOR) activity and specific components of hippocampal synaptic reorganization associated with altered cortical excitability and seizure susceptibility. Reemergence of seizures after cessation of rapamycin treatment suggests, however, an incomplete suppression of epileptogenesis. Hilar inhibitory interneurons regulate dentate granule cell (DGC) activity, and de novo synaptic input from both DGCs and CA3 pyramidal cells after TBI increases their excitability but effects of rapamycin treatment on the injury-induced plasticity of interneurons is only partially described. Using transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed in the somatostatinergic subset of hilar inhibitory interneurons, we tested the effect of daily systemic rapamycin treatment (3 mg/kg) on the excitability of hilar inhibitory interneurons after controlled cortical impact (CCI)-induced focal brain injury. Rapamycin treatment reduced, but did not normalize, the injury-induced increase in excitability of surviving eGFP+ hilar interneurons. The injury-induced increase in response to selective glutamate photostimulation of DGCs was reduced to normal levels after mTOR inhibition, but the postinjury increase in synaptic excitation arising from CA3 pyramidal cell activity was unaffected by rapamycin treatment. The incomplete suppression of synaptic reorganization in inhibitory circuits after brain injury could contribute to hippocampal hyperexcitability and the eventual reemergence of the epileptogenic process upon cessation of mTOR inhibition. Further, the cell-selective effect of mTOR inhibition on synaptic reorganization after CCI suggests possible mechanisms by which rapamycin treatment modifies epileptogenesis in some models but not others.

  16. Protective effect of pyruvate against ethanol-induced apoptotic neurodegeneration in the developing rat brain.

    Science.gov (United States)

    Ullah, Najeeb; Naseer, Muhammad Imran; Ullah, Ikram; Lee, Hae Young; Koh, Phil Ok; Kim, Myeong Ok

    2011-12-01

    Exposure to alcohol during the early stages of brain development can lead to neurological disorders in the CNS. Apoptotic neurodegeneration due to ethanol exposure is a main feature of alcoholism. Exposure of developing animals to alcohol (during the growth spurt period in particular) elicits apoptotic neuronal death and causes fetal alcohol effects (FAE) or fetal alcohol syndrome (FAS). A single episode of ethanol intoxication (at 5 g/kg) in a seven-day-old developing rat can activate the apoptotic cascade, leading to widespread neuronal death in the brain. In the present study, we investigated the potential protective effect of pyruvate against ethanol-induced neuroapoptosis. After 4h, a single dose of ethanol induced upregulation of Bax, release of mitochondrial cytochrome-c into the cytosol, activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP-1), all of which promote apoptosis. These effects were all reversed by co-treatment with pyruvate at a well-tolerated dosage (1000 mg/kg). Histopathology performed at 24 and 48 h with Fluoro-Jade-B and cresyl violet stains showed that pyruvate significantly reduced the number of dead cells in the cerebral cortex, hippocampus and thalamus. Immunohistochemical analysis at 24h confirmed that ethanol-induced cell death is both apoptotic and inhibited by pyruvate. These findings suggest that pyruvate treatment attenuates ethanol-induced neuronal cell loss in the developing rat brain and holds promise as a safe therapeutic and neuroprotective agent in the treatment of neurodegenerative disorders in newborns and infants. Copyright © 2011 Elsevier Ltd. All rights reserved.

  17. Minocycline inhibits brain inflammation and attenuates spontaneous recurrent seizures following pilocarpine-induced status epilepticus.

    Science.gov (United States)

    Wang, N; Mi, X; Gao, B; Gu, J; Wang, W; Zhang, Y; Wang, X

    2015-02-26

    Mounting evidence suggests that brain inflammation mediated by glial cells may contribute to epileptogenesis. Minocycline is a second-generation tetracycline and has potent antiinflammatory effects independent of its antimicrobial action. The present study aimed to investigate whether minocycline could exert antiepileptogenic effects in a rat lithium-pilocarpine model of temporal lobe epilepsy. The temporal patterns of microglial and astrocytic activation were examined in the hippocampal CA1 and the adjacent cortex following pilocarpine-induced status epilepticus (SE). These findings displayed that SE caused acute and persistent activation of microglia and astrocytes. Based on these findings, Minocycline was administered once daily at 45 mg/kg for 14 days following SE. Six weeks after termination of minocycline treatment, spontaneous recurrent seizures (SRS) were recorded by continuous video monitoring. Minocycline inhibited the SE-induced microglial activation and the increased production of interleukin-1β and tumor necrosis factor-α in the hippocampal CA1 and the adjacent cortex, without affecting astrocytic activation. In addition, Minocycline prevented the SE-induced neuronal loss in the brain regions examined. Moreover, minocycline significantly reduced the frequency, duration, and severity of SRS during the two weeks monitoring period. These results demonstrated that minocycline could mitigate SE-induced brain inflammation and might exert disease-modifying effects in an animal model of temporal lobe epilepsy. These findings offer new insights into deciphering the molecular mechanisms of epileptogenesis and exploring a novel therapeutic strategy for prevention of epilepsy. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  18. Intranasal pyrrolidine dithiocarbamate decreases brain inflammatory mediators and provides neuroprotection after brain hypoxia-ischemia in neonatal rats

    OpenAIRE

    Wang, Zhi; Zhao, Huijuan; Peng, Shuling; Zuo, Zhiyi

    2013-01-01

    Brain injury due to birth asphyxia is the major cause of death and long-term disabilities in newborns. We determined whether intranasal pyrrolidine dithiocarbamate (PDTC) could provide neuroprotection in neonatal rats after brain hypoxia-ischemia (HI). Seven-day old male and female Sprague-Dawley rats were subjected to brain HI. They were then treated by intranasal PDTC. Neurological outcome were evaluated 7 or 30 days after the brain HI. Brain tissues were harvested 6 or 24 h after the brain...

  19. CT cold areas in both putamens in cases with history of perinatal asphyxia

    Energy Technology Data Exchange (ETDEWEB)

    Ishizaki, Asayo; Maruyama, Hiroshi (Tokyo Women' s Medical Coll. (Japan))

    1982-12-01

    CT bilaterally showed a cold area in the putamen of 5 infants with cerebral palsy who had had asphyxia at birth. The etiology was discussed, and 4 of the cases were clinically studied. All four patients had convulsive tetraplegia, or convulsive bilateral paralysis with the element of athetosis. Three of them had a history of infantile epilepsy, accompanied by abnormal ocular movement. Two patients with tetraplegia showed marked hypotonia of the trunk in ventral support (Landau). Impairment of the bilateral putamens in the abnormal muscle tone was inferred.

  20. Cannabinoids: Well-Suited Candidates for the Treatment of Perinatal Brain Injury

    Directory of Open Access Journals (Sweden)

    José Martínez-Orgado

    2013-07-01

    Full Text Available Perinatal brain injury can be induced by a number of different damaging events occurring during or shortly after birth, including neonatal asphyxia, neonatal hypoxia-ischemia and stroke-induced focal ischemia. Typical manifestations of these conditions are the presence of glutamate excitoxicity, neuroinflammation and oxidative stress, the combination of which can potentially result in apoptotic-necrotic cell death, generation of brain lesions and long-lasting functional impairment. In spite of the high incidence of perinatal brain injury, the number of clinical interventions available for the treatment of the affected newborn babies is extremely limited. Hence, there is a dramatic need to develop new effective therapies aimed to prevent acute brain damage and enhance the endogenous mechanisms of long-term brain repair. The endocannabinoid system is an endogenous neuromodulatory system involved in the control of multiple central and peripheral functions. An early responder to neuronal injury, the endocannabinoid system has been described as an endogenous neuroprotective system that once activated can prevent glutamate excitotoxicity, intracellular calcium accumulation, activation of cell death pathways, microglia activation, neurovascular reactivity and infiltration of circulating leukocytes across the blood-brain barrier. The modulation of the endocannabinoid system has proven to be an effective neuroprotective strategy to prevent and reduce neonatal brain injury in different animal models and species. Also, the beneficial role of the endocannabinoid system on the control of the endogenous repairing responses (neurogenesis and white matter restoration to neonatal brain injury has been described in independent studies. This review addresses the particular effects of several drugs that modulate the activity of the endocannabinoid system on the progression of different manifestations of perinatal brain injury during both the acute and chronic

  1. Chronic Fluoxetine Treatment Induces Brain Region-Specific Upregulation of Genes Associated with BDNF-Induced Long-Term Potentiation

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    Maria Nordheim Alme

    2007-01-01

    Full Text Available Several lines of evidence implicate BDNF in the pathogenesis of stress-induced depression and the delayed efficacy of antidepressant drugs. Antidepressant-induced upregulation of BDNF signaling is thought to promote adaptive neuronal plasticity through effects on gene expression, but the effector genes downstream of BDNF has not been identified. Local infusion of BDNF into the dentate gyrus induces a long-term potentiation (BDNF-LTP of synaptic transmission that requires upregulation of the immediate early gene Arc. Recently, we identified five genes (neuritin, Narp, TIEG1, Carp, and Arl4d that are coupregulated with Arc during BDNF-LTP. Here, we examined the expression of these genes in the dentate gyrus, hippocampus proper, and prefrontal cortex after antidepressant treatment. We show that chronic, but not acute, fluoxetine administration leads to upregulation of these BDNF-LTP-associated genes in a brain region-specific pattern. These findings link chronic effects of antidepressant treatment to molecular mechanisms underlying BDNF-induced synaptic plasticity.

  2. Immune-induced fever is mediated by IL-6 receptors on brain endothelial cells coupled to STAT3-dependent induction of brain endothelial prostaglandin synthesis.

    Science.gov (United States)

    Eskilsson, Anna; Mirrasekhian, Elahe; Dufour, Sylvie; Schwaninger, Markus; Engblom, David; Blomqvist, Anders

    2014-11-26

    The cytokine IL-6, which is released upon peripheral immune challenge, is critical for the febrile response, but the mechanism by which IL-6 is pyrogenic has remained obscure. Here we generated mice with deletion of the membrane bound IL-6 receptor α (IL-6Rα) on neural cells, on peripheral nerves, on fine sensory afferent fibers, and on brain endothelial cells, respectively, and examined its role for the febrile response to peripherally injected lipopolysaccharide. We show that IL-6Rα on neural cells, peripheral nerves, and fine sensory afferents are dispensable for the lipopolysaccharide-induced fever, whereas IL-6Rα in the brain endothelium plays an important role. Hence deletion of IL-6Rα on brain endothelial cells strongly attenuated the febrile response, and also led to reduced induction of the prostaglandin synthesizing enzyme Cox-2 in the hypothalamus, the temperature-regulating center in the brain, as well as reduced expression of SOCS3, suggesting involvement of the STAT signaling pathway. Furthermore, deletion of STAT3 in the brain endothelium also resulted in attenuated fever. These data show that IL-6, when endogenously released during systemic inflammation, is pyrogenic by binding to IL-6Rα on brain endothelial cells to induce prostaglandin synthesis in these cells, probably in concerted action with other peripherally released cytokines. Copyright © 2014 the authors 0270-6474/14/3415957-05$15.00/0.

  3. Pharmaco-thermodynamics of deuterium-induced oedema in living rat brain via 1H2O MRI: implications for boron neutron capture therapy of malignant brain tumours

    Science.gov (United States)

    Medina, Daniel C.; Li, Xin; Springer, Charles S., Jr.

    2005-05-01

    In addition to its common usage as a tracer in metabolic and physiological studies, deuterium possesses anti-tumoural activity and confers protection against γ-irradiation. A more recent interest in deuterium emanates from the search for alternatives capable of improving neutron penetrance whilst reducing healthy tissue radiation dose deposition in boron neutron capture therapy of malignant brain tumours. Despite this potential clinical application, deuterium induces brain oedema, which is detrimental to neutron capture therapy. In this study, five adult male rats were titrated with deuterated drinking water while brain oedema was monitored via water proton magnetic resonance imaging. This report concludes that deuterium, as well as deuterium-induced brain oedema, possesses a uniform brain bio-distribution. At a steady-state blood fluid deuteration value of 16%, when the deuterium isotope fraction in drinking water was 25%, a mean oedematous volume change of 9 ± 2% (p-value body fluid deuteration enhances thermal neutron flux penetrance and reduces dose deposition, oedema has the opposite effect because it increases the volume of interest, e.g., the brain volume. Thermal neutron enhancement and effective dose reduction factors could be reduced by as much as ~10% in the presence of a 9% water volume increase (oedema). All three authors have contributed equally to this work.

  4. Comparison of the Incidence of Perinatal Asphyxia before and after the Health Improvement Program in Bentolhoda Hospital of Bojnurd, Iran

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    Mahvan Khodaparast

    2016-12-01

    Full Text Available Background: Perinatal asphyxia is a common cause of infant morbidity and mortality and long-term neurological disabilities. Due to the high costs of admission, a large proportion of births and neonatal deaths occur in non-hospital settings. This study aimed to evaluate the incidence rate of perinatal asphyxia before and after the implementation of the health improvement program. Methods: This descriptive-analytical study was conducted on all the infants with moderate and severe asphyxia during April 2013-2015. Subjects were divided into two groups of A and B (born after and before the health improvement program, respectively. Maternal and neonatal data were recorded in checklists and compared between these  groups. Data analysis was performed in SPSS version 17. Results: In total, 111 asphyxiated neonates were classified into two groups of A and B, and incidence rate of asphyxia was estimated at 0.54% and 1.05%, respectively. Severe asphyxia was observed in 35.7% and 28.9% of the infants in groups A and B, respectively. Moreover, mean duration of mechanical ventilation was 25 and 79 hours in groups A and B, respectively. Conclusion: According to the results of this study, implementation of the health improvement program reduced the incidence of perinatal asphyxia. In addition, number of cesarean cases due to previous C-section was observed to decrease. Therefore, it could be concluded that high-quality resuscitation efforts and restricted rules in the health improvement program lower the risk of long-term complications in asphyxiated neonates. However, no significant difference was observed in the mortality rate of the asphyxiated newborns in this study.

  5. Flexible, AAV-equipped Genetic Modules for Inducible Control of Gene Expression in Mammalian Brain

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    Godwin K Dogbevia

    2016-01-01

    Full Text Available Controlling gene expression in mammalian brain is of utmost importance to causally link the role of gene function to cell circuit dynamics under normal conditions and disease states. We have developed recombinant adeno-associated viruses equipped with tetracycline-controlled genetic switches for inducible and reversible control of gene expression in a cell type specific and brain subregion selective manner. Here, we characterize a two-virus approach to efficiently and reliably switch gene expression on and off, repetitively, both in vitro and in vivo. Our recombinant adeno-associated virus (rAAV-Tet approach is highly flexible and it has great potential for application in basic and biomedical neuroscience research and gene therapy.

  6. Working toward exposure thresholds for blast-induced traumatic brain injury: thoracic and acceleration mechanisms

    CERN Document Server

    Courtney, Michael; 10.1016/j.neuroimage.2010.05.025

    2011-01-01

    Research in blast-induced lung injury resulted in exposure thresholds that are useful in understanding and protecting humans from such injury. Because traumatic brain injury (TBI) due to blast exposure has become a prominent medical and military problem, similar thresholds should be identified that can put available research results in context and guide future research toward protecting warfighters as well as diagnosis and treatment. At least three mechanical mechanisms by which the blast wave may result in brain injury have been proposed - a thoracic mechanism, head acceleration and direct cranial transmission. These mechanisms need not be mutually exclusive. In this study, likely regions of interest for the first two mechanisms based on blast characteristics (positive pulse duration and peak effective overpressure) are developed using available data from blast experiments and related studies, including behind-armor blunt trauma and ballistic pressure wave studies. These related studies are appropriate to in...

  7. Chronic cocaine induces HIF-VEGF pathway activation along with angiogenesis in the brain.

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    Wei Yin

    Full Text Available Cocaine induces vasoconstriction in cerebral vessels, which with repeated use can result in transient ischemic attacks and cerebral strokes. However, the neuroadaptations that follow cocaine's vasoconstricting effects are not well understood. Here, we investigated the effects of chronic cocaine exposure (2 and 4 weeks on markers of vascular function and morphology in the rat brain. For this purpose we measured nitric oxide (NO concentration in plasma, brain neuronal nitric oxide synthase (nNOS or NOS1, HIF-1α, and VEGF expression in different brain regions, i.e., middle prefrontal cortex, somatosensory cortex, nucleus accumbens, and dorsal striatum, using ELISA or Western blot. Additionally, microvascular density in these brain regions was measured using immunofluorescence microscopy. We showed that chronic cocaine significantly affected NOS1, HIF-1α and VEGF expression, in a region- and cocaine treatment-time- dependent manner. Cerebral microvascular density increased significantly in parallel to these neurochemical changes. Furthermore, significant correlations were detected between VEGF expression and microvascular density in cortical regions (middle prefrontal cortex and somatosensory cortex, but not in striatal regions (nucleus accumbens and dorsal striatum. These results suggest that following chronic cocaine use, as cerebral ischemia developed, NOS1, the regulatory protein to counteract blood vessel constriction, was upregulated; meanwhile, the HIF-VEGF pathway was activated to increase microvascular density (i.e., angiogenesis and thus restore local blood flow and oxygen supply. These physiological responses were triggered presumably as an adaptation to minimize ischemic injury caused by cocaine. Therefore, effectively promoting such physiological responses may provide novel and effective therapeutic solutions to treat cocaine-induced cerebral ischemia and stroke.

  8. Ecto- and endoparasite induce similar chemical and brain neurogenomic responses in the honey bee (Apis mellifera)

    Science.gov (United States)

    2013-01-01

    Background Exclusion from a social group is an effective way to avoid parasite transmission. This type of social removal has also been proposed as a form of collective defense, or social immunity, in eusocial insect groups. If parasitic modification of host behavior is widespread in social insects, the underlying physiological and neuronal mechanisms remain to be investigated. We studied this phenomenon in honey bees parasitized by the mite Varroa destructor or microsporidia Nosema ceranae, which make bees leave the hive precociously. We characterized the chemical, behavioral and neurogenomic changes in parasitized bees, and compared the effects of both parasites. Results Analysis of cuticular hydrocarbon (CHC) profiles by gas chromatography coupled with mass spectrophotometry (GC-MS) showed changes in honey bees parasitized by either Nosema ceranae or Varroa destructor after 5 days of infestation. Levels of 10-HDA, an antiseptic important for social immunity, did not change in response to parasitism. Behavioral analysis of N. ceranae- or V. destructor- parasitized bees revealed no significant differences in their behavioral acts or social interactions with nestmates. Digital gene expression (DGE) analysis of parasitized honey bee brains demonstrated that, despite the difference in developmental stage at which the bee is parasitized, Nosema and Varroa-infested bees shared more gene changes with each other than with honey bee brain expression gene sets for forager or nurse castes. Conclusions Parasitism by Nosema or Varroa induces changes to both the CHC profiles on the surface of the bee and transcriptomic profiles in the brain, but within the social context of the hive, does not result in observable effects on her behavior or behavior towards her. While parasitized bees are reported to leave the hive as foragers, their brain transcription profiles suggest that their behavior is not driven by the same molecular pathways that induce foraging behavior. PMID:23866001

  9. Stress-induced changes of neurosteroid profiles in rat brain and plasma under immobilized condition.

    Science.gov (United States)

    Park, Myeong Hyeon; Rehman, Shaheed Ur; Kim, In Sook; Choi, Min Sun; Yoo, Hye Hyun

    2017-05-10

    In this study, various neurosteroids in brain and plasma were simultaneously determined using liquid chromatography-tandem mass spectrometry and their profile changes in a stress-induced rats were investigated. The investigated neurosteroids are as follows: progesterone (P4), 5α-dihydroprogesterone (5α-DHP), 5β-dihydroprogesterone, estrone, androstenedione (AE), cortisol, cortisone, corticosterone (CORT), dehydroepiandrosterone (DHEA), pregnanolone (3α,5β-THP), allopregnanolone (ALLO), 11-deoxycorticosterone (DOC), 11-deoxycortisol, pregnenolone (PREG), and 5α/5β-tetrahydrodeoxycorticosterone (5α/5β-THDOC). Brain and plasma samples were processed using solid-phase extraction with methanol and acetic acid (99:1), and derivatized with a hydroxylamine reagent. Separation was achieved within 13min at a flow rate of 0.4mL/min with a C18 column (3.0×50mm, 2.7μm). The triple quadrupole mass spectrometer was operated in the positive electrospray ionization mode. Using this method, the neurosteroid level variation was quantitated and investigated in the brain and plasma upon immobilization stress in rats. As a result, AE, CORT, DOC, P4, 5α-DHP, 5α/5β-THDOC, DHEA, 3α,5β-THP, ALLO, and PREG levels were significantly altered in both the brain and plasma samples when stress was induced. These findings demonstrated that stress leads to the alteration of the GABAergic neurosteroid profile. The present results will be helpful for furthering an understanding of the role of neurosteroids in stressed conditions. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Exposures to conditioned flavours with different hedonic values induce contrasted behavioural and brain responses in pigs.

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    Caroline Clouard

    Full Text Available This study investigated the behavioural and brain responses towards conditioned flavours with different hedonic values in juvenile pigs. Twelve 30-kg pigs were given four three-day conditioning sessions: they received three different flavoured meals paired with intraduodenal (i.d. infusions of 15% glucose (F(Glu, lithium chloride (F(LiCl, or saline (control treatment, F(NaCl. One and five weeks later, the animals were subjected to three two-choice feeding tests without reinforcement to check the acquisition of a conditioned flavour preference or aversion. In between, the anaesthetised pigs were subjected to three (18FDG PET brain imaging coupled with an olfactogustatory stimulation with the conditioned flavours. During conditioning, the pigs spent more time lying inactive, and investigated their environment less after the F(LiCl than the F(NaCl or F(Glu meals. During the two-choice tests performed one and five weeks later, the F(NaCl and F(Glu foods were significantly preferred over the F(LICl food even in the absence of i.d. infusions. Surprisingly, the F(NaCl food was also preferred over the F(Glu food during the first test only, suggesting that, while LiCl i.d. infusions led to a strong flavour aversion, glucose infusions failed to induce flavour preference. As for brain imaging results, exposure to aversive or less preferred flavours triggered global deactivation of the prefrontal cortex, specific activation of the posterior cingulate cortex, as well as asymmetric brain responses in the basal nuclei and the temporal gyrus. In conclusion, postingestive visceral stimuli can modulate the flavour/food hedonism and further feeding choices. Exposure to flavours with different hedonic values induced metabolism differences in neural circuits known to be involved in humans in the characterization of food palatability, feeding motivation, reward expectation, and more generally in the regulation of food intake.

  11. Chronic cocaine induces HIF-VEGF pathway activation along with angiogenesis in the brain.

    Science.gov (United States)

    Yin, Wei; Clare, Kevin; Zhang, Qiujia; Volkow, Nora D; Du, Congwu

    2017-01-01

    Cocaine induces vasoconstriction in cerebral vessels, which with repeated use can result in transient ischemic attacks and cerebral strokes. However, the neuroadaptations that follow cocaine's vasoconstricting effects are not well understood. Here, we investigated the effects of chronic cocaine exposure (2 and 4 weeks) on markers of vascular function and morphology in the rat brain. For this purpose we measured nitric oxide (NO) concentration in plasma, brain neuronal nitric oxide synthase (nNOS or NOS1), HIF-1α, and VEGF expression in different brain regions, i.e., middle prefrontal cortex, somatosensory cortex, nucleus accumbens, and dorsal striatum, using ELISA or Western blot. Additionally, microvascular density in these brain regions was measured using immunofluorescence microscopy. We showed that chronic cocaine significantly affected NOS1, HIF-1α and VEGF expression, in a region- and cocaine treatment-time- dependent manner. Cerebral microvascular density increased significantly in parallel to these neurochemical changes. Furthermore, significant correlations were detected between VEGF expression and microvascular density in cortical regions (middle prefrontal cortex and somatosensory cortex), but not in striatal regions (nucleus accumbens and dorsal striatum). These results suggest that following chronic cocaine use, as cerebral ischemia developed, NOS1, the regulatory protein to counteract blood vessel constriction, was upregulated; meanwhile, the HIF-VEGF pathway was activated to increase microvascular density (i.e., angiogenesis) and thus restore local blood flow and oxygen supply. These physiological responses were triggered presumably as an adaptation to minimize ischemic injury caused by cocaine. Therefore, effectively promoting such physiological responses may provide novel and effective therapeutic solutions to treat cocaine-induced cerebral ischemia and stroke.

  12. Effects of experimentally-induced maternal hypothyroidism on crucial offspring rat brain enzyme activities.

    Science.gov (United States)

    Koromilas, Christos; Liapi, Charis; Zarros, Apostolos; Stolakis, Vasileios; Tsagianni, Anastasia; Skandali, Nikolina; Al-Humadi, Hussam; Tsakiris, Stylianos

    2014-06-01

    Hypothyroidism is known to exert significant structural and functional changes to the developing central nervous system, and can lead to the establishment of serious mental retardation and neurological problems. The aim of the present study was to shed more light on the effects of gestational and/or lactational maternal exposure to propylthiouracil-induced experimental hypothyroidism on crucial brain enzyme activities of Wistar rat offspring, at two time-points of their lives: at birth (day-1) and at 21 days of age (end of lactation). Under all studied experimental conditions, offspring brain acetylcholinesterase (AChE) activity was found to be significantly decreased due to maternal hypothyroidism, in contrast to the two studied adenosinetriphosphatase (Na(+),K(+)-ATPase and Mg(2+)-ATPase) activities that were only found to be significantly altered right after birth (increased and decreased, respectively, following an exposure to gestational maternal hypothyroidism) and were restored to control levels by the end of lactation. As our findings regarding the pattern of effects that maternal hypothyroidism has on the above-mentioned crucial offspring brain enzyme activities are compared to those reported in the literature, several differences are revealed that could be attributed to both the mode of the experimental simulation approach followed as well as to the time-frames examined. These findings could provide the basis for a debate on the need of a more consistent experimental approach to hypothyroidism during neurodevelopment as well as for a further evaluation of the herein presented and discussed neurochemical (and, ultimately, neurodevelopmental) effects of experimentally-induced maternal hypothyroidism, in a brain region-specific manner. Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.

  13. Possible effects of rosuvastatin on noise-induced oxidative stress in rat brain

    Directory of Open Access Journals (Sweden)

    Alevtina Ersoy

    2014-01-01

    Full Text Available The problem of noise has recently gained more attention as it has become an integral part of our daily lives. However, its influence has yet to be fully elucidated. Other than being an unpleasant stimulus, noise may cause health disorders through annoyance and stress, including oxidative stress. Rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, may possess antioxidant properties. Based on rat models, our project investigates the effect of rosuvastatin on noise-induced oxidative stress in the brain tissue. Thirty-two male Wistar albino rats were used. The rats were divided into four groups: Noise exposure plus rosuvastatin usage, only noise exposure, only rosuvastatin usage, and control. After the data had been collected, oxidant and antioxidant parameters were analyzed in the cerebral cortex, brain stem, and cerebellum. Results indicated that superoxide dismutase values were significantly decreased in the cerebral cortex, while malondialdehyde values in the brainstem and cerebellum were significantly increased in the group with only noise exposure. Superoxide dismutase values in the brainstem were significantly increased, but nitric oxide values in the cerebellum and brainstem and malondialdehyde values in the cerebellum and cerebral cortex were significantly decreased in the group where only rosuvastatin was used. During noise exposure, the use of rosuvastatin caused significantly increased superoxide dismutase values in the cerebral cortex and brainstem, but significantly reduced malondialdehyde values in the brain stem. Consequently, our data show that brain tissue was affected by oxidative stress due to continued exposure to noise. This noise-induced stress decreases with rosuvastatin therapy.

  14. Aprepitant reduces chemotherapy-induced vomiting in children and young adults with brain tumors.

    Science.gov (United States)

    Duggin, Kelly; Tickle, Kelly; Norman, Gina; Yang, Jie; Wang, Chong; Cross, Shane J; Gajjar, Amar; Mandrell, Belinda

    2014-01-01

    Chemotherapy-induced nausea and vomiting are common and distressing side effects in patients with brain tumors and may be associated with radiation and the administration of highly emetogenic chemotherapy (HEC). Pediatric antiemetic guidelines recommend administration of a 5-hydroxytryptamine-3 (5HT3) receptor antagonists and the addition of aprepitant, a neurokinin 1 (NK1) antagonist with corticosteroids for the treatment of HEC. However, challenges persist in treating chemotherapy-induced nausea and vomiting in patients with brain tumors as corticosteroids are contraindicated due to potential impairment of the blood-brain barrier permeability. The objective was to determine whether a 5HT3 receptor antagonist and the addition of aprepitant, an NK1 antagonist without a corticosteroid, were effective in reducing HEC vomiting in pediatric brain tumor patients. A retrospective review found that 18 patients with a history of high-grade vomiting during radiation were prescribed a 5HT3 receptor antagonist and aprepitant without a corticosteroid during their first course of HEC. To determine the efficacy of aprepitant without a corticosteroid, each recipient was matched with 2 controls who did not receiv aprepitant. During HEC, controls without aprepitant were more likely to have Grade 2 or higher vomiting than the aprepitant recipients (P = .03; odds ratio = 4.15; 95% confidence interval = 1.59-10.82), after controlling for radiation-associated vomiting toxicity. Significantly less vomiting was identified in children receiving HEC and prescribed a 5HT3 receptor antagonist and aprepitant. Findings suggest that the addition of an NK1 antagonist may be beneficial to emetic control in this highly vulnerable population. © 2014 by Association of Pediatric Hematology/Oncology Nurses.

  15. Neuronal over-expression of ACE2 protects brain from ischemia-induced damage.

    Science.gov (United States)

    Chen, Ji; Zhao, Yuhui; Chen, Shuzhen; Wang, Jinju; Xiao, Xiang; Ma, Xiaotang; Penchikala, Madhuri; Xia, Huijing; Lazartigues, Eric; Zhao, Bin; Chen, Yanfang

    2014-04-01

    Angiotensin (Ang) II exaggerates cerebral injury in ischemic damage. Angiotensin-converting enzyme type 2 (ACE2) converts Ang II into Ang (1-7) and thus, may protect against the effects of Ang II. We hypothesized that neuronal ACE2 over-expression decreases ischemic stroke in mice with Ang II overproduction. Human renin and angiotensinogen double transgenic (RA) mice and RA mice with neuronal over-expression of ACE2 (SARA) were used for the study. The mean arterial pressure (MAP) was calculated from telemetry-recorded blood pressure (BP). SARA mice were infused peripherally with Norepinephrine to "clamp" the BP, or intracerebroventricularly-infused with a Mas receptor antagonist (A-779). Middle cerebral artery occlusion (MCAO) surgery was performed to induce permanent focal ischemic stroke. Cerebral blood flow (CBF) and neurological function were determined. Two days after surgery, brain samples were collected for various analyses. Results showed: 1) When compared to chronically hypertensive RA mice, SARA mice had lower basal MAP, less MCAO-induced infarct volume, and increased CBF, neurological function and cerebral microvascular density in the peri-infarct area; 2) These changes in SARA mice were not altered after MAP "clamping", but partially reversed by brain infusion of A-779; 3) Ang (1-7)/Ang II ratio, angiogenic factors, endothelial nitric oxide synthase (eNOS) expression and nitric oxide production were increased, whereas, NADPH oxidase subunits and reactive oxygen species were decreased in the brain of SARA mice. ACE2 protects brain from ischemic injury via the regulation of NADPH oxidase/eNOS pathways by changing Ang (1-7)/Ang II ratio, independently of MAP changes. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Pathology of perinatal brain damage: background and oxidative stress markers.

    Science.gov (United States)

    Tonni, Gabriele; Leoncini, Silvia; Signorini, Cinzia; Ciccoli, Lucia; De Felice, Claudio

    2014-07-01

    To review historical scientific background and new perspective on the pathology of perinatal brain damage. The relationship between birth asphyxia and subsequent cerebral palsy has been extensively investigated. The role of new and promising clinical markers of oxidative stress (OS) is presented. Electronic search of PubMed-Medline/EMBASE database has been performed. Laboratory and clinical data involving case series from the research group are reported. The neuropathology of birth asphyxia and subsequent perinatal brain damage as well as the role of electronic fetal monitoring are reported following a review of the medical literature. This review focuses on OS mechanisms underlying the neonatal brain damage and provides different perspective on the most reliable OS markers during the perinatal period. In particular, prior research work on neurodevelopmental diseases, such as Rett syndrome, suggests the measurement of oxidized fatty acid molecules (i.e., F4-Neuroprostanes and F2-Dihomo-Isoprostanes) closely related to brain white and gray matter oxidative damage.

  17. A noninvasive brain computer interface using visually-induced near-infrared spectroscopy responses.

    Science.gov (United States)

    Chen, Cheng-Hsuan; Ho, Ming-Shan; Shyu, Kuo-Kai; Hsu, Kou-Cheng; Wang, Kuo-Wei; Lee, Po-Lei

    2014-09-19

    Visually-induced near-infrared spectroscopy (NIRS) response was utilized to design a brain computer interface (BCI) system. Four circular checkerboards driven by distinct flickering sequences were displayed on a LCD screen as visual stimuli to induce subjects' NIRS responses. Each flickering sequence was a concatenated sequence of alternative flickering segments and resting segments. The flickering segment was designed with fixed duration of 3s whereas the resting segment was chosen randomly within 15-20s to create the mutual independencies among different flickering sequences. Six subjects were recruited in this study and subjects were requested to gaze at the four visual stimuli one-after-one in a random order. Since visual responses in human brain are time-locked to the onsets of visual stimuli and the flicker sequences of distinct visual stimuli were designed mutually independent, the NIRS responses induced by user's gazed targets can be discerned from non-gazed targets by applying a simple averaging process. The accuracies for the six subjects were higher than 90% after 10 or more epochs being averaged. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. Intervention-induced enhancement in intrinsic brain activity in healthy older adults.

    Science.gov (United States)

    Yin, Shufei; Zhu, Xinyi; Li, Rui; Niu, Yanan; Wang, Baoxi; Zheng, Zhiwei; Huang, Xin; Huo, Lijuan; Li, Juan

    2014-12-04

    This study examined the effects of a multimodal intervention on spontaneous brain activity in healthy older adults. Seventeen older adults received a six-week intervention that consisted of cognitive training, Tai Chi exercise, and group counseling, while 17 older adults in a control group attended health knowledge lectures. The intervention group demonstrated enhanced memory and social support compared to the control group. The amplitude of low frequency fluctuations (ALFF) in the middle frontal gyrus, superior frontal gyrus, and anterior cerebellum lobe was enhanced for the intervention group, while the control group showed reduced ALFF in these three regions. Moreover, changes in trail-making performance and well-being could be predicted by the intervention-induced changes in ALFF. Additionally, individual differences in the baseline ALFF were correlated with intervention-related changes in behavioral performance. These findings suggest that a multimodal intervention is effective in improving cognitive functions and well-being and can induce functional changes in the aging brain. The study extended previous training studies by suggesting resting-state ALFF as a marker of intervention-induced plasticity in older adults.

  19. Mesenchymal Stem Cells Attenuate Radiation-Induced Brain Injury by Inhibiting Microglia Pyroptosis

    Directory of Open Access Journals (Sweden)

    Huan Liao

    2017-01-01

    Full Text Available Radiation-induced brain injury (RI commonly occurs in patients who received head and neck radiotherapy. However, the mechanism of RI remains unclear. We aimed to evaluate whether pyroptosis was involved in RI and the impact of mesenchymal stem cells (MSCs on it. BALB/c male mice (6–8 weeks were cranially irradiated (15 Gy, and MSCs were transplanted into the bilateral cortex 2 days later; then mice were sacrificed 1 month later. Meanwhile, irradiated BV-2 microglia cells (10 Gy were cocultured with MSCs for 24 hours. We observed that irradiated mice brains presented NLRP3 and caspase-1 activation. RT-PCR then indicated that it mainly occurred in microglia cells but not in neurons. Further, irradiated BV-2 cells showed pyroptosis and increased production of IL-18 and IL-1β. RT-PCR also demonstrated an increased expression of several inflammasome genes in irradiated BV-2 cells, including NLRP3 and AIM2. Particularly, NLRP3 was activated. Knockdown of NLRP3 resulted in decreased LDH release. Noteworthily, in vivo, MSCs transplantation alleviated radiation-induced NLRP3 and caspase-1 activation. Moreover, in vitro, MSCs could decrease caspase-1 dependent pyroptosis, NLRP3 inflammasome activation, and ROS production induced by radiation. Thus, our findings proved that microglia pyroptosis occurred in RI. MSCs may act as a potent therapeutic tool in attenuating pyroptosis.

  20. Lack of estradiol modulation of sleep deprivation-induced c-Fos in the rat brain.

    Science.gov (United States)

    Mashoodh, Rahia; Stamp, Jennifer A; Wilkinson, Michael; Rusak, Benjamin; Semba, Kazue

    2008-11-28

    Women recover from sleep deprivation more efficiently than men, but the mechanism for this difference is unknown. Effects of estrogen on sleep suggest that it could play a role, but the brain targets on which estrogen may act to have this effect have not been identified. Sleep deprivation increases levels of the immediate-early gene protein c-Fos in selected brain regions, but it is unknown whether estrogen modulates this response. We investigated the influence of different levels of exogenous estradiol on the c-Fos response to sleep deprivation in ovariectomized female rats. Female rats were treated with low or high levels of estradiol (mimicking diestrous and proestrous levels, respectively) delivered via subcutaneous silastic tubes. Control ovariectomized females and sham-operated males were implanted with tubes filled with cholesterol. One week after surgery, half of the rats underwent a 3 h period of sleep deprivation during the light phase in a motorized Wahmann activity wheel that rotated constantly at a slow speed, while half were confined to fixed wheels. Immediately after sleep deprivation, animals were killed and their brains processed to detect c-Fos using immunohistochemistry. Sleep deprivation increased the number of c-Fos positive cells in a number of brain areas, including the caudate putamen, medial preoptic area, perifornical hypothalamus, and anterior paraventricular thalamic nucleus. Other areas, including the suprachiasmatic nucleus, posterior paraventricular hypothalamic nucleus, posterior paraventricular thalamic nucleus, arcuate nucleus, and central amygdala, did not respond to 3 h sleep deprivation with a significant increase in c-Fos levels. Levels of c-Fos induced in the selected brain regions by sleep deprivation were not modulated by estrogen levels, nor by sex.

  1. Neither xenon nor fentanyl induces neuroapoptosis in the newborn pig brain.

    Science.gov (United States)

    Sabir, Hemmen; Bishop, Sarah; Cohen, Nicki; Maes, Elke; Liu, Xun; Dingley, John; Thoresen, Marianne

    2013-08-01

    Some inhalation anesthetics increase apoptotic cell death in the developing brain. Xenon, an inhalation anesthetic, increases neuroprotection when combined with therapeutic hypothermia after hypoxic-ischemic brain injury in newborn animals. The authors, therefore, examined whether there was any neuroapoptotic effect of breathing 50% xenon with continuous fentanyl sedation for 24 h at normothermia or hypothermia on newborn pigs. Twenty-six healthy pigs (inhaled xenon with fentanyl at hypothermia (Trec = 33.5 °C), (2) 24 h of 50% inhaled xenon with fentanyl at normothermia (Trec = 38.5 °C), (3) 24 h of fentanyl at normothermia, or (4) nonventilated juvenile controls at normothermia. Five additional nonrandomized pigs inhaled 2% isoflurane at normothermia for 24 h to verify any proapoptotic effect of inhalation anesthetics in our model. Pathological cells were morphologically assessed in cortex, putamen, hippocampus, thalamus, and white matter. To quantify the findings, immunostained cells (caspase-3 and terminal deoxynucleotidyl transferase-mediated deoxyuridine-triphosphate nick-end labeling) were counted in the same brain regions. For groups (1) to (4), the total number of apoptotic cells was less than 5 per brain region, representing normal developmental neuroapoptosis. After immunostaining and cell counting, regression analysis showed that neither 50% xenon with fentanyl nor fentanyl alone increased neuroapoptosis. Isoflurane caused on average a 5- to 10-fold increase of immunostained cells. At normothermia or hypothermia, neither 24 h of inhaled 50% xenon with fentanyl sedation nor fentanyl alone induces neuroapoptosis in the neonatal pig brain. Breathing 2% isoflurane increases neuroapoptosis in neonatal pigs.

  2. Propofol Inhibits NLRP3 Inflammasome and Attenuates Blast-Induced Traumatic Brain Injury in Rats.

    Science.gov (United States)

    Ma, Jie; Xiao, Wenjing; Wang, Junrui; Wu, Juan; Ren, Jiandong; Hou, Jun; Gu, Jianwen; Fan, Kaihua; Yu, Botao

    2016-12-01

    Increasing evidence has demonstrated that inflammatory response plays a crucial role in the pathogenesis of secondary injury following blast-induced traumatic brain injury (bTBI). Propofol, a lipid-soluble intravenous anesthetic, has been shown to possess therapeutic benefit during neuroinflammation on various brain injury models. Recent findings have proved that the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome involved in the process of the inflammatory response following brain trauma, may probably be a promising target in the treatment of bTBI. Rats were randomly divided into six groups (n = 8): normal group; bTBI-12 and 24 h group; bTBI-12 h and bTBI-24 h group treated with propofol; and bTBI treated with control dimethyl sulfoxide (DMSO) group. The effect of propofol on the expression and activation of NLRP3 inflammasome and the degree of oxidative stress and inflammatory cascades, as well as the brain trauma biomarkers were evaluated in rats suffering from bTBI. The enhanced expressions and activation of NLRP3 inflammasome in the cerebral cortex of bTBI rats were substantially suppressed by the administration of propofol, which was paralleled with the decreased oxidative stress, cytokines production, and the amelioration of cerebral cortex damage. Our results have, for the first time, revealed that over-activation of NLRP3 inflammasome in the cerebral cortex may be involved in the process of neuroinflammation during the secondary injury of bTBI in rats. Propofol might relieve the inflammatory response and attenuate brain injury by inhibiting ROS and reluctant depressing NLRP3 inflammasome activation and pro-inflammatory cytokines maturation.

  3. Effects of defibrotide on aorta and brain malondialdehyde and antioxidants in cholesterol-induced atherosclerotic rabbits.

    Science.gov (United States)

    Aydemir, E O; Duman, C; Celik, H A; Turgan, N; Uysal, A; Mutaf, I; Habif, S; Ozmen, D; Nişli, N; Bayindir, O

    2000-01-01

    The effects of a high-cholesterol diet in the presence and absence of defibrotide, a single-stranded polydeoxyribonucleotide compound, on the lipid peroxidation product malondialdehyde, endogenous antioxidant enzymes catalase, glutathione peroxidase, and the antioxidant thiol compound GSH were investigated. Forty male New Zeland white rabbits were divided into four groups each consisting of 10 rabbits. Group I received a regular rabbit chow diet and group II 1% cholesterol plus regular chow, group III was given defibrotide (60 mg/kg per day p.o. in water) and was fed with regular chow, and group IV received defibrotide plus 1% cholesterol for 9 weeks. Blood cholesterol and malondialdehyde, catalase, glutathione peroxidase, and GSH were determined before starting the experimental diet regimen (basal). After 9 weeks, the same parameters were determined in blood, aorta, and brain tissues (end -experiment). Aortic tissue was examined under a light microscope for morphological alterations indicative of atherosclerosis. The increase in serum total cholesterol was greater in group II than group IV. Plasma malondialdehyde in group II was higher than in group III. Brain malondialdehyde in group II was higher than all other groups, and aortic malondialdehyde in this group was higher than group I and III. Serum catalase activity decreased in group II and increased in group III, compared with basal values. Brain catalase activity in group I was higher than group II, and aorta catalase in group IV was higher than in group I and III. Blood glutathione peroxidase activity in group III and IV was higher than basal. GSH concentrations decreased significantly in the cholesterol-fed groups (group II and IV). Histological alterations in the cholesterol-fed groups were more pronounced in group II. The increased levels of malondialdehyde in plasma, aorta, and brain tissue of group II suggest a role of oxygen free radicals in the pathogenesis of cholesterol-induced atherosclerosis. The

  4. Spaced Noninvasive Brain Stimulation: Prospects for Inducing Long-Lasting Human Cortical Plasticity.

    Science.gov (United States)

    Goldsworthy, Mitchell R; Pitcher, Julia B; Ridding, Michael C

    2015-09-01

    Neuroplasticity is critical for learning, memory, and recovery of lost function following neurological damage. Noninvasive brain stimulation (NIBS) techniques can induce neuroplastic changes in the human cortex that are behaviorally relevant, raising the exciting possibility that these techniques might be therapeutically beneficial for neurorehabilitation following brain injury. However, the short duration and instability of induced effects currently limits their usefulness. To date, trials investigating the therapeutic value of neuroplasticity-inducing NIBS have used either single or multiple treatment sessions, typically repeated once-daily for 1 to 2 weeks. Although multiple stimulation sessions are presumed to have cumulative effects on neuroplasticity induction, there is little direct scientific evidence to support this "once-daily" approach. In animal models, the repeated application of stimulation protocols spaced using relatively short intervals (typically of the order of minutes) induces long-lasting and stable changes in synaptic efficacy. Likewise, learning through spaced repetition facilitates the establishment of long-term memory. In both cases, the spacing interval is critical in determining the outcome. Emerging evidence in healthy human populations suggests that the within-session spacing of NIBS protocols may be an effective approach for significantly prolonging the duration of induced neuroplastic changes. Similar to findings in the animal and learning literature, the interval at which spaced NIBS is applied seems to be a critical factor influencing the neuroplastic response. In this Point of View article, we propose that to truly exploit the therapeutic opportunities provided by NIBS, future clinical trials should consider the optimal spacing interval for repeated applications. © The Author(s) 2014.

  5. Permeability of Brain Tumor Vessels Induced by Uniform or Spatially Microfractionated Synchrotron Radiation Therapies.

    Science.gov (United States)

    Bouchet, Audrey; Potez, Marine; Coquery, Nicolas; Rome, Claire; Lemasson, Benjamin; Bräuer-Krisch, Elke; Rémy, Chantal; Laissue, Jean; Barbier, Emmanuel L; Djonov, Valentin; Serduc, Raphael

    2017-08-01

    To compare the blood-brain barrier permeability changes induced by synchrotron microbeam radiation therapy (MRT, which relies on spatial fractionation of the incident x-ray beam into parallel micron-wide beams) with changes induced by a spatially uniform synchrotron x-ray radiation therapy. Male rats bearing malignant intracranial F98 gliomas were randomized into 3 groups: untreated, exposed to MRT (peak and valley dose: 241 and 10.5 Gy, respectively), or exposed to broad beam irradiation (BB) delivered at comparable doses (ie, equivalent to MRT valley dose); both applied by 2 arrays, intersecting orthogonally the tumor region. Vessel permeability was monitored in vivo by magnetic resonance imaging 1 day before (T-1) and 1, 2, 7, and 14 days after treatment start. To determine whether physiologic parameters influence vascular permeability, we evaluated vessel integrity in the tumor area with different values for cerebral blood flow, blood volume, edema, and tissue oxygenation. Microbeam radiation therapy does not modify the vascular permeability of normal brain tissue. Microbeam radiation therapy-induced increase of tumor vascular permeability was detectable from T2 with a maximum at T7 after exposure, whereas BB enhanced vessel permeability only at T7. At this stage MRT was more efficient at increasing tumor vessel permeability (BB vs untreated: +19.1%; P=.0467; MRT vs untreated: +44.8%; Ptumor than BB. Microbeam radiation therapy-induced increased tumor vascular permeability is: (1) significantly greater; (2) earlier and more prolonged than that induced by BB irradiation, especially in highly proliferative tumor areas; and (3) targets all tumor areas discriminated by physiologic characteristics, including those not damaged by homogeneous irradiation. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction.

    Directory of Open Access Journals (Sweden)

    Gabriela Hurtado-Alvarado

    Full Text Available Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261 in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1, adherens junction protein (E-cadherin, A2A adenosine receptor, adenosine-synthesizing enzyme (CD73, and neuroinflammatory markers (Iba-1 and GFAP in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent

  7. A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction.

    Science.gov (United States)

    Hurtado-Alvarado, Gabriela; Domínguez-Salazar, Emilio; Velázquez-Moctezuma, Javier; Gómez-González, Beatriz

    2016-01-01

    Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261) in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans) and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1), adherens junction protein (E-cadherin), A2A adenosine receptor, adenosine-synthesizing enzyme (CD73), and neuroinflammatory markers (Iba-1 and GFAP) in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent inflammation and

  8. A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction

    Science.gov (United States)

    Hurtado-Alvarado, Gabriela; Domínguez-Salazar, Emilio; Velázquez-Moctezuma, Javier

    2016-01-01

    Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261) in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans) and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1), adherens junction protein (E-cadherin), A2A adenosine receptor, adenosine-synthesizing enzyme (CD73), and neuroinflammatory markers (Iba-1 and GFAP) in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent inflammation and

  9. Controlled single bubble cavitation collapse results in jet-induced injury in brain tissue.

    Science.gov (United States)

    Canchi, Saranya; Kelly, Karen; Hong, Yu; King, Michael A; Subhash, Ghatu; Sarntinoranont, Malisa

    2017-10-01

    Multiscale damage due to cavitation is considered as a potential mechanism of traumatic brain injury (TBI) associated with explosion. In this study, we employed a TBI relevant hippocampal ex vivo slice model to induce bubble cavitation. Placement of single reproducible seed bubbles allowed control of size, number, and tissue location to visualize and measure deformation parameters. Maximum strain value was measured at 45 µs after bubble collapse, presented with a distinct contour and coincided temporally and spatially with the liquid jet. Composite injury maps combined this maximum strain value with maximum measured bubble size and location along with histological injury patterns. This facilitated the correlation of bubble location and subsequent jet direction to the corresponding regions of high strain which overlapped with regions of observed injury. A dynamic threshold strain range for tearing of cerebral cortex was estimated to be between 0.5 and 0.6. For a seed bubble placed underneath the hippocampus, cavitation induced damage was observed in hippocampus (local), proximal cerebral cortex (marginal) and the midbrain/forebrain (remote) upon histological evaluation. Within this test model, zone of cavitation injury was greater than the maximum radius of the bubble. Separation of apposed structures, tissue tearing, and disruption of cellular layers defined early injury patterns that were not detected in the blast-exposed half of the brain slice. Ultrastructural pathology of the neurons exposed to cavitation was characterized by disintegration of plasma membrane along with loss of cellular content. The developed test system provided a controlled experimental platform to study cavitation induced high strain deformations on brain tissue slice. The goal of the future studies will be to lower underpressure magnitude and cavitation bubble size for more sensitive evaluation of injury. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Enhanced Lithium-Induced Brain Recovery Following Cranial Irradiation Is Not Impeded by Inflammation

    Science.gov (United States)

    Malaterre, Jordane; McPherson, Cameron S.; Denoyer, Delphine; Lai, Emily; Hagekyriakou, Jim; Lightowler, Sally; Shudo, Koishi; Ernst, Matthias; Ashley, David M.; Short, Jennifer L.; Wheeler, Greg

    2012-01-01

    Radiation-induced brain injury occurs in many patients receiving cranial radiation therapy, and these deleterious effects are most profound in younger patients. Impaired neurocognitive functions in both humans and rodents are associated with inflammation, demyelination, and neural stem cell dysfunction. Here we evaluated the utility of lithium and a synthetic retinoid receptor agonist in reducing damage in a model of brain-focused irradiation in juvenile mice. We found that lithium stimulated brain progenitor cell proliferation and differentiation following cranial irradiation while also preventing oligodendrocyte loss in the dentate gyrus of juvenile mice. In response to inflammation induced by radiation, which may have encumbered the optimal reparative action of lithium, we used the anti-inflammatory synthetic retinoid Am80 that is in clinical use in the treatment of acute promyelocytic leukemia. Although Am80 reduced the number of cyclooxygenase-2-positive microglial cells following radiation treatment, it did not enhance lithium-induced neurogenesis recovery, and this alone was not significantly different from the effect of lithium on this proinflammatory response. Similarly, lithium was superior to Am80 in supporting the restoration of new doublecortin-positive neurons following irradiation. These data suggest that lithium is superior in its restorative effects to blocking inflammation alone, at least in the case of Am80. Because lithium has been in routine clinical practice for 60 years, these preclinical studies indicate that this drug might be beneficial in reducing post-therapy late effects in patients receiving cranial radiotherapy and that blocking inflammation in this context may not be as advantageous as previously suggested. PMID:23197851

  11. Moderately delayed post-insult treatment with normobaric hyperoxia reduces excitotoxin-induced neuronal degeneration but increases ischemia-induced brain damage

    Directory of Open Access Journals (Sweden)

    Haelewyn Benoit

    2011-04-01

    Full Text Available Abstract Background The use and benefits of normobaric oxygen (NBO in patients suffering acute ischemic stroke is still controversial. Results Here we show for the first time to the best of our knowledge that NBO reduces both NMDA-induced calcium influxes in vitro and NMDA-induced neuronal degeneration in vivo, but increases oxygen and glucose deprivation-induced cell injury in vitro and ischemia-induced brain damage produced by middle cerebral artery occlusion in vivo. Conclusions Taken together, these results indicate that NBO reduces excitotoxin-induced calcium influx and subsequent neuronal degeneration but favors ischemia-induced brain damage and neuronal death. These findings highlight the complexity of the mechanisms involved by the use of NBO in patients suffering acute ischemic stroke.

  12. Long-term intensive training induced brain structural changes in world class gymnasts.

    Science.gov (United States)

    Huang, Ruiwang; Lu, Min; Song, Zheng; Wang, Jun

    2015-03-01

    intersecting regions from multiple between-group comparison can considerably reduce the false positives, and our results provide new insights into the brain structure changes induced by long-term intensive gymnastic training.

  13. Cognitive impairments at two years of age after prenatal alcohol exposure or perinatal asphyxia.

    Science.gov (United States)

    Korkman, M; Hilakivi-Clarke, L A; Autti-Rämö, I; Fellman, V; Granström, M L

    1994-04-01

    The purpose of this follow-up study was to assess and describe early cognitive impairments in two-year-old children exposed to alcohol (1) until the second trimester (n = 20), (2) until the third trimester (n = 20), (3) throughout pregnancy (n = 20), (4) children to mothers with preeclampsia (n = 37), (5) children surviving acute birth asphyxia (n = 14), and (6) a normal control group (n = 48). Alcohol exposure throughout pregnancy was found to be associated with impairments in language (mean SD score = -1.3) and visuo-motor development (mean SD score = -2.0). Preeclampsia was related to impairment in visuo-motor development (mean SD score = -1.2) and attention (mean SD score = -0.7). Alcohol exposure until the third trimester was associated with attention deficit alone (mean SD score = -0.9). Alcohol exposure until the second trimester and acute birth asphyxia were not associated with an increased risk of cognitive impairment. The study also showed that neuropsychological test profiles of language, visuo-motor functions and attention may be obtained with the aid of an adapted version of the Bayley Mental Scale and an evaluation of attention.

  14. Asphyxia, Neurologic Morbidity, and Perinatal Mortality in Early-Term and Postterm Birth.

    Science.gov (United States)

    Seikku, Laura; Gissler, Mika; Andersson, Sture; Rahkonen, Petri; Stefanovic, Vedran; Tikkanen, Minna; Paavonen, Jorma; Rahkonen, Leena

    2016-06-01

    Neonatal outcomes vary by gestational age. We evaluated the association of early-term, full-term, and postterm birth with asphyxia, neurologic morbidity, and perinatal mortality. Our register-based study used retrospective data on 214 465 early-term (37(+0)-38(+6) gestational weeks), 859 827 full-term (39(+0)-41(+6)), and 55 189 postterm (≥42(+0)) live-born singletons during 1989-2008 in Finland. Asphyxia parameters were umbilical cord pH and Apgar score at 1 and 5 minutes. Neurologic morbidity outcome measures were cerebral palsy (CP), epilepsy, intellectual disability, and sensorineural defects diagnosed by the age of 4 years. Newborns with major congenital anomalies were excluded from perinatal deaths. Multivariate analysis showed that, compared with full-term pregnancies, early-term birth increased the risk for low Apgar score (Postterm birth increased the risk for low Apgar score (postterm births, but general neurologic morbidity and perinatal mortality were not increased. Copyright © 2016 by the American Academy of Pediatrics.

  15. Pediatric constrictive asphyxia a rare form of child abuse: A report of two cases.

    Science.gov (United States)

    Vester, M E M; Bilo, R A C; Nijs, H G T; van Rijn, R R

    2018-01-10

    We present two cases of infants who died under suspicious circumstances. After clinical and legal investigations, non-accidental constrictive asphyxia inflicted by one of the parents was established. The first case presents a to date not yet reported, unique mechanism of trauma. In order to stop his daughter from crying, the father admitted that he sometimes sat on his baby while she was lying on the bed. Occasionally increasing his force by pulling with his hands on the bottom of the bed. In the second case tight swaddling and encircling chest compression was the causative mechanism. In both cases the father was sentenced to imprisonment with mandate psychiatric care. Only two previous reports of this uncommon and relatively unknown cause of child abuse, called constrictive asphyxia, are known. In all reported cases static loading of the chest resulted in rib fractures and demise of the child. This rare abusive mechanism should be known to pediatric radiologists and pathologists. Copyright © 2018 Elsevier B.V. All rights reserved.

  16. Neuroprotective effect of osmotin against ethanol-induced apoptotic neurodegeneration in the developing rat brain.

    Science.gov (United States)

    Naseer, M I; Ullah, I; Narasimhan, M L; Lee, H Y; Bressan, R A; Yoon, G H; Yun, D J; Kim, M O

    2014-03-27

    Fetal alcohol syndrome is a neurological and developmental disorder caused by exposure of developing brain to ethanol. Administration of osmotin to rat pups reduced ethanol-induced apoptosis in cortical and hippocampal neurons. Osmotin, a plant protein, mitigated the ethanol-induced increases in cytochrome c, cleaved caspase-3, and PARP-1. Osmotin and ethanol reduced ethanol neurotoxicity both in vivo and in vitro by reducing the protein levels of cleaved caspase-3, intracellular [Ca(2+)]cyt, and mitochondrial transmembrane potential collapse, and also upregulated antiapoptotic Bcl-2 protein. Osmotin is a homolog of adiponectin, and it controls energy metabolism via phosphorylation. Adiponectin can protect hippocampal neurons against ethanol-induced apoptosis. Abrogation of signaling via receptors AdipoR1 or AdipoR2, by transfection with siRNAs, reduced the ability of osmotin and adiponectin to protect neurons against ethanol-induced neurodegeneration. Metformin, an activator of AMPK (adenosine monophosphate-activated protein kinase), increased whereas Compound C, an inhibitor of AMPK pathway, reduced the ability of osmotin and adiponectin to protect against ethanol-induced apoptosis. Osmotin exerted its neuroprotection via Bcl-2 family proteins and activation of AMPK signaling pathway. Modulation of AMPK pathways by osmotin, adiponectin, and metformin hold promise as a preventive therapy for fetal alcohol syndrome.

  17. Modulation of gamma-irradiation and carbon tetrachloride induced oxidative stress in the brain of female rats by flaxseed oil.

    Science.gov (United States)

    Ismail, Amel F M; Salem, Asmaa A M; Eassawy, Mamdouh M T

    2016-08-01

    The activity of flaxseed oil (FSO) on gamma-irradiation (7Gy) and/or carbon tetrachloride (CCl4) induced acute neurotoxicity in rats' brain was investigated. The results revealed a significant decrease (pbrain tissues of γ-irradiated and CCl4 intoxicated animals. Those effects were augmented due to the effect of CCl4-induced toxicity in γ-irradiated rats. The treatment of FSO displayed significant amendment of the studied parameters in the brain tissues of γ-irradiated and CCl4 intoxicated animals. FSO has a neuroprotective effect against CCl4-induced brain injury in gamma-irradiated rats. This effect is interrelated to the ability of FSO to scavenges the free radicals, enhances the antioxidant enzymes activity, increases GSH contents, down-regulates the inflammatory responses, ameliorates the iron, calcium, copper, magnesium, manganese levels and inhibiting the gene expression level of XO and iNOS in the brain tissues of intoxicated animals. In conclusion, this study demonstrated that the potent antioxidant and anti-inflammatory activities of FSO have the ability to improve the antioxidant status, suppress the inflammatory responses, and regulate the trace elements in the brain tissues of γ-irradiated, CCl4, and their combined effect in intoxicated animals. Consequently, FSO exhibited neuroprotective activity on γ-irradiated, CCl4, and their combined effect induced brain injury in rats. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Aldrin-induced stimulation of locomotor activity and brain regional glutamate.

    Science.gov (United States)

    Jamaluddin, S; Poddar, M K

    2001-05-01

    Single administration of aldrin (2-10 mg/kg) to adult male albino rats (120-130 g) enhanced locomotor activity (LA), with the maximum effect reached 2 h after treatment. The measurement of steady state levels of glutamate, glutamine and the activities of their metabolizing enzymes in different regions of the brains of rats treated with aldrin under its nontolerant condition showed that aldrin enhanced the activity of the neuronal glutamate system in the cerebral cortex, cerebellum and hypothalamus. Moreover, treatment with the glutamatergic NMDA receptor antagonist D,L-2-amino-7-phosphonoheptanoic acid, in the absence and presence of aldrin, reduced the LA of control rats and attenuated the aldrin-induced increase in LA of treated rats. These results suggest that aldrin-induced activation of the central glutamate system may be a cause of stimulation of LA with aldrin under its nontolerant condition.

  19. Fluorescent nanodiamond tracking reveals intraneuronal transport abnormalities induced by brain-disease-related genetic risk factors

    Science.gov (United States)

    Haziza, Simon; Mohan, Nitin; Loe-Mie, Yann; Lepagnol-Bestel, Aude-Marie; Massou, Sophie; Adam, Marie-Pierre; Le, Xuan Loc; Viard, Julia; Plancon, Christine; Daudin, Rachel; Koebel, Pascale; Dorard, Emilie; Rose, Christiane; Hsieh, Feng-Jen; Wu, Chih-Che; Potier, Brigitte; Herault, Yann; Sala, Carlo; Corvin, Aiden; Allinquant, Bernadette; Chang, Huan-Cheng; Treussart, François; Simonneau, Michel

    2017-05-01

    Brain diseases such as autism and Alzheimer's disease (each inflicting >1% of the world population) involve a large network of genes displaying subtle changes in their expression. Abnormalities in intraneuronal transport have been linked to genetic risk factors found in patients, suggesting the relevance of measuring this key biological process. However, current techniques are not sensitive enough to detect minor abnormalities. Here we report a sensitive method to measure the changes in intraneuronal transport induced by brain-disease-related genetic risk factors using fluorescent nanodiamonds (FNDs). We show that the high brightness, photostability and absence of cytotoxicity allow FNDs to be tracked inside the branches of dissociated neurons with a spatial resolution of 12 nm and a temporal resolution of 50 ms. As proof of principle, we applied the FND tracking assay on two transgenic mouse lines that mimic the slight changes in protein concentration (∼30%) found in the brains of patients. In both cases, we show that the FND assay is sufficiently sensitive to detect these changes.

  20. The role and dynamics of β-catenin in precondition induced neuroprotection after traumatic brain injury.

    Directory of Open Access Journals (Sweden)

    Gali Umschweif

    Full Text Available Preconditioning via heat acclimation (34°C 30 d results in neuroprotection from traumatic brain injury due to constitutive as well as dynamic changes triggered by the trauma. Among these changes is Akt phosphorylation, which decreases apoptosis and induces HIF1α. In the present study we investigated the Akt downstream GSK3β/β-catenin pathway and focused on post injury alternations of β catenin and its impact on the cellular response in preconditioned heat acclimated mice. We found that the reduction in motor disability is accompanied with attenuation of depressive like behavior in heat acclimated mice that correlates with the GSK3β phosphorylation state. Concomitantly, a robust β catenin phosphorylation is not followed by its degradation, or by reduced nuclear accumulation. Enhanced tyrosine phosphorylation of β catenin in the injured area weakens the β catenin-N cadherin complex. Membrane β catenin is transiently reduced in heat acclimated mice and its recovery 7 days post TBI is accompanied by induction of the synaptic marker synaptophysin. We suggest a set of cellular events following traumatic brain injury in heat acclimated mice that causes β catenin to participate in cell-cell adhesion alternations rather than in Wnt signaling. These events may contribute to synaptogenesis and the improved motor and cognitive abilities seen heat acclimated mice after traumatic brain injury.

  1. Measuring Brain Stimulation Induced Changes in Cortical Properties Using TMS-EEG.

    Science.gov (United States)

    Chung, Sung Wook; Rogasch, Nigel C; Hoy, Kate E; Fitzgerald, Paul B

    2015-01-01

    Neuromodulatory brain stimulation can induce plastic reorganization of cortical circuits that persist beyond the period of stimulation. Most of our current knowledge about the physiological properties has been derived from the motor cortex. The integration of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) is a valuable method for directly probing excitability, connectivity and oscillatory dynamics of regions throughout the brain. Offering in depth measurement of cortical reactivity, TMS-EEG allows the evaluation of TMS-evoked components that may act as a marker for cortical excitation and inhibition. A growing body of research is using concurrent TMS and EEG (TMS-EEG) to explore the effects of different neuromodulatory techniques such as repetitive TMS and transcranial direct current stimulation on cortical function, particularly in non-motor regions. In this review, we outline studies examining TMS-evoked potentials and oscillations before and after, or during a single session of brain stimulation. Investigating these studies will aid in our understanding of mechanisms involved in the modulation of excitability and inhibition by neuroplasticity following different stimulation paradigms. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Neighborhood matters: divergent patterns of stress-induced plasticity across the brain.

    Science.gov (United States)

    Chattarji, Sumantra; Tomar, Anupratap; Suvrathan, Aparna; Ghosh, Supriya; Rahman, Mohammed Mostafizur

    2015-10-01

    The fact that exposure to severe stress leads to the development of psychiatric disorders serves as the basic rationale for animal models of stress disorders. Clinical and neuroimaging studies have shown that three brain areas involved in learning and memory--the hippocampus, amygdala and prefrontal cortex--undergo distinct structural and functional changes in individuals with stress disorders. These findings from patient studies pose several challenges for animal models of stress disorders. For instance, why does stress impair cognitive function, yet enhance fear and anxiety? Can the same stressful experience elicit contrasting patterns of plasticity in the hippocampus, amygdala and prefrontal cortex? How does even a brief exposure to traumatic stress lead to long-lasting behavioral abnormalities? Thus, animal models of stress disorders must not only capture the unique spatio-temporal features of structural and functional alterations in these brain areas, but must also provide insights into the underlying neuronal plasticity mechanisms. This Review will address some of these key questions by describing findings from animal models on how stress-induced plasticity varies across different brain regions and thereby gives rise to the debilitating emotional and cognitive symptoms of stress-related psychiatric disorders.

  3. Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism.

    Science.gov (United States)

    Shin, Andrew C; Fasshauer, Martin; Filatova, Nika; Grundell, Linus A; Zielinski, Elizabeth; Zhou, Jian-Ying; Scherer, Thomas; Lindtner, Claudia; White, Phillip J; Lapworth, Amanda L; Ilkayeva, Olga; Knippschild, Uwe; Wolf, Anna M; Scheja, Ludger; Grove, Kevin L; Smith, Richard D; Qian, Wei-Jun; Lynch, Christopher J; Newgard, Christopher B; Buettner, Christoph

    2014-11-04

    Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of hepatic protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats and genetic modulation of brain insulin receptors in mice demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Short-term overfeeding impairs the ability of brain insulin to lower BCAAs in rats. High-fat feeding in nonhuman primates and obesity and/or diabetes in humans is associated with reduced BCKDH protein in liver. These findings support the concept that decreased hepatic BCKDH is a major cause of increased plasma BCAAs and that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Helium preconditioning attenuates hypoxia/ischemia-induced injury in the developing brain.

    Science.gov (United States)

    Liu, Yi; Xue, Feng; Liu, Guoke; Shi, Xin; Liu, Yun; Liu, Wenwu; Luo, Xu; Sun, Xuejun; Kang, Zhimin

    2011-02-28

    Recent studies show helium may be one kind of neuroprotective gas. This study aimed to examine the short and long-term neuroprotective effects of helium preconditioning in an established neonatal cerebral hypoxia-ischemia (HI) model. Seven-day-old rat pups were subjected to left common carotid artery ligation and then 90 min of hypoxia (8% oxygen at 37°C). The preconditioning group inhaled 70% helium-30% oxygen for 5 min three times with an interval of 5 min 24h before HI insult. Pups were decapitated 24h after HI and brain morphological injury was assessed by 2,3,5-triphenyltetrazolium chloride (TTC) staining, Nissl and TUNEL staining. Caspase-3 activity in the brain was measured. Five weeks after HI, postural reflex testing and Morris water maze testing were conducted. Our results showed that helium preconditioning reduced the infarct ratio, increased the number of survival neurons, and inhibited apoptosis at the early stage of HI insult. Furthermore, the sensorimotor function and the cognitive function were improved significantly in rats with helium preconditioning. The results indicate that helium preconditioning attenuates HI induced brain injury. Copyright © 2010 Elsevier B.V. All rights reserved.

  5. Blast-induced color change in photonic crystals corresponds with brain pathology.

    Science.gov (United States)

    Cullen, D Kacy; Browne, Kevin D; Xu, Yongan; Adeeb, Saleena; Wolf, John A; McCarron, Richard M; Yang, Shu; Chavko, Mikulas; Smith, Douglas H

    2011-11-01

    A high incidence of blast exposure is a 21st century reality in counter-insurgency warfare. However, thresholds for closed-head blast-induced traumatic brain injury (bTBI) remain unknown. Moreover, without objective information about relative blast exposure, warfighters with bTBI may not receive appropriate medical care and may remain in harm's way. Accordingly, we have engineered a blast injury dosimeter (BID) using a photonic crystalline material that changes color following blast exposure. The photonic crystals are fabricated using SU-8 via multi-beam interference laser lithography. The final BID is similar in appearance to an array of small colored stickers that may be affixed to uniforms or helmets in multiple locations. Although durable under normal conditions, the photonic crystalline micro- and nano-structure are precisely altered by blast to create a color change. These BIDs were evaluated using a rat model of bTBI, for which blast shockwave exposure was generated via a compressed air-driven shock tube. With prototype BID arrays affixed to the animals, we found that BID color changes corresponded with subtle brain pathologies, including neuronal degeneration and reactive astrocytosis. These subtle changes were most notable in the dentate gyrus of the hippocampus, cerebral cortex, and cerebellum. These data demonstrate the feasibility of using a materials-based, power-free colorimetric BID as the first self-contained blast sensor calibrated to correspond with brain pathology.

  6. Why and how physical activity promotes experience-induced brain plasticity

    Directory of Open Access Journals (Sweden)

    Gerd eKempermann

    2010-12-01

    Full Text Available Adult hippocampal neurogenesis is an unusual case of brain plasticity, since new neurons (and not just neurites and synapses are added to the network in an activity-dependent way. At the behavioral level the plasticity-inducing stimuli include both physical and cognitive activity. In reductionistic animal studies these types of activity can be studied separately in paradigms like voluntary wheel running and environmental enrichment. In both of these, adult neurogenesis is increased but the net effect is primarily due to different mechanisms at the cellular level. Locomotion appears to stimulate the precursor cells, from which adult neurogenesis originates, to increased proliferation and maintenance over time, whereas environmental enrichment, as well as learning, predominantly promotes survival of immature neurons, that is the progeny of the proliferating precursor cells. Surprisingly, these effects are additive: boosting the potential for adult neurogenesis by physical activity increases the recruitment of cells following cognitive stimulation in an enriched environment. Why is that? We argue that locomotion actually serves as an intrinsic feedback mechanism, signaling to the brain, including its neural precursor cells, that the likelihood of cognitive challenges increases. In the wild (other than in front of a TV, no separation of physical and cognitive activity occurs. Physical activity might thus be much more than a generally healthy garnish to leading an active life but an evolutionarily fundamental aspect of activity, which is needed to provide the brain and its systems of plastic adaptation with the appropriate regulatory input and feedback.

  7. Childhood Music Training Induces Change in Micro and Macroscopic Brain Structure: Results from a Longitudinal Study.

    Science.gov (United States)

    Habibi, Assal; Damasio, Antonio; Ilari, Beatriz; Veiga, Ryan; Joshi, Anand A; Leahy, Richard M; Haldar, Justin P; Varadarajan, Divya; Bhushan, Chitresh; Damasio, Hanna

    2017-11-08

    Several studies comparing adult musicians and nonmusicians have shown that music training is associated with structural brain differences. It is not been established, however, whether such differences result from pre-existing biological traits, lengthy musical training, or an interaction of the two factors, or if comparable changes can be found in children undergoing music training. As part of an ongoing longitudinal study, we investigated the effects of music training on the developmental trajectory of children's brain structure, over two years, beginning at age 6. We compared these children with children of the same socio-economic background but either involved in sports training or not involved in any systematic after school training. We established at the onset that there were no pre-existing structural differences among the groups. Two years later we observed that children in the music group showed (1) a different rate of cortical thickness maturation between the right and left posterior superior temporal gyrus, and (2) higher fractional anisotropy in the corpus callosum, specifically in the crossing pathways connecting superior frontal, sensory, and motor segments. We conclude that music training induces macro and microstructural brain changes in school-age children, and that those changes are not attributable to pre-existing biological traits. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  8. Comparative routes of oxytocin administration in crated farrowing sows and its effects on fetal and postnatal asphyxia.

    Science.gov (United States)

    Mota-Rojas, Daniel; Trujillo, Ma Elena; Martínez, Julio; Rosales, Ana Ma; Orozco, Héctor; Ramírez, Ramiro; Sumano, Héctor; Alonso-Spilsbury, María

    2006-03-01

    Oxytocin is used to induce and control parturition; nevertheless, an increase in uterine contractions decreases blood flow and gaseous exchange through the uterus predisposing to intra-partum mortality in pigs. The objective of the present study was to evaluate the effect of different oxytocin administration routes on myometrial activity, fetal intrauterine hypoxia and postnatal asphyxia in crated farrowing sows. Yorkshire x Landrace hybrid sows (n = 300), that were approaching the time of parturition, were randomly assigned into six groups. Each group included 50 sows, 10 for each of the parities from one to five. A 40-IU oxytocin dosage was administered by intramuscular (IM), or intravulvar (IVU) routes, or 20 IU was administered via intravenous (IV) route. Groups 1 (G1), 3 (G3) and 5 (G5) were administered 0.9% saline solution (NaCl) IM, IVU and IV, respectively, whereas groups 2 (G2), 4 (G4) and 6 (G6) were treated with oxytocin IM, IVU and IV, respectively. There was a significantly (P fetal cardiac frequency deceleration which determines acute fetal suffering. Independent of the route of oxytocin administration, the treatments resulted in twice as many dips II compared with the respective control groups. The use of the cardiotocograph proved to be an excellent tool for establishing the oxytocin response dose in farrowing sows. A greater number of piglets born alive, which had undergone bradycardia, also showed severe acidosis and greater meconium staining in oxytocin-treated sows, indicating that the administration time (at birth of the first piglet) as well as the dosage used were not adequate treatment regimens in the present study. Further studies will be conducted to evaluate different dosages and oxytocin administration timing to determine the most desirable treatment regimen to increase myometrial contractibility without compromising fetal welfare and neonatal survival.

  9. Mineralocorticoid receptor blockade prevents stress-induced modulation of multiple memory systems in the human brain.

    Science.gov (United States)

    Schwabe, Lars; Tegenthoff, Martin; Höffken, Oliver; Wolf, Oliver T

    2013-12-01

    Accumulating evidence suggests that stress may orchestrate the engagement of multiple memory systems in the brain. In particular, stress is thought to favor dorsal striatum-dependent procedural over hippocampus-dependent declarative memory. However, the neuroendocrine mechanisms underlying these modulatory effects of stress remain elusive, especially in humans. Here, we targeted the role of the mineralocorticoid receptor (MR) in the stress-induced modulation of dorsal striatal and hippocampal memory systems in the human brain using a combination of event-related functional magnetic resonance imaging and pharmacologic blockade of the MR. Eighty healthy participants received the MR antagonist spironolactone (300 mg) or a placebo and underwent a stressor or control manipulation before they performed, in the scanner, a classification task that can be supported by the hippocampus and the dorsal striatum. Stress after placebo did not affect learning performance but reduced explicit task knowledge and led to a relative increase in the use of more procedural learning strategies. At the neural level, stress promoted striatum-based learning at the expense of hippocampus-based learning. Functional connectivity analyses showed that this shift was associated with altered coupling of the amygdala with the hippocampus and dorsal striatum. Mineralocorticoid receptor blockade before stress prevented the stress-induced shift toward dorsal striatal procedural learning, same as the stress-induced alterations of amygdala connectivity with hippocampus and dorsal striatum, but resulted in significantly impaired performance. Our findings indicate that the stress-induced shift from hippocampal to dorsal striatal memory systems is mediated by the amygdala, required to preserve performance after stress, and dependent on the MR. © 2013 Society of Biological Psychiatry.

  10. Effects of oxidative stress on hyperglycaemia-induced brain malformations in a diabetes mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Ya [Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China (China); Wang, Guang [Division of Histology & Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou 510632 (China); Han, Sha-Sha; He, Mei-Yao [Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China (China); Cheng, Xin; Ma, Zheng-Lai [Division of Histology & Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou 510632 (China); Wu, Xia [Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China (China); Yang, Xuesong, E-mail: yang_xuesong@126.com [Division of Histology & Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou 510632 (China); Liu, Guo-Sheng, E-mail: tlgs@jnu.edu.cn [Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China (China)

    2016-09-10

    Pregestational diabetes mellitus (PGDM) enhances the risk of fetal neurodevelopmental defects. However, the mechanism of hyperglycaemia-induced neurodevelopmental defects is not fully understood. In this study, several typical neurodevelopmental defects were identified in the streptozotocin-induced diabetes mouse model. The neuron-specific class III beta-tubulin/forkhead box P1-labelled neuronal differentiation was suppressed and glial fibrillary acidic protein-labelled glial cell lineage differentiation was slightly promoted in pregestational diabetes mellitus (PGDM) mice. Various concentrations of glucose did not change the U87 cell viability, but glial cell line-derived neurotrophic factor expression was altered with varying glucose concentrations. Mouse maternal hyperglycaemia significantly increased Tunel{sup +} apoptosis but did not dramatically affect PCNA{sup +} cell proliferation in the process. To determine the cause of increased apoptosis, we determined the SOD activity, the expression of Nrf2 as well as its downstream anti-oxidative factors NQO1 and HO1, and found that all of them significantly increased in PGDM fetal brains compared with controls. However, Nrf2 expression in U87 cells was not significantly changed by different glucose concentrations. In mouse telencephalon, we observed the co-localization of Tuj-1 and Nrf2 expression in neurons, and down-regulating of Nrf2 in SH-SY5Y cells altered the viability of SH-SY5Y cells exposed to high glucose concentrations. Taken together, the data suggest that Nrf2-modulated antioxidant stress plays a crucial role in maternal hyperglycaemia-induced neurodevelopmental defects. - Highlights: • Typical neurodevelopmental defects could be observed in STZ-treated mouse fetuses. • Nrf2 played a crucial role in hyperglycaemia-induced brain malformations. • The effects of hyperglycaemia on neurons and glia cells were not same.

  11. Arachidonic Acid Induces ARE/Nrf2-Dependent Heme Oxygenase-1 Transcription in Rat Brain Astrocytes.

    Science.gov (United States)

    Lin, Chih-Chung; Yang, Chien-Chung; Chen, Yu-Wen; Hsiao, Li-Der; Yang, Chuen-Mao

    2017-05-11

    Arachidonic acid (AA) is a major product of phospholipid hydrolysis catalyzed by phospholipase A2 during neurodegenerative diseases. AA exerts as a second messenger to regulate various signaling components which may be involved in different pathophysiological processes. Astrocytes are the main types of CNS resident cells which maintain and support the physiological function of brain. AA has been shown to induce ROS generation through activation of NADPH oxidases (Noxs) which may play a key role in the expression of heme oxygenase-1 (HO-1). Therefore, this study was designed to investigate the mechanisms underlying AA-induced HO-1 expression in rat brain astrocytes (RBA-1). We found that AA induced HO-1 protein and mRNA expression and promoter activity in RBA-1, which was mediated through the synthesis of 15-deoxy-Δ12,14-prostaglandin D2-activated peroxisome proliferator-activated receptor-γ (PPARγ) receptors. This note was confirmed by transfection with PPARγ small interfering RNAs (siRNA) which attenuated the AA-mediated responses. AA-induced HO-1 expression was mediated through Nox/ROS generation, which was inhibited by Nox inhibitors (diphenyleneiodonium and apocynin) and ROS scavengers (N-acetyl cysteine). Moreover, AA-induced HO-1 expression was mediated through phosphorylation of Src, Pyk2, platelet-derived growth factor, PI3K/Akt, and ERK1/2 which were inhibited by the pharmacological inhibitors including PP1, PF431396, AG1296, LY294002, and U0126 or by transfection with respective siRNAs. AA-enhanced Nrf2 expression and HO-1 promoter activity was inhibited by transfection with Nrf2 siRNA or by these pharmacological inhibitors. Furthermore, chromatin immunoprecipitation assay confirmed that Nrf2 and PPARγ were associated with the proximal antioxidant response element (ARE)-binding site on HO-1 promoter, suggesting that Nrf2/PPARγ are key transcription factors modulating HO-1 expression. AA-induced ARE promoter activity was also reduced by these

  12. Neuroprotective effects of nitric oxide donor NOC-18 against brain ischemia-induced mitochondrial damages: role of PKG and PKC.

    Science.gov (United States)

    Arandarcikaite, Odeta; Jokubka, Ramunas; Borutaite, Vilmante

    2015-01-23

    In this study we sought to determine whether NO donor NOC-18 can protect brain mitochondria against ischemia-induced dysfunction, particularly opening of mitochondrial permeability transition pore (MPTP), and cell death. We found that inhibition of respiration with NAD-dependent substrates, but not with succinate, was observed after 30 min ischemia indicating that complex I of the mitochondrial respiratory chain is the primary site affected by ischemia. There was no loss of mitochondrial cytochrome c during 30-120 min of brain ischemia. Prolonged, 90 min ischemia substantially decreased calcium retention capacity of brain mitochondria suggesting sensitization of mitochondria to Ca(2+)-induced MPTP opening, and this was prevented by NOC-18 infusion prior to ischemia. NOC-18 did not prevent ischemia-induced inhibition of mitochondrial respiration, however, it partially protected against ischemia-induced necrosis. Protective effects of NOC-18 were abolished in the presence of selective inhibitors of protein kinase G (PKG) and protein kinase C (PKC). These results indicate that pre-treatment with NOC-18 protected brain mitochondria against ischemia-induced MPTP opening by decreasing mitochondrial sensitivity to calcium and partly protected brain cells against necrotic death in PKG- and PKC-depending manner. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  13. Programmed Cell Death in the Honey Bee (Apis mellifera) (Hymenoptera: Apidae) Worker Brain Induced by Imidacloprid.

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    Wu, Yan-Yan; Zhou, Ting; Wang, Qiang; Dai, Ping-Li; Xu, Shu-Fa; Jia, Hui-Ru; Wang, Xing

    2015-08-01

    Honey bees are at an unavoidable risk of exposure to neonicotinoid pesticides, which are used worldwide. Compared with the well-studied roles of these pesticides in nontarget site (including midgut, ovary, or salivary glands), little has been reported in the target sites, the brain. In the current study, laboratory-reared adult worker honey bees (Apis mellifera L.) were treated with sublethal doses of imidacloprid. Neuronal apoptosis was detected using the TUNEL technique for DNA labeling. We observed significantly increased apoptotic markers in dose- and time-dependent manners in brains of bees exposed to imidacloprid. Neuronal activated caspase-3 and mRNA levels of caspase-1, as detected by immunofluorescence and real-time quantitative PCR, respectively, were significantly increased, suggesting that sublethal doses of imidacloprid may induce the caspase-dependent apoptotic pathway. Additionally, the overlap of apoptosis and autophagy in neurons was confirmed by transmission electron microscopy. It further suggests that a relationship exists between neurotoxicity and behavioral changes induced by sublethal doses of imidacloprid, and that there is a need to determine reasonable limits for imidacloprid application in the field to protect pollinators. © The Authors 2015. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. Role of ghrelin in exhaustive exercise- induced oxidative stress in rat Brain and liver

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    Shereen Samir

    2013-09-01

    Full Text Available Strenuous exercise increases oxygen consumption and causes disturbance of intracellular pro-oxidant–antioxidant homeostasis. Ghrelin has been reported to possess free radical scavenging and antioxidant effect. in this study we aim to evaluate the beneficial effect of ghrelin on the oxidative stress and antioxidant enzyme systems in brain cortex and liver of rats after exhaustive swimming exercise. Sprague- Dawley rats (50 were subdivided into 3 main groups: control, exercise, exercise and ghrelin (50,100,200 ng group. Animals in the two exercise groups swam for 5 days/week for 4 weeks. stress induced a decrease in the level of GSH and the activities of SOD, GST and catalase, while the levels of TBARS were found elevated. Ghrelin groups’ animals, especially G3 subgroup, have higher SOD, CAT, GSH and GST activity which reflect higher antioxidant enzyme activity and can be attributed to lower rates of oxidative stress which can be proved by reduced level of TBARS. The results of the study provides evidence that ghrelin pretreatment even in low dose reduces the level of lipid peroxidation and enhances the antioxidant defense against exercise-induced stress oxidative injury in rats’ vital organs like brain and liver.

  15. Neuroprotective effect of punicalagin against cerebral ischemia reperfusion-induced oxidative brain injury in rats.

    Science.gov (United States)

    Yaidikar, Lavanya; Byna, Bavya; Thakur, Santh Rani

    2014-01-01

    Punicalagin (PG) is a hydrolyzable polyphenol in Punica granatum. It has been previously reported that it has a protective effect against hypoxia-induced ischemia brain injury. It is a potent antioxidant. The present study is aimed to evaluate the antioxidant potential of PG against focal cerebral ischemia-reperfusion injury in rats subjected to middle cerebral artery occlusion (MCAO). Rats were randomly divided into sham, MCAO, PG-treated groups. PG (15 and 30 mg/kg) vehicle was administered orally for 7 days before MCAO. Rats were anesthetized with ketamine (100 mg/kg), xylazine (10 mg/kg), and subjected to 2 hours occlusion, and 22 hours reperfusion. Neurologic deficit, brain water content (BWC), histopathology changes, and oxidative stress markers were evaluated after 22 hours of reperfusion. In comparison with MCAO model group, treatment with PG significantly reduced the neurologic deficit scores and BWC. PG-attenuated neuronal damage occurred by downregulating the levels of malondialdehyde, sodium-potassium adenosine triphosphatase activity, nitric oxide, protein carbonyl content, and mitochondria-generated reactive oxygen species and upregulating the superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, glutathione reductase activities. Taken together, these results suggested that supplementation of PG treatment effectively ameliorates the cerebral ischemia/reperfusion induced oxidative damage by virtue of its antioxidant potential. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  16. Hypoxia inducible factor-1 alpha stabilization for regenerative therapy in traumatic brain injury

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    Mushfiquddin Khan

    2017-01-01

    Full Text Available Mild traumatic brain injury (TBI, also called concussion, initiates sequelae leading to motor deficits, cognitive impairments and subtly compromised neurobehaviors. While the acute phase of TBI is associated with neuroinflammation and nitroxidative burst, the chronic phase shows a lack of stimulation of the neurorepair process and regeneration. The deficiency of nitric oxide (NO, the consequent disturbed NO metabolome, and imbalanced mechanisms of S-nitrosylation are implicated in blocking the mechanisms of neurorepair processes and functional recovery in the both phases. Hypoxia inducible factor-1 alpha (HIF-1α, a master regulator of hypoxia/ischemia, stimulates the process of neurorepair and thus aids in functional recovery after brain trauma. The activity of HIF-1α is regulated by NO via the mechanism of S-nitrosylation of HIF-1α. S-nitrosylation is dynamically regulated by NO metabolites such as S-nitrosoglutathione (GSNO and peroxynitrite. GSNO stabilizes, and peroxynitrite destabilizes HIF-1α. Exogenously administered GSNO was found not only to stabilize HIF-1α and to induce HIF-1α-dependent genes but also to stimulate the regeneration process and to aid in functional recovery in TBI animals.

  17. Molecular mechanisms of increased cerebral vulnerability after repeated mild blast-induced traumatic brain injury

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    Alaa Kamnaksh

    2014-06-01

    Full Text Available The consequences of a mild traumatic brain injury can be especially severe if it is repeated within the period of increased cerebral vulnerability (ICV that follows the initial insult. To better understand the molecular mechanisms that contribute to ICV, we exposed rats to different levels of mild blast overpressure (5 exposures; total pressure range: 15.54–19.41 psi or 107.14–133.83 kPa at a rate of 1 per 30 min, monitored select physiological parameters, and assessed behavior. Two days post-injury or sham, we determined changes in protein biomarkers related to various pathologies in behaviorally relevant brain regions and in plasma. We found that oxygen saturation and heart rate were transiently depressed following mild blast exposure and that injured rats exhibited significantly increased anxiety- and depression-related behaviors. Proteomic analyses of the selected brain regions showed evidence of substantial oxidative stress and vascular changes, altered cell adhesion, and inflammation predominantly in the prefrontal cortex. Importantly, these pathological changes as well as indications of neuronal and glial cell loss/damage were also detected in the plasma of injured rats. Our findings illustrate some of the complex molecular changes that contribute to the period of ICV in repeated mild blast-induced traumatic brain injury. Further studies are needed to determine the functional and temporal relationship between the various pathomechanisms. The validation of these and other markers can help to diagnose individuals with ICV using a minimally invasive procedure and to develop evidence-based treatments for chronic neuropsychiatric conditions.

  18. Adolescent brain maturation, the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia.

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    Bossong, Matthijs G; Niesink, Raymond J M

    2010-11-01

    Cannabis use during adolescence increases the risk of developing psychotic disorders later in life. However, the neurobiological processes underlying this relationship are unknown. This review reports the results of a literature search comprising various neurobiological disciplines, ultimately converging into a model that might explain the neurobiology of cannabis-induced schizophrenia. The article briefly reviews current insights into brain development during adolescence. In particular, the role of the excitatory neurotransmitter glutamate in experience-dependent maturation of specific cortical circuitries is examined. The review also covers recent hypotheses regarding disturbances in strengthening and pruning of synaptic connections in the prefrontal cortex, and the link with latent psychotic disorders. In the present model, cannabis-induced schizophrenia is considered to be a distortion of normal late postnatal brain maturation. Distortion of glutamatergic transmission during critical periods may disturb prefrontal neurocircuitry in specific brain areas. Our model postulates that adolescent exposure to Δ9-tetrahydrocannabinol (THC), the primary psychoactive substance in cannabis, transiently disturbs physiological control of the endogenous cannabinoid system over glutamate and GABA release. As a result, THC may adversely affect adolescent experience-dependent maturation of neural circuitries within prefrontal cortical areas. Depending on dose, exact time window and duration of exposure, this may ultimately lead to the development of psychosis or schizophrenia. The proposed model provides testable hypotheses which can be addressed in future studies, including animal experiments, reanalysis of existing epidemiological data, and prospective epidemiological studies in which the role of the dose-time-effect relationship should be central. Copyright © 2010 Elsevier Ltd. All rights reserved.

  19. Role of gap junction protein connexin43 in astrogliosis induced by brain injury.

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    Nicolas Theodoric

    Full Text Available Astrogliosis is a process that involves morphological and biochemical changes associated with astrocyte activation in response to cell damage in the brain. The upregulation of intermediate filament proteins including glial fibrillary acidic protein (GFAP, nestin and vimentin are often used as indicators for astrogliosis. Although connexin43 (Cx43, a channel protein widely expressed in adult astrocytes, exhibits enhanced immunoreactivity in the peri-lesion region, its role in astrogliosis is still unclear. Here, we correlated the temporal and spatial expression of Cx43 to the activation of astrocytes and microglia in response to an acute needle stab wound in vivo. We found large numbers of microglia devoid of Cx43 in the needle wound at 3 days post injury (dpi while reactive astrocytes expressing Cx43 were present in the peripheral zone surrounding the injury site. A redistribution of Cx43 to the needle site, corresponding to the increased presence of GFAP-positive reactive astrocytes in the region, was only apparent from 6 dpi and sustained until at least 15 dpi. Interestingly, the extent of microglial activation and subsequent astrogliosis in the brain of Cx43 knockout mice was significantly larger than those of wild type, suggesting that Cx43 expression limits the degree of microgliosis. Although Cx43 is not essential for astrogliosis and microglial activation induced by a needle injury, our results demonstrate that Cx43 is a useful marker for injury induced astrogliosis due to its enhanced expression specifically within a small region of the lesion for an extended period. As a channel protein, Cx43 is a potential in vivo diagnostic tool of asymptomatic brain injury.

  20. Estrogen protects the blood-brain barrier from inflammation-induced disruption and increased lymphocyte trafficking.

    Science.gov (United States)

    Maggioli, E; McArthur, S; Mauro, C; Kieswich, J; Kusters, D H M; Reutelingsperger, C P M; Yaqoob, M; Solito, E

    2016-01-01

    Sex differences have been widely reported in neuroinflammatory disorders, focusing on the contributory role of estrogen. The microvascular endothelium of the brain is a critical component of the blood-brain barrier (BBB) and it is recognized as a major interface for communication between the periphery and the brain. As such, the cerebral capillary endothelium represents an important target for the peripheral estrogen neuroprotective functions, leading us to hypothesize that estrogen can limit BBB breakdown following the onset of peripheral inflammation. Comparison of male and female murine responses to peripheral LPS challenge revealed a short-term inflammation-induced deficit in BBB integrity in males that was not apparent in young females, but was notable in older, reproductively senescent females. Importantly, ovariectomy and hence estrogen loss recapitulated an aged phenotype in young females, which was reversible upon estradiol replacement. Using a well-established model of human cerebrovascular endothelial cells we investigated the effects of estradiol upon key barrier features, namely paracellular permeability, transendothelial electrical resistance, tight junction integrity and lymphocyte transmigration under basal and inflammatory conditions, modeled by treatment with TNFα and IFNγ. In all cases estradiol prevented inflammation-induced defects in barrier function, action mediated in large part through up-regulation of the central coordinator of tight junction integrity, annexin A1. The key role of this protein was then further confirmed in studies of human or murine annexin A1 genetic ablation models. Together, our data provide novel mechanisms for the protective effects of estrogen, and enhance our understanding of the beneficial role it plays in neurovascular/neuroimmune disease. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

  1. Curcumin attenuates collagen-induced inflammatory response through the "gut-brain axis".

    Science.gov (United States)

    Dou, Yannong; Luo, Jinque; Wu, Xin; Wei, Zhifeng; Tong, Bei; Yu, Juntao; Wang, Ting; Zhang, Xinyu; Yang, Yan; Yuan, Xusheng; Zhao, Peng; Xia, Yufeng; Hu, Huijuan; Dai, Yue

    2018-01-06

    Previous studies have demonstrated that oral administration of curcumin exhibited an anti-arthritic effect despite its poor bioavailability. The present study aimed to explore whether the gut-brain axis is involved in the therapeutic effect of curcumin. The collagen-induced arthritis (CIA) rat model was induced by immunization with an emulsion of collagen II and complete Freund's adjuvant. Sympathetic and parasympathetic tones were measured by electrocardiographic recordings. Unilateral cervical vagotomy (VGX) was performed before the induction of CIA. The ChAT, AChE activities, and serum cytokine levels were determined by ELISA. The expression of the high-affinity choline transporter 1 (CHT1), ChAT, and vesicular acetylcholine transporter (VAChT) were determined by real-time PCR and immunohistochemical staining. The neuronal excitability of the vagus nerve was determined by whole-cell patch clamp recording. Oral administration of curcumin restored the imbalance between the sympathetic and parasympathetic tones in CIA rats and increased ChAT activity and expression of ChAT and VAChT in the gut, brain, and synovium. Additionally, VGX eliminated the effects of curcumin on arthritis and ACh biosynthesis and transport. Electrophysiological data showed that curcumin markedly increased neuronal excitability of the vagus nerve. Furthermore, selective α7 nAChR antagonists abolished the effects of curcumin on CIA. Our results demonstrate that curcumin attenuates CIA through the "gut-brain axis" by modulating the function of the cholinergic system. These findings provide a novel approach for mechanistic studies of anti-arthritic compounds with low oral absorption and bioavailability.

  2. Increased brain L-arginine availability facilitates cutaneous heat loss induced by running exercise.

    Science.gov (United States)

    Wanner, Samuel Penna; Leite, Laura Hora Rios; Guimarães, Juliana Bohnen; Coimbra, Cândido Celso

    2015-06-01

    The effects of increased brain availability of L-arginine (L-arg), a precursor for nitric oxide synthesis, on core body temperature (Tcore ) and cutaneous heat loss were evaluated in running rats. One week prior to the experiments, adult male Wistar rats received the following implants: a chronic guide cannula in the lateral cerebral ventricle and a temperature sensor in the abdominal cavity. On the day of the experiments, the rats were assigned to receive a 2-μL intracerebroventricular injection of either NaCl (0.15 mol/L) or L-arg solution (0.825, 1.65 or 3.30 mol/L); Tcore and tail skin temperature were measured while the rats ran at a speed of 18 m/min until they were fatigued. L-arginine induced a dose-dependent reduction in the threshold Tcore required for cutaneous heat loss (38.09 ± 0.20°C for 3.30-mol/L L-arg vs 38.61 ± 0.10°C for saline; P exercise-induced hyperthermia. Although the rats treated with L-arg presented a lower Tcore at the end of exercise (~0.7°C lower after treatment with the highest dose), no changes in the time to fatigue were observed relative to the control trial. These results suggest that brain L-arg controls heat loss during exercise, most likely by modulating the sympathetic vasoconstrictor tonus to skin vessels. Furthermore, despite facilitating cutaneous heat loss mechanisms, increased brain L-arg availability did not enhance physical performance. © 2015 Wiley Publishing Asia Pty Ltd.

  3. Environment as a risk factor in delayed development in premature, low-birthweight and mild asphyxia children.

    Science.gov (United States)

    Yanuarti, Hestu Putri; Rusmil, Kusnandi; Effendi, Sjarif Hidajat

    2014-10-01

    Premature infants with low birthweight (LBW) and asphyxia are at high risk of delay of language and visual-motor development. Environmental risk factors contributing to the delay include parents' education, family income, number of children in the family, exclusive breast-feeding, and the mother's parenting time. Lack of research in Indonesia on premature, LBW and mild asphyxia children minimizes information to parents on the importance of an optimal environment. The aim of this study was to observe the role of the environment as a risk factor for delay in language and visual-motor development. A cross-sectional study was carried out from June to December 2011 of 12-24-month-old children born premature, with LBW and mild asphyxia at the Hasan Sadikin, Bandung City, and Muhammadiyah Hospitals. Language and visual-motor development were measured by Capute scales. Risk factors were analyzed using chi-squared test and multivariate logistic regression analysis. Of the 70 subjects, 49% had language and visual-motor delay. Environmental factors related to the delay were low parental education, low family income, non-exclusive breast-feeding (P breast-feeding was associated with a 175-fold risk (prevalence rate [PR], 174.756; 95% confidence interval [CI]: 10.407-2934.516, P breast-feeding are risk factors for delay in language and visual-motor development in 12-24-month-old children born premature, with LBW and mild asphyxia. © 2014 Japan Pediatric Society.

  4. Effects of exercise on brain and peripheral inflammatory biomarkers induced by total sleep deprivation in rats.

    Science.gov (United States)

    Chennaoui, M; Gomez-Merino, D; Drogou, C; Geoffroy, H; Dispersyn, G; Langrume, C; Ciret, S; Gallopin, T; Sauvet, F

    2015-01-01

    Physical exercise induces neuroprotection through anti-inflammatory effects and total sleep deprivation is reported an inflammatory process. We examined whether 7 weeks of exercise training attenuates markers of inflammation during total sleep deprivation (24-h wakefulness) in the rat brain and periphery. Four groups of 10 rats were investigated: Sedentary control, Sedentary sleep-deprived, Exercised control, and Exercised sleep-deprived. Sleep deprivation and exercise training were induced using slowly rotating wheels and a motorized treadmill. We examined mRNA expression of pro-inflammatory (IL-1β, TNF-α, and IL-6) cytokine-related genes using real-time PCR, and protein levels in the hippocampus and frontal cortex, as well as circulating concentrations. Compared to Sedentary control rats, hippocampal and cortical IL-1β mRNA expressions in Sedentary sleep-deprived rats were up-regulated (p rats (p rats compared to Sedentary control (p Exercise training reduced the sleep deprivation-induced hippocampal IL-1β increases (mRNA expression and protein content) (p exercise reduced sleep deprivation-induced increase of IL-6 concentration (p effect on TNF-α and norepinephrine. We demonstrate that a 7-week exercise training program before acute total sleep deprivation prevents pro-inflammatory responses in the rat hippocampus, particularly the IL-1β cytokine at the gene expression level and protein content.

  5. Brain microvascular endothelium induced-annexin A1 secretion contributes to small cell lung cancer brain metastasis.

    Science.gov (United States)

    Liu, Yi; Liu, Yong-Shuo; Wu, Peng-Fei; Li, Qiang; Dai, Wu-Min; Yuan, Shuai; Xu, Zhi-Hua; Liu, Ting-Ting; Miao, Zi-Wei; Fang, Wen-Gang; Chen, Yu-Hua; Li, Bo

    2015-09-01

    Small cell lung cancer is the most aggressive histologic subtype of lung cancer, with a strong predilection for metastasizing to brain early. However, the cellular and molecular basis is poorly known. Here, we provided evidence to reveal the role of annexin A1 in small cell lung cancer metastasis to brain. Firstly, the elevated annexin A1 serum levels in small cell lung cancer patients were associated with brain metastasis. The levels of annexin A1 were also upregulated in NCI-H446 cells, a small cell lung cancer cell line, upon migration into the mice brain. More interestingly, annexin A1 was secreted by NCI-H446 cells in a time-dependent manner when co-culturing with human brain microvascular endothelial cells, which was identified with the detections of annexin A1 in the co-cultured cellular supernatants by ELISA and western blot. Further results showed that blockage of annexin A1 in the co-cultured cellular supernatants using a neutralized antibody significantly inhibited NCI-H446 cells adhesion to brain endothelium and its transendothelial migration. Conversely, the addition of Ac2-26, an annexin A1 mimic peptide, enhanced these effects. Furthermore, knockdown of annexin A1 in NCI-H446 cells prevented its transendothelial migration in vitro and metastasis to mice brain in vivo. Our data showed that small cell lung cancer cell in brain microvasculature microenvironment could express much more annexin A1 and release it outside, which facilitated small cell lung cancer cell to gain malignant properties of entry into brain. These findings provided a potential target for the management of SCLC brain metastasis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Protective effect of Kombucha tea on brain damage induced by transient cerebral ischemia and reperfusion in rat

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    Najmeh Kabiri

    2016-09-01

    Full Text Available The aim of study was to investigate the potential neuroprotective effects of Kombucha on cerebral damage induced by ischemia in rats (n=99. Cerebral infarct volume in the ischemic rats received Kombucha solution showed no significance alteration. However, the permeability of blood-brain barrier significantly decreased in both ischemic rats received 15 mg/kg Kombucha tea and Sham group. In addition, brain water content in the ischemic groups treated with Kombucha solution was significantly higher than the Sham group, although right hemispheres in all of the treated groups illustrated higher brain water content than the left ones. Brain anti-oxidant capacity elevated in the ischemic rats treated with Kombucha and in the Sham group. Brain and plasma malondialdehyde concentrations significantly decreased in both of the ischemic groups injected with Kombucha. The findings suggest that Kombucha tea could be useful for the prevention of cerebral damage.

  7. Colony-stimulating factor 1 receptor blockade prevents fractionated whole-brain irradiation-induced memory deficits.

    Science.gov (United States)

    Feng, Xi; Jopson, Timothy D; Paladini, Maria Serena; Liu, Sharon; West, Brian L; Gupta, Nalin; Rosi, Susanna

    2016-08-30

    Primary central nervous system (CNS) neoplasms and brain metastases are routinely treated with whole-brain radiation. Long-term survival occurs in many patients, but their quality of life is severely affected by the development of cognitive deficits, and there is no treatment to prevent these adverse effects. Neuroinflammation, associated with activation of brain-resident microglia and infiltrating monocytes, plays a pivotal role in loss of neurological function and has been shown to be associated with acute and long-term effects of brain irradiation. Colony-stimulating factor 1 receptor (CSF-1R) signaling is essential for the survival and differentiation of microglia and monocytes. Here, we tested the effects of CSF-1R blockade by PLX5622 on cognitive function in mice treated with three fractions of 3.3 Gy whole-brain irradiation. Young adult C57BL/6J mice were given three fractions of 3.3 Gy whole-brain irradiation while they were on diet supplemented with PLX5622, and the effects on periphery monocyte accumulation, microglia numbers, and neuronal functions were assessed. The mice developed hippocampal-dependent cognitive deficits at 1 and 3 months after they received fractionated whole-brain irradiation. The impaired cognitive function correlated with increased number of periphery monocyte accumulation in the CNS and decreased dendritic spine density in hippocampal granule neurons. PLX5622 treatment caused temporary reduction of microglia numbers, inhibited monocyte accumulation in the brain, and prevented radiation-induced cognitive deficits. Blockade of CSF-1R by PLX5622 prevents fractionated whole-brain irradiation-induced memory deficits. Therapeutic targeting of CSF-1R may provide a new avenue for protection from radiation-induced memory deficits.

  8. Protective Effects of Beta Glucan and Gliclazide on Brain Tissue and Sciatic Nerve of Diabetic Rats Induced by Streptozosin

    Directory of Open Access Journals (Sweden)

    Harun Alp

    2012-01-01

    Full Text Available There have not been yet enough studies about effects of beta glucan and gliclazide on oxidative stress created by streptozotocin in the brain and sciatic nerve of diabetic rats. The aim of this paper was to investigate the antioxidant effects of gliclazide and beta glucan on oxidative stress and lipid peroxidation created by streptozotosin in brain and sciatic nerve. Total of 42 rats were divided into 6 groups including control, diabetic untreated (DM (only STZ, diabetic, STZ (DM + beta glucan, STZ (DM + gliclazide, only beta glucan treated (no diabetic, and only gliclazide treated (no diabetic. The brain and sciatic nerve tissue samples were analyzed for malondialdehyde (MDA, total oxidant status (TOS, total antioxidant status (TAS, oxidative stress index (OSI, and paraoxonase (PON-1 levels. We found a significant increase in MDA, TOS, and OSI along with a reduction in TAS level, catalase, and PON-1 activities in brain and sciatic nerve of streptozotocin-induced diabetic rats. Also, this study shows that in terms of these parameters both gliclazide and beta glucan have a neuroprotective effect on the brain and sciatic nerve of the streptozotocin-induced diabetic rat. Our conclusion was that gliclazide and beta glucan have antioxidant effects on the brain and sciatic nerve of the streptozotocin-induced diabetic rat.

  9. Sustained NMDA receptor hypofunction induces compromised neural systems integration and schizophrenia-like alterations in functional brain networks.

    Science.gov (United States)

    Dawson, Neil; Xiao, Xiaolin; McDonald, Martin; Higham, Desmond J; Morris, Brian J; Pratt, Judith A

    2014-02-01

    Compromised functional integration between cerebral subsystems and dysfunctional brain network organization may underlie the neurocognitive deficits seen in psychiatric disorders. Applying topological measures from network science to brain imaging data allows the quantification of complex brain network connectivity. While this approach has recently been used to further elucidate the nature of brain dysfunction in schizophrenia, the value of applying this approach in preclinical models of psychiatric disease has not been recognized. For the first time, we apply both established and recently derived algorithms from network science (graph theory) to functional brain imaging data from rats treated subchronically with the N-methyl-D-aspartic acid (NMDA) receptor antagonist phencyclidine (PCP). We show that subchronic PCP treatment induces alterations in the global properties of functional brain networks akin to those reported in schizophrenia. Furthermore, we show that subchronic PCP treatment induces compromised functional integration between distributed neural systems, including between the prefrontal cortex and hippocampus, that have established roles in cognition through, in part, the promotion of thalamic dysconnectivity. We also show that subchronic PCP treatment promotes the functional disintegration of discrete cerebral subsystems and also alters the connectivity of neurotransmitter systems strongly implicated in schizophrenia. Therefore, we propose that sustained NMDA receptor hypofunction contributes to the pathophysiology of dysfunctional brain network organization in schizophrenia.

  10. Brain injury induces specific changes in the caecal microbiota of mice via altered autonomic activity and mucoprotein production.

    Science.gov (United States)

    Houlden, A; Goldrick, M; Brough, D; Vizi, E S; Lénárt, N; Martinecz, B; Roberts, I S; Denes, A

    2016-10-01

    Intestinal microbiota are critical for health with changes associated with diverse human diseases. Research suggests that altered intestinal microbiota can profoundly affect brain function. However, whether altering brain function directly affects the microbiota is unknown. Since it is currently unclear how brain injury induces clinical complications such as infections or paralytic ileus, key contributors to prolonged hospitalization and death post-stroke, we tested in mice the hypothesis that brain damage induced changes in the intestinal microbiota. Experimental stroke altered the composition of caecal microbiota, with specific changes in Peptococcaceae and Prevotellaceae correlating with the extent of injury. These effects are mediated by noradrenaline release from the autonomic nervous system with altered caecal mucoprotein production and goblet cell numbers. Traumatic brain injury also caused changes in the gut microbiota, confirming brain injury effects gut microbiota. Changes in intestinal microbiota after brain injury may affect recovery and treatment of patients should appreciate such changes. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Alcohol drinking produces brain region-selective changes in expression of inducible transcription factors.

    Science.gov (United States)

    Bachtell, R K; Wang, Y M; Freeman, P; Risinger, F O; Ryabinin, A E

    1999-11-20

    Mapping the effects of alcohol consumption on neural activity could provide valuable information on mechanisms of alcohol's effects on behavior. The present study sought to identify effects of alcohol consumption on expression of inducible transcription factors (ITFs) in mouse brain. C57BL/6J mice were trained to consume 10% ethanol/10% sucrose solution during a 30-min limited access period. Control animals were given access to 10% sucrose solution or water. Following the final day of the procedure, animals were sacrificed and immunohistochemical analyses were performed for three ITFs (c-Fos, FosB, and Zif268). Alcohol-consuming animals had increased ITF expression in several brain areas. Specifically, c-Fos was significantly induced in the nucleus accumbens core (AcbC), the medial posteroventral portion of the central nucleus of the amygdala (CeMPV), and the Edinger-Westphal nucleus (EW). Expression of c-Fos was significantly lower in the dentate gyrus of alcohol-consuming animals vs. sucrose-consuming animals. However, it was not significantly different from the water controls. Induction of c-Fos in AcbC, CeMPV and EW was significantly related to blood alcohol concentrations (BAC). Furthermore, FosB expression in the CeMPV and the EW was also significantly higher in the alcohol-consuming animals vs. water controls. FosB expression in the EW was significantly related to BAC. The significance of these results is two-fold. First, our experiments demonstrate that ITF mapping is an effective strategy in identifying alcohol-induced changes following voluntary consumption. Second, they suggest a relationship between ITF expression in AcbC, CeMPV and EW and the level of alcohol intoxication.

  12. Lysergic acid diethylamide-induced Fos expression in rat brain: role of serotonin-2A receptors.

    Science.gov (United States)

    Gresch, P J; Strickland, L V; Sanders-Bush, E

    2002-01-01

    Lysergic acid diethylamide (LSD) produces altered mood and hallucinations in humans and binds with high affinity to serotonin-2A (5-HT(2A)) receptors. Although LSD interacts with other receptors, the activation of 5-HT(2A) receptors is thought to mediate the hallucinogenic properties of LSD. The goal of this study was to identify the brain sites activated by LSD and to determine the influence of 5-HT(2A) receptors in this activation. Rats were pretreated with the 5-HT(2A) receptor antagonist MDL 100907 (0.3 mg/kg, i.p.) or vehicle 30 min prior to LSD (500 microg/kg, i.p.) administration and killed 3 h later. Brain tissue was examined for Fos protein expression by immunohistochemistry. LSD administration produced a five- to eight-fold increase in Fos-like immunoreactivity in medial prefrontal cortex, anterior cingulate cortex, and central nucleus of amygdala. However, in dorsal striatum and nucleus accumbens no increase in Fos-like immunoreactivity was observed. Pretreatment with MDL 100907 completely blocked LSD-induced Fos-like immunoreactivity in medial prefrontal cortex and anterior cingulate cortex, but only partially blocked LSD-induced Fos-like immunoreactivity in amygdala. Double-labeled immunohistochemistry revealed that LSD did not induce Fos-like immunoreactivity in cortical cells expressing 5-HT(2A) receptors, suggesting an indirect activation of cortical neurons. These results indicate that the LSD activation of medial prefrontal cortex and anterior cingulate cortex is mediated by 5-HT(2A) receptors, whereas in amygdala 5-HT(2A) receptor activation is a component of the response. These findings support the hypothesis that the medial prefrontal cortex, anterior cingulate cortex, and perhaps the amygdala, are important regions involved in the production of hallucinations. Copyright 2002 IBRO

  13. Linking binge alcohol-induced neurodamage to brain edema and potential aquaporin-4 upregulation: evidence in rat organotypic brain slice cultures and in vivo.

    Science.gov (United States)

    Sripathirathan, Kumar; Brown, James; Neafsey, Edward J; Collins, Michael A

    2009-02-11

    Brain edema and derived oxidative stress potentially are critical events in the hippocampal-entorhinal cortical (HEC) neurodegeneration caused by binge alcohol (ethanol) intoxication and withdrawal in adult rats. Edema's role is based on findings that furosemide diuretic antagonizes binge alcohol-dependent brain overhydration and neurodamage in vivo and in rat organotypic HEC slice cultures. However, evidence that furosemide has significant antioxidant potential and knowledge that alcohol can cause oxidative stress through non-edemic pathways has placed edema's role in question. We therefore studied three other diuretics and a related non-diuretic that, according to our oxygen radical antioxidant capacity (ORAC) assays or the literature, possess minimal antioxidant potential. Acetazolamide (ATZ), a carbonic anhydrase inhibitor/diuretic with negligible ORAC effectiveness and, interestingly, an aquaporin-4 (AQP4) water channel inhibitor, prevented alcohol-dependent tissue edema and neurodegeneration in HEC slice cultures. Likewise, in binge alcohol-intoxicated rats, ATZ suppressed brain edema while inhibiting neurodegeneration. Torasemide, a loop diuretic lacking furosemide's ORAC capability, also prevented alcohol-induced neurodamage in HEC slice cultures. However, bumetanide (BUM), a diuretic blocker of Na(+)-K(+)-2Cl(-) channels, and L-644, 711, a nondiuretic anion channel inhibitor--both lacking antioxidant capabilities as well as reportedly ineffective against alcohol-dependent brain damage in vivo--reduced neither alcohol-induced neurotoxicity nor (with BUM) edema in HEC slices. Because an AQP4 blocker (ATZ) was neuroprotective, AQP4 expression in the HEC slices was examined and found to be elevated by binge alcohol. The results further indicate that binge ethanol-induced brain edema/swelling, potentially associated with AQP4 upregulation, may be important in consequent neurodegeneration that could derive from neuroinflammatory processes, for example, membrane

  14. Diffusion tensor imaging detects ventilation-induced brain injury in preterm lambs.

    Directory of Open Access Journals (Sweden)

    Dhafer M Alahmari

    Full Text Available Injurious mechanical ventilation causes white matter (WM injury in preterm infants through inflammatory and haemodynamic pathways. The relative contribution of each of these pathways is not known. We hypothesised that in vivo magnetic resonance imaging (MRI can detect WM brain injury resulting from mechanical ventilation 24 h after preterm delivery. Further we hypothesised that the combination of inflammatory and haemodynamic pathways, induced by umbilical cord occlusion (UCO increases brain injury at 24 h.Fetuses at 124±2 days gestation were exposed, instrumented and either ventilated for 15 min using a high tidal-volume (VT injurious strategy with the umbilical cord intact (INJ; inflammatory pathway only, or occluded (INJ+UCO; inflammatory and haemodynamic pathway. The ventilation groups were compared to lambs that underwent surgery but were not ventilated (Sham, and lambs that did not undergo surgery (unoperated control; Cont. Fetuses were placed back in utero after the 15 min intervention and ewes recovered. Twenty-four hours later, lambs were delivered, placed on a protective ventilation strategy, and underwent MRI of the brain using structural, diffusion tensor imaging (DTI and magnetic resonance spectroscopy (MRS techniques.Absolute MRS concentrations of creatine and choline were significantly decreased in INJ+UCO compared to Cont lambs (P = 0.03, P = 0.009, respectively; no significant differences were detected between the INJ or Sham groups and the Cont group. Axial diffusivities in the internal capsule and frontal WM were lower in INJ and INJ+UCO compared to Cont lambs (P = 0.05, P = 0.04, respectively. Lambs in the INJ and INJ+UCO groups had lower mean diffusivities in the frontal WM compared to Cont group (P = 0.04. DTI colour mapping revealed lower diffusivity in specific WM regions in the Sham, INJ, and INJ+UCO groups compared to the Cont group, but the differences did not reach significance. INJ+UCO lambs more likely to exhibit

  15. Brain Research to Ameliorate Impaired Neurodevelopment - Home-based Intervention Trial (BRAIN-HIT)

    Science.gov (United States)

    2010-01-01

    Background This randomized controlled trial aims to evaluate the effects of an early developmental intervention program on the development of young children in low- and low-middle-income countries who are at risk for neurodevelopmental disability because of birth asphyxia. A group of children without perinatal complications are evaluated in the same protocol to compare the effects of early developmental intervention in healthy infants in the same communities. Birth asphyxia is the leading specific cause of neonatal mortality in low- and low-middle-income countries and is also the main cause of neonatal and long-term morbidity including mental retardation, cerebral palsy, and other neurodevelopmental disorders. Mortality and morbidity from birth asphyxia disproportionately affect more infants in low- and low-middle-income countries, particularly those from the lowest socioeconomic groups. There is evidence that relatively inexpensive programs of early developmental intervention, delivered during home visit by parent trainers, are capable of improving neurodevelopment in infants following brain insult due to birth asphyxia. Methods/Design This trial is a block-randomized controlled trial that has enrolled 174 children with birth asphyxia and 257 without perinatal complications, comparing early developmental intervention plus health and safety counseling to the control intervention receiving health and safety counseling only, in sites in India, Pakistan, and Zambia. The interventions are delivered in home visits every two weeks by parent trainers from 2 weeks after birth until age 36 months. The primary outcome of the trial is cognitive development, and secondary outcomes include social-emotional and motor development. Child, parent, and family characteristics and number of home visits completed are evaluated as moderating factors. Discussion The trial is supervised by a trial steering committee, and an independent data monitoring committee monitors the trial

  16. Neurons but not glial cells overexpress ubiquitin in the rat brain following focused ultrasound-induced opening of the blood-brain barrier.

    Science.gov (United States)

    Alonso, A; Reinz, E; Fatar, M; Jenne, J; Hennerici, M G; Meairs, S

    2010-08-11

    Focused ultrasound-induced opening of the blood-brain barrier (BBB) in the presence of ultrasound contrast agents is a promising strategy for a targeted drug delivery to the brain. The aim of our study was to identify whether brain molecular stress pathways are targeted by ultrasound treatment. Using an upper level of acoustic pressures in combination with microbubbles, which have been previously reported as reliable for BBB opening without causing tissue damage, we found that ultrasound leads to an increased ubiquitinylation of proteins in neuronal (11+/-3 ubiquitin-overexpressing cells per optical field) but not glial cells 6 h post-insonation, increasing to 16 (+/-4) labelled cells after 24 h. No changes in the expression of Hsp70 and Hsc70 were detected over 24 h. Ultrasound treatment was followed by limited apoptosis after 24 h (32+/-6 cleaved-caspase 3-positive cells per optical field) in the insonated areas. Only neurons were identified in the apoptotic population. Although these observations may not be applicable for all acoustic parameters useful for BBB opening, they demonstrate that insonation of the rat brain with the parameters used in our experiments is a useful tool for BBB opening and induces specific cellular stress response restricted to neuronal cells. Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

  17. Cigarette smoking exacerbates chronic alcohol-induced brain damage: a preliminary metabolite imaging study.

    Science.gov (United States)

    Durazzo, Timothy C; Gazdzinski, Stefan; Banys, Peter; Meyerhoff, Dieter J

    2004-12-01

    Cigarette smoking is common among alcohol-dependent individuals. Nevertheless, previous research has typically not accounted for the potential independent or compounding effects of cigarette smoking on alcohol-induced brain injury and neurocognition. Twenty-four 1-week-abstinent recovering alcoholics (RAs; 14 smokers and 10 nonsmokers) in treatment and 26 light-drinking controls (7 smokers and 19 nonsmokers) were compared on measures of common brain metabolites in gray matter and white matter of the major lobes, basal ganglia, midbrain, and cerebellar vermis, obtained via multislice short-echo time proton magnetic resonance spectroscopic imaging. Smoking and nonsmoking RAs were also contrasted on measures of neurocognitive functioning, as well as laboratory markers of drinking severity and nutritional status. Chronic alcohol dependence, independent of smoking, was associated with lower concentrations of frontal N-acetylaspartate (NAA) and frontal choline-containing compounds, as well as lower parietal and thalamic choline. Smoking RAs had lower NAA concentrations in frontal white matter and midbrain and lower midbrain choline than nonsmoking RAs. A four-group analysis of covariance also demonstrated that chronic cigarette smoking was associated with lower midbrain NAA and choline and with lower vermian choline. In smoking RAs, heavier drinking was associated with heavier smoking, which correlated with numerous subcortical metabolite abnormalities. The 1-week-abstinent smoking and nonsmoking RAs did not differ significantly on a brief neurocognitive battery. In smoking RAs, lower cerebellar vermis NAA was associated with poorer visuomotor scanning speed and incidental learning, and in nonsmoking RAs lower vermis NAA was related to poorer visuospatial learning and memory. These human in vivo proton magnetic resonance spectroscopic imaging findings indicate that chronic cigarette smoking exacerbates chronic alcohol-induced neuronal injury and cell membrane damage in

  18. Successfully reducing newborn asphyxia in the labour unit in a large academic medical centre

    DEFF Research Database (Denmark)

    Hollesen, Rikke von Benzon; Johansen, Rie Laurine Rosenthal; Rørbye, Christina

    2018-01-01

    ) an implementation theory, including improving skills in interpretation of cardiotocography, use of QI methods and participation in a national learning network. The Model for Improvement and Deming's system of profound knowledge were used as a methodological framework. Data on compliance with the care bundles...... and the number of deliveries between newborns with asphyxia (Apgar using statistical process control. RESULTS: Compliance with all three clinical care bundles improved to 95% or more, and the percentages of newborns with pH ...% and 31%, respectively. In general, the QI approach strengthened multidisciplinary teamwork, systematised workflow and structured communication around the deliveries. Changes included making a standard memo in the medical record, the use of a bedside whiteboard, bedside handovers, shared decisions...

  19. Firing probability and mean firing rates of human muscle vasoconstrictor neurones are elevated during chronic asphyxia

    DEFF Research Database (Denmark)

    Ashley, Cynthia; Burton, Danielle; Sverrisdottir, Yrsa B

    2010-01-01

    are chronically asphyxic. We tested the hypothesis that this elevated chemical drive would shift the firing pattern from that seen in healthy subjects to that seen in OSAS. The mean firing probability (52%) and mean firing rate (0.92 Hz) of 17 muscle vasoconstrictor neurones recorded in COPD were comparable...... in the obstructive sleep apnoea syndrome (OSAS) is associated with an increase in firing probability and mean firing rate, and an increase in multiple within-burst firing. Here we characterize the firing properties of muscle vasoconstrictor neurones in patients with chronic obstructive pulmonary disease (COPD), who...... in the healthy group (78%). Conversely, single neurones fired twice in 25% of cardiac intervals, similar to OSAS (27%), but significantly higher than in the healthy group (18%). We conclude that the chronic asphyxia associated with COPD results in an increase in the firing probability and mean firing frequency...

  20. Role of brain regional GABA: aldrin-induced stimulation of locomotor activity in rat.

    Science.gov (United States)

    Jamaluddin, S K; Poddar, M K

    2001-04-01

    Aldrin, a chlorinated hydrocarbon group of pesticide, is a well known central nervous system (CNS) stimulant. The CNS stimulating effect of aldrin is manifested in the form of an increase in locomotor activity (LA) of animals. Maximum increase in LA was observed at 2 h following aldrin (2-10 mg/kg, p.o.) treatment and this aldrin-induced increase in LA attained a peak at a dose of 10 mg/kg, p.o. Administration of aldrin (2 or 5 mg/kg/day, p.o.) enhanced LA of rats and reached a maxima after 12 consecutive days of treatment following which aldrin-induced LA was gradually reduced and restored to control value after 20 consecutive days of aldrin treatment. A single administration of aldrin (2-10 mg/kg, p.o.) reduced the GABA system in cerebellum, hypothalamus and pons-medulla. The treatment with aldrin (2 mg/kg/day, p.o.) for 12 consecutive days produced more inhibition in those brain regional GABA system than that observed with a single dose of aldrin. These results, thus, suggest that aldrin-induced inhibition of central GABA may be a cause of stimulation of LA with aldrin either at a single dose or for 12 consecutive days.

  1. Ketamine induces brain-derived neurotrophic factor expression via phosphorylation of histone deacetylase 5 in rats.

    Science.gov (United States)

    Choi, Miyeon; Lee, Seung Hoon; Park, Min Hyeop; Kim, Yong-Seok; Son, Hyeon

    2017-08-05

    Ketamine shows promise as a therapeutic agent for the treatment of depression. The increased expression of brain-derived neurotrophic factor (BDNF) has been associated with the antidepressant-like effects of ketamine, but the mechanism of BDNF induction is not well understood. In the current study, we demonstrate that the treatment of rats with ketamine results in the dose-dependent rapid upregulation of Bdnf promoter IV activity and expression of Bdnf exon IV mRNAs in rat hippocampal neurons. Transfection of histone deacetylase 5 (HDAC5) into rat hippocampal neurons similarly induces Bdnf mRNA expression in response to ketamine, whereas transfection of a HDAC5 phosphorylation-defective mutant (Ser259 and Ser498 replaced by Ala259 and Ala498), results in the suppression of ketamine-mediated BDNF promoter IV transcriptional activity. Viral-mediated hippocampal knockdown of HDAC5 induces Bdnf mRNA and protein expression, and blocks the enhancing effects of ketamine on BDNF expression in both unstressed and stressed rats, and thereby providing evidence for the role of HDAC5 in the regulation of Bdnf expression. Taken together, our findings implicate HDAC5 in the ketamine-induced transcriptional regulation of Bdnf, and suggest that the phosphorylation of HDAC5 regulates the therapeutic actions of ketamine. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Characterization of Different Microbubbles in Assisting Focused Ultrasound-Induced Blood-Brain Barrier Opening

    Science.gov (United States)

    Wu, Sheng-Kai; Chu, Po-Chun; Chai, Wen-Yen; Kang, Shih-Tsung; Tsai, Chih-Hung; Fan, Ching-Hsiang; Yeh, Chih-Kuang; Liu, Hao-Li

    2017-04-01

    Microbubbles (MBs) serve as a critical catalyst to amplify local cavitation in CNS capillary lumen to facilitate focused ultrasound (FUS) to transiently open the blood-brain barrier (BBB). However, limited understanding is available regarding the effect of different microbubbles to induce BBB opening. The aim of this study is to characterize different MBs on their effect in FUS-induced BBB opening. Three MBs, SonoVue, Definity, and USphere, were tested, with 0.4-MHz FUS exposure at 0.62-1.38 of mechanical index (MI) on rats. Evans blue, dynamic contrast-enhanced (DCE) MRI and small-animal ultrasound imaging were used as surrogates to allow molecule-penetrated quantification, BBB-opened observation, and MBs circulation/persistence. Cavitation activity was measured via the passive cavitation detection (PCD) setup to correlate with the exposure level and the histological effect. Under given and identical MB concentrations, the three MBs induced similar and equivalent BBB-opening effects and persistence. In addition, a treatment paradigm by adapting exposure time is proposed to compensate MB decay to retain the persistence of BBB-opening efficiency in multiple FUS exposures. The results potentially improve understanding of the equivalence among MBs in focused ultrasound CNS drug delivery, and provide an effective strategy for securing persistence in this treatment modality.

  3. Incidence of Acute Renal Failure in Birth Asphyxia and its Correlation with Hypoxic Ischemic Encephalopathy (HIE

    Directory of Open Access Journals (Sweden)

    Sugunakar Reddy B

    2017-04-01

    Full Text Available Introduction: Perinatal asphyxia is an essential reason for neonatal mortality and neurological morbidity. The general rate of this condition is assessed to be between 1 to 10 for every 1000 live births and is affected by the birth weight and gestational age of the infant furthermore by the neighbourhood accessibility of therapeutic assets. Methods: The underlying administration of every single such neonate comprised of putting the child under a servocontrolled radiant warmer and nursing them in the thermo-neutral range of temperature. About 41 cases accomplished for early identification of confusions and difficulties and their convenient administration. Following 72 h of birth and before 96 h of birth in the wake of getting educated composed assent from the guardians, under aseptic safety measures 3 ml blood was drawn and was assessed for blood urea (Berthelot strategy, serum creatinine (Jaffe’s test, serum electrolytes (Calorimetric technique and urine yield was observed by applying plastic accumulation pack (minicom and clinical state of the child was checked. Results: A sum of 1285 neonates were conceded in NICU for different issues, among them an aggregate of 90 neonates were conceded for perinatal asphyxia. A sum of 75 cases and 50 controls were chosen. The accompanying tables and figures represent the outcomes in subtle element. The outcomes got were examine blood urea and serum creatinine levels were essentially lifted in cases with renal disappointment, when contrasted with controls (P=0.001. Nevertheless, there was no distinction in electrolyte levels in both the gatherings. Conclusion: The most common perinatal danger component was MSAF (40%. In our study the commonest type of ARF in every one of the three phases of HIE was non-oliguric sort. The frequency of inherent renal disappointment in our study was 9.4%. Checking of blood urea, serum creatinine and urine yield helps in the early finding and administration of renal

  4. Prenatal nicotine exposure increases hyperventilation in α4-knock-out mice during mild asphyxia.

    Science.gov (United States)

    Avraam, Joanne; Cohen, Gary; Drago, John; Frappell, Peter B

    2015-03-01

    Prenatal nicotine exposure alters breathing and ventilatory responses to stress through stimulation of nicotine acetylcholine receptors (nAChRs). We tested the hypothesis that α4-containing nAChRs are involved in mediating the effects of prenatal nicotine exposure on ventilatory and metabolic responses to intermittent mild asphyxia (MA). Using open-flow plethysmography, we measured ventilation (V̇(E)) and rate of O2 consumption ( V̇(O2)) of wild-type (WT) and α4-knock-out (KO) mice, at postnatal (P) days 1-2 and 7-8, with and without prenatal nicotine exposure (6 mg kg(-1) day(-1) beginning on embryonic day 14). Mice were exposed to seven 2 min cycles of mild asphyxia (10% O2 and 5% CO2), each interspersed with 2 min of air. Compared to WT, α4 KO mice had increased air V̇(E) and V̇(O2) at P7-8, but not P1-2. Irrespective of age, genotype had no effect on the hyperventilatory response (increase in V̇(E)/V̇(O2)) to MA. At P1-2, nicotine suppressed air V̇(E) and V̇(O2) in both genotypes but did not affect the hyperventilatory response to MA. At P7-8 nicotine suppressed air V̇(E) and V̇(O2) of only α4 KO's but also significantly enhanced V̇(E) during MA (nearly double that of WT; p<0.001). This study has revealed complex effects of α4 nAChR deficiency and prenatal nicotine exposure on ventilatory and metabolic interactions and responses to stress. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Small RNA sequencing-microarray analyses in Parkinson leukocytes reveal deep brain stimulation-induced and splicing changes that classify brain region transcriptomes

    Directory of Open Access Journals (Sweden)

    Lilach eSoreq

    2013-05-01

    Full Text Available MicroRNAs (miRNAs are key post transcriptional regulators of their multiple target genes. However, the detailed profile of miRNA expression in Parkinson's disease, the second most common neurodegenerative disease worldwide and the first motor disorder has not been charted yet. Here, we report comprehensive miRNA profiling by next-generation small-RNA sequencing, combined with targets inspection by splice-junction and exon arrays interrogating leukocyte RNA in Parkinson’s disease patients before and after deep brain stimulation (DBS treatment and of matched healthy control volunteers (HC. RNA-Seq analysis identified 254 miRNAs and 79 passenger strand forms as expressed in blood leukocytes, 16 of which were modified in patients pre treatment as compared to HC. 11 miRNAs were modified following brain stimulation, 5 of which were changed inversely to the disease induced changes. Stimulation cessation further induced changes in 11 miRNAs. Transcript isoform abundance analysis yielded 332 changed isoforms in patients compared to HC, which classified brain transcriptomes of 47 PD and control independent microarrays. Functional enrichment analysis highlighted mitochondrion organization. DBS induced 155 splice changes, enriched in ubiquitin homeostasis. Cellular composition analysis revealed immune cell activity pre and post treatment. Overall, 217 disease and 74 treatment alternative isoforms were predictably targeted by modified miRNAs within both 3’ and 5’ untranslated ends and coding sequence sites. The stimulation-induced network sustained 4 miRNAs and 7 transcripts of the disease network. We believe that the presented dynamic networks provide a novel avenue for identifying disease and treatment-related therapeutic targets. Furthermore, the identification of these networks is a major step forward in the road for understanding the molecular basis for neurological and neurodegenerative diseases and assessment of the impact of brain stimulation

  6. Subacute administration of fluoxetine prevents short-term brain hypometabolism and reduces brain damage markers induced by the lithium-pilocarpine model of epilepsy in rats.

    Science.gov (United States)

    Shiha, Ahmed Anis; de Cristóbal, Javier; Delgado, Mercedes; Fernández de la Rosa, Rubén; Bascuñana, Pablo; Pozo, Miguel A; García-García, Luis

    2015-02-01

    The role of serotonin (5-hydroxytryptamine; 5-HT) in epileptogenesis still remains controversial. In this regard, it has been reported that serotonergic drugs can alter epileptogenesis in opposite ways. The main objective of this work was to investigate the effect of the selective 5-HT selective reuptake inhibitor (SSRI) fluoxetine administered subacutely (10mg/kg/day×7 days) on the eventual metabolic impairment induced by the lithium-pilocarpine model of epilepsy in rats. In vivo 2-deoxy-2-[(18)F]fluoro-d-glucose ([(18)F] FDG) positron emission tomography (PET) was performed to assess the brain glucose metabolic activity on days 3 and 30 after the insult. In addition, at the end of the experiment (day 33), several histochemical and neurochemical assessments were performed for checking the neuronal functioning and integrity. Three days after the insult, a marked reduction of [(18)F] FDG uptake (about 30% according to the brain region) was found in all brain areas studied. When evaluated on day 30, although a hypometabolism tendency was observed, no statistically significant reduction was present in any region analyzed. In addition, lithium-pilocarpine administration was associated with medium-term hippocampal and cortical damage, since it induced neurodegeneration, glial activation and augmented caspase-9 expression. Regarding the effect of fluoxetine, subacute treatment with this SSRI did not significantly reduce the mortality rate observed after pilocarpine-induced seizures. However, fluoxetine did prevent not only the short-term metabolic impairment, but also the aforementioned signs of neuronal damage in surviving animals to lithium-pilocarpine protocol. Finally, fluoxetine increased the density of GABAA receptor both at the level of the dentate gyrus and CA1-CA2 regions in pilocarpine-treated animals. Overall, our data suggest a protective role for fluoxetine against pilocarpine-induced brain damage. Moreover, this action may be associated with an increase of

  7. Small RNA sequencing-microarray analyses in Parkinson leukocytes reveal deep brain stimulation-induced splicing changes that classify brain region transcriptomes

    Science.gov (United States)

    Soreq, Lilach; Salomonis, Nathan; Bronstein, Michal; Greenberg, David S.; Israel, Zvi; Bergman, Hagai; Soreq, Hermona

    2013-01-01

    MicroRNAs (miRNAs) are key post transcriptional regulators of their multiple target genes. However, the detailed profile of miRNA expression in Parkinson's disease, the second most common neurodegenerative disease worldwide and the first motor disorder has not been charted yet. Here, we report comprehensive miRNA profiling by next-generation small-RNA sequencing, combined with targets inspection by splice-junction and exon arrays interrogating leukocyte RNA in Parkinson's disease patients before and after deep brain stimulation (DBS) treatment and of matched healthy control volunteers (HC). RNA-Seq analysis identified 254 miRNAs and 79 passenger strand forms as expressed in blood leukocytes, 16 of which were modified in patients pre-treatment as compared to HC. 11 miRNAs were modified following brain stimulation 5 of which were changed inversely to the disease induced changes. Stimulation cessation further induced changes in 11 miRNAs. Transcript isoform abundance analysis yielded 332 changed isoforms in patients compared to HC, which classified brain transcriptomes of 47 PD and control independent microarrays. Functional enrichment analysis highlighted mitochondrion organization. DBS induced 155 splice changes, enriched in ubiquitin homeostasis. Cellular composition analysis revealed immune cell activity pre and post treatment. Overall, 217 disease and 74 treatment alternative isoforms were predictably targeted by modified miRNAs within both 3′ and 5′ untranslated ends and coding sequence sites. The stimulation-induced network sustained 4 miRNAs and 7 transcripts of the disease network. We believe that the presented dynamic networks provide a novel avenue for identifying disease and treatment-related therapeutic targets. Furthermore, the identification of these networks is a major step forward in the road for understanding the molecular basis for neurological and neurodegenerative diseases and assessment of the impact of brain stimulation on human diseases

  8. Dexmedetomidine-mediated neuroprotection against sevoflurane-induced neurotoxicity extends to several brain regions in neonatal rats.

    Science.gov (United States)

    Perez-Zoghbi, J F; Zhu, W; Grafe, M R; Brambrink, A M

    2017-09-01

    Exposure of infant animals to clinically used anaesthetics is associated with acute structural brain abnormalities and development functional alterations. The α 2 -adrenoceptor agonist dexmedetomidine (DEX) induces sedation, analgesia, and provides neuroprotection in experimental brain injury models. However, it is unknown whether DEX also affords protection in the developing brain against anaesthesia using sevoflurane (SEVO), which is commonly used in paediatric anaesthesia. Infant rats were exposed on postnatal day seven for six h to 2.5% SEVO and were given i.p. injections of saline or DEX (1-50 µg kg -1 ) three times during the exposure. Level of anaesthesia, respiratory rates, and arterial blood gasses were assessed for each animal. Apoptosis was determined in brain slices immunostained for activated caspase-3 (AC-3) using a computerised approach. SEVO alone induced a surgical plane of anaesthesia, and all animals survived the study. SEVO induced an approximately 10-fold increase in AC-3 positive cells in several cortical and subcortical brain regions compared with untreated control animals. Co-administration of DEX 1 µg kg -1 with SEVO significantly reduced apoptosis in all brain areas, affording the highest protection in the thalamus (84% reduction) and lowest in the hippocampus and cortical areas (∼50% reduction). DEX 5-25 µg kg -1 plus SEVO dose-dependently increased infant rat mortality. SEVO anaesthesia induced widespread apoptosis in infant rat brain. Co-administration of DEX (1 µg kg -1 ) provided significant protection, whereas DEX (5 µg kg -1 or higher) plus SEVO increased mortality. Our findings suggest that DEX could be an attractive therapeutic for future studies investigating its neuroprotective potential in a translational animal model.

  9. MDMA, Methylone, and MDPV: Drug-Induced Brain Hyperthermia and Its Modulation by Activity State and Environment.

    Science.gov (United States)

    Kiyatkin, Eugene A; Ren, Suelynn E

    2017-01-01

    Psychomotor stimulants are frequently used by humans to intensify the subjective experience of different types of social interactions. Since psychomotor stimulants enhance metabolism and increase body temperatures, their use under conditions of physiological activation and in warm humid environments could result in pathological hyperthermia, a life-threatening symptom of acute drug intoxication. Here, we will describe the brain hyperthermic effects of MDMA, MDPV, and methylone, three structurally related recreational drugs commonly used by young adults during raves and other forms of social gatherings. After a short introduction on brain temperature and basic mechanisms underlying its physiological fluctuations, we will consider how MDMA, MDPV, and methylone affect brain and body temperatures in awake freely moving rats. Here, we will discuss the role of drug-induced heat production in the brain due to metabolic brain activation and diminished heat dissipation due to peripheral vasoconstriction as two primary contributors to the hyperthermic effects of these drugs. Then, we will consider how the hyperthermic effects of these drugs are modulated under conditions that model human drug use (social interaction and warm ambient temperature). Since social interaction results in brain and body heat production, coupled with skin vasoconstriction that impairs heat loss to the external environment, these physiological changes interact with drug-induced changes in heat production and loss, resulting in distinct changes in the hyperthermic effects of each tested drug. Finally, we present our recent data, in which we compared the efficacy of different pharmacological strategies for reversing MDMA-induced hyperthermia in both the brain and body. Specifically, we demonstrate increased efficacy of the centrally acting atypical neuroleptic compound clozapine over the peripherally acting vasodilator drug, carvedilol. These data could be important for understanding the potential

  10. Hyperthermia-induced disruption of functional connectivity in the human brain network.

    Directory of Open Access Journals (Sweden)

    Gang Sun

    Full Text Available BACKGROUND: Passive hyperthermia is a potential risk factor to human cognitive performance and work behavior in many extreme work environments. Previous studies have demonstrated significant effects of passive hyperthermia on human cognitive performance and work behavior. However, there is a lack of a clear understanding of the exact affected brain regions and inter-regional connectivities. METHODOLOGY AND PRINCIPAL FINDINGS: We simulated 1 hour environmental heat exposure to thirty-six participants under two environmental temperature conditions (25 °C and 50 °C, and collected resting-state functional brain activity. The functional connectivities with a preselected region of interest (ROI in the posterior cingulate cortex and precuneus (PCC/PCu, furthermore, inter-regional connectivities throughout the entire brain using a prior Anatomical Automatic Labeling (AAL atlas were calculated. We identified decreased correlations of a set of regions with the PCC/PCu, including the medial orbitofrontal cortex (mOFC and bilateral medial temporal cortex, as well as increased correlations with the partial orbitofrontal cortex particularly in the bilateral orbital superior frontal gyrus. Compared with the normal control (NC group, the hyperthermia (HT group showed 65 disturbed functional connectivities with 50 of them being decreased and 15 of them being increased. While the decreased correlations mainly involved with the mOFC, temporal lobe and occipital lobe, increased correlations were mainly located within the limbic system. In consideration of physiological system changes, we explored the correlations of the number of significantly altered inter-regional connectivities with differential rectal temperatures and weight loss, but failed to obtain significant correlations. More importantly, during the attention network test (ANT we found that the number of significantly altered functional connectivities was positively correlated with an increase in

  11. Prereader to beginning reader: changes induced by reading acquisition in print and speech brain networks.

    Science.gov (United States)

    Chyl, Katarzyna; Kossowski, Bartosz; Dębska, Agnieszka; Łuniewska, Magdalena; Banaszkiewicz, Anna; Żelechowska, Agata; Frost, Stephen J; Mencl, William Einar; Wypych, Marek; Marchewka, Artur; Pugh, Kenneth R; Jednoróg, Katarzyna

    2018-01-01

    Literacy acquisition is a demanding process that induces significant changes in the brain, especially in the spoken and written language networks. Nevertheless, large-scale paediatric fMRI studies are still limited. We analyzed fMRI data to show how individual differences in reading performance correlate with brain activation for speech and print in 111 children attending kindergarten or first grade and examined group differences between a matched subset of emergent-readers and prereaders. Across the entire cohort, individual differences analysis revealed that reading skill was positively correlated with the magnitude of activation difference between words and symbol strings in left superior temporal, inferior frontal and fusiform gyri. Group comparisons of the matched subset of pre- and emergent-readers showed higher activity for emergent-readers in left inferior frontal, precentral, and postcentral gyri. Individual differences in activation for natural versus vocoded speech were also positively correlated with reading skill, primarily in the left temporal cortex. However, in contrast to studies on adult illiterates, group comparisons revealed higher activity in prereaders compared to readers in the frontal lobes. Print-speech coactivation was observed only in readers and individual differences analyses revealed a positive correlation between convergence and reading skill in the left superior temporal sulcus. These results emphasise that a child's brain undergoes several modifications to both visual and oral language systems in the process of learning to read. They also suggest that print-speech convergence is a hallmark of acquiring literacy. © 2017 Association for Child and Adolescent Mental Health.

  12. Non-invasive brain stimulation of motor cortex induces embodiment when integrated with virtual reality feedback.

    Science.gov (United States)

    Bassolino, M; Franza, M; Bello Ruiz, J; Pinardi, M; Schmidlin, T; Stephan, M A; Solca, M; Serino, A; Blanke, O

    2018-02-20

    Previous evidence highlighted the multisensory-motor origin of embodiment - i.e., the experience of having a body and of being in control of it- and the possibility of experimentally manipulating it. For instance, an illusory feeling of embodiment towards a fake hand can be triggered by providing synchronous visuo-tactile stimulation to the hand of participants and to a fake hand or by asking participants to move their hand and observe a fake hand moving accordingly (rubber hand illusion, RHI). Here we tested whether it is possible to manipulate embodiment not through stimulation of the participant's hand, but by directly tapping into the brain's hand representation via non-invasive brain stimulation. To this aim, we combined transcranial magnetic stimulation (TMS) to activate the hand corticospinal representation with virtual reality (VR) to provide matching (as contrasted to non-matching) visual feedback, mimicking involuntary hand movements evoked by TMS. We show that the illusory embodiment occurred when TMS pulses were temporally matched with VR feedback, but not when TMS was administered outside primary motor cortex, (M1, over the vertex) or when stimulating M1 at a lower intensity (that did not activate peripheral muscles). Behavioral (questionnaires) and neurophysiological (motor-evoked-potentials, TMS-evoked-movements) measures further indicated that embodiment was not explained by stimulation per se, but depended on the temporal coherence between TMS-induced activation of hand corticospinal representation and the virtual bodily feedback. This reveals that non-invasive brain stimulation may replace the application of external tactile hand cues and motor components related to volition, planning, and anticipation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  13. Changes in calcium and iron levels in the brains of rats during kainate induced epilepsy

    Energy Technology Data Exchange (ETDEWEB)

    Ren, M.-Q.; Ong, W.-Y.; Makjanic, Jagoda; Watt, Frank E-mail: phywattf@nus.edu.sg

    1999-09-02

    Epilepsy is a recurrent disorder of cerebral function characterised by sudden brief attacks of altered consciousness, motor activity or sensory phenomena, and affects approximately 1% of the population. Kainic acid injection induces neuronal degeneration in rats, is associated with glial hypertrophy and proliferation in the CA3-CA4 fields of hippocampal complex, and is a model for temporal lobe epilepsy. In this study we have applied Nuclear Microscopy to the investigation of the elemental changes within the hippocampus and the cortex areas of the rat brain following kainate injection. Analyses of unstained freeze dried tissue sections taken at 1 day and 1, 2, 3 and 4 weeks following injection were carried out using the Nuclear Microscopy facility at the Research Centre for Nuclear Microscopy, National University of Singapore. Quantitative analysis and elemental mapping indicates that there are significant changes in the calcium levels and distributions in the hippocampus as early as 1 day following injection. Preliminary results indicate a rapid increase in cellular calcium. High levels of calcium can activate calcium dependent proteins and phospholipases. Activation of phospholipase A{sub 2} can be harmful to surrounding neurons through free radical damage. In addition to observed increases in calcium, there was evidence of increases in iron levels. This is consistent with measurements in other degenerative brain disorders, and may signal a late surge in free radical production.

  14. Human umbilical cord blood cells restore brain damage induced changes in rat somatosensory cortex.

    Directory of Open Access Journals (Sweden)

    Maren Geissler

    Full Text Available Intraperitoneal transplantation of human umbilical cord blood (hUCB cells has been shown to reduce sensorimotor deficits after hypoxic ischemic brain injury in neonatal rats. However, the neuronal correlate of the functional recovery and how such a treatment enforces plastic remodelling at the level of neural processing remains elusive. Here we show by in-vivo recordings that hUCB cells have the capability of ameliorating the injury-related impairment of neural processing in primary somatosensory cortex. Intact cortical processing depends on a delicate balance of inhibitory and excitatory transmission, which is disturbed after injury. We found that the dimensions of cortical maps and receptive fields, which are significantly altered after injury, were largely restored. Additionally, the lesion induced hyperexcitability was no longer observed in hUCB treated animals as indicated by a paired-pulse behaviour resembling that observed in control animals. The beneficial effects on cortical processing were reflected in an almost complete recovery of sensorimotor behaviour. Our results demonstrate that hUCB cells reinstall the way central neurons process information by normalizing inhibitory and excitatory processes. We propose that the intermediate level of cortical processing will become relevant as a new stage to investigate efficacy and mechanisms of cell therapy in the treatment of brain injury.

  15. High resolution mapping of modafinil induced changes in glutamate level in rat brain.

    Directory of Open Access Journals (Sweden)

    Mohammad Haris

    Full Text Available Modafinil is marketed in the United States for the treatment of narcolepsy and daytime somnolence due to shift-work or sleep apnea. Investigations of this drug in the treatment of cocaine and nicotine dependence in addition to disorders of executive function are also underway. Modafinil has been known to increase glutamate levels in rat brain models. Proton magnetic resonance spectroscopy (1HMRS has been commonly used to detect the glutamate (Glu changes in vivo. In this study, we used a recently described glutamate chemical exchange saturation transfer (GluCEST imaging technique to measure Modafinil induced regional Glu changes in rat brain and compared the results with Glu concentration measured by single voxel 1HMRS. No increases in either GluCEST maps or 1HMRS were observed after Modafinil injection over a period of 5 hours. However, a significant increase in GluCEST (19 ± 4.4% was observed 24 hours post Modafinil administration, which is consistent with results from previous biochemical studies. This change was not consistently seen with 1HMRS. GluCEST mapping allows regional cerebral Glu changes to be measured and may provide a useful clinical biomarker of Modafinil effects for the management of patients with sleep disorders and addiction.

  16. Effective analgesic doses of tramadol or tapentadol induce brain, lung and heart toxicity in Wistar rats.

    Science.gov (United States)

    Faria, Juliana; Barbosa, Joana; Leal, Sandra; Afonso, Luís Pedro; Lobo, João; Moreira, Roxana; Queirós, Odília; Carvalho, Félix; Dinis-Oliveira, Ricardo Jorge

    2017-06-15

    Tramadol and tapentadol are extensively prescribed for the treatment of moderate to severe pain. Although these drugs are very effective in pain treatment, the number of intoxications and deaths due to both opioids is increasing, and the underlying toxic mechanisms are not fully understood. The present work aimed to study the potential biochemical and histopathological alterations induced by acute effective (analgesic) doses of tramadol and tapentadol, in Wistar rats. Forty-two male Wistar rats were divided into different groups: a control, administered with normal saline solution, and tramadol- or tapentadol-treated groups (10, 25 or 50mg/kg - typical effective analgesic dose, intermediate and maximum recommended doses, respectively). 24h after intraperitoneal administration, biochemical and oxidative stress analyses were performed in blood, and specimens from brain, lung and heart were taken for histopathological and oxidative stress studies. Both drugs caused an increase in the AST/ALT ratio, in LDH, CK and CK-MB activities in serum samples, and an increase in lactate levels in serum and brain samples. Oxidative damage, namely protein oxidation, was found in heart and lung tissues. In histological analyses, tramadol and tapentadol were found to cause alterations in cell morphology, inflammatory cell infiltrates and cell death in all tissues under study, although tapentadol caused more damage than tramadol. Our results confirmed the risks of tramadol exposure, and demonstrated the higher risk of tapentadol, especially at high doses. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Oscillatory brain activity related to control mechanisms during laboratory-induced reactive aggression

    Directory of Open Access Journals (Sweden)

    Ulrike M Krämer

    2009-11-01

    Full Text Available Aggressive behavior is a common reaction in humans after an interpersonal provocation, but little is known about the underlying brain mechanisms. The present study analyzed oscillatory brain activity while participants were involved in an aggressive interaction to examine the neural processes subserving the associated decision and evaluation processes. Participants were selected from a larger sample because of their high scores in trait aggressiveness. We used a competitive reaction time task that induces aggressive behavior through provocation. Each trial is separated in a decision phase, during which the punishment for the opponent is set, and an outcome phase, during which the actual punishment is applied or received. We observed provocation-related differences during the decision phase in the theta band which differed depending on participants’ aggressive behavior: High provocation was associated with an increased frontal theta response in participants refraining from retaliation, but with reduced theta power in those who got back to the opponent. Moreover, more aggressive decisions after being punished were associated with a decrease of frontal theta power. Non-aggressive and aggressive participants differed also in their outcome-related response: Being punished led to an increased frontal theta power compared to win trials in the latter only, pointing to differences in evaluation processes associated with their different behavioral reactions. The data thus support previous evidence for a role of prefrontal areas in the control of reactive aggression and extend behavioral studies on associations between aggression or violence and impaired prefrontal functions.

  18. Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers.

    Science.gov (United States)

    Lawrence, Catherine B; Snape, Amelie C; Baudoin, Florence M-H; Luckman, Simon M

    2002-01-01

    Ghrelin was recently identified as the endogenous ligand for the GH secretagogue (GHS) receptor. Like the synthetic GHSs [e.g. GH-releasing peptide-6 (GHRP-6)], ghrelin stimulates feeding and increases body weight in rats. The aim of this study was to identify brain regions that are activated by GHSs and determine whether the responses observed were secondary to food intake. In addition, possible mediators of GHS actions were examined. Intracerebroventricular (icv) injection of ghrelin or GHRP-6 into rats significantly stimulated food intake and transiently reduced core body temperature. The effect of both ghrelin and GHRP-6 on food intake was blocked by preadministration of a Y1 NPY receptor antagonist (BIBO3304). Using c-Fos immunohistochemistry, we demonstrated that icv ghrelin or GHRP-6 activated several hypothalamic brain regions, including the arcuate nucleus, paraventricular nucleus, dorsomedial nucleus, lateral hypothalamus, and two regions of the brainstem, the nucleus of the tractus solitarius and the area postrema. The cell activation induced by GHRP-6 was independent of food intake, as the same pattern and extent of c-Fos expression were observed in animals that were denied access to food following treatment. Finally, double immunohistochemistry indicated that orexin-containing, but not melanin-concentrating hormone-containing, neurons in the lateral hypothalamus were activated significantly by central administration of GHRP-6.

  19. Changes in calcium and iron levels in the brains of rats during kainate induced epilepsy

    Science.gov (United States)

    Ren, Min-Qin; Ong, Wei-Yi; Makjanic, Jagoda; Watt, Frank

    1999-10-01

    Epilepsy is a recurrent disorder of cerebral function characterised by sudden brief attacks of altered consciousness, motor activity or sensory phenomena, and affects approximately 1% of the population. Kainic acid injection induces neuronal degeneration in rats, is associated with glial hypertrophy and proliferation in the CA3-CA4 fields of hippocampal complex, and is a model for temporal lobe epilepsy. In this study we have applied Nuclear Microscopy to the investigation of the elemental changes within the hippocampus and the cortex areas of the rat brain following kainate injection. Analyses of unstained freeze dried tissue sections taken at 1 day and 1, 2, 3 and 4 weeks following injection were carried out using the Nuclear Microscopy facility at the Research Centre for Nuclear Microscopy, National University of Singapore. Quantitative analysis and elemental mapping indicates that there are significant changes in the calcium levels and distributions in the hippocampus as early as 1 day following injection. Preliminary results indicate a rapid increase in cellular calcium. High levels of calcium can activate calcium dependent proteins and phospholipases. Activation of phospholipase A 2 can be harmful to surrounding neurons through free radical damage. In addition to observed increases in calcium, there was evidence of increases in iron levels. This is consistent with measurements in other degenerative brain disorders, and may signal a late surge in free radical production.

  20. Fornix deep brain stimulation induced long-term spatial memory independent of hippocampal neurogenesis.

    Science.gov (United States)

    Hescham, Sarah; Temel, Yasin; Schipper, Sandra; Lagiere, Mélanie; Schönfeld, Lisa-Maria; Blokland, Arjan; Jahanshahi, Ali

    2017-03-01

    Deep brain stimulation (DBS) is an established symptomatic treatment modality for movement disorders and constitutes an emerging therapeutic approach for the treatment of memory impairment. In line with this, fornix DBS has shown to ameliorate cognitive decline associated with dementia. Nonetheless, mechanisms mediating clinical effects in demented patients or patients with other neurological disorders are largely unknown. There is evidence that DBS is able to modulate neurophysiological activity in targeted brain regions. We therefore hypothesized that DBS might be able to influence cognitive function via activity-dependent regulation of hippocampal neurogenesis. Using stimulation parameters, which were validated to restore memory loss in a previous behavioral study, we here assessed long-term effects of fornix DBS. To do so, we injected the thymidine analog, 5-bromo-2'-deoxyuridine (BrdU), after DBS and perfused the animals 6.5 weeks later. A week prior to perfusion, memory performance was assessed in the water maze. We found that acute stimulation of the fornix improved spatial memory performance in the water maze when the probe trial was performed 1 h after the last training session. However, no evidence for stimulation-induced neurogenesis was found in fornix DBS rats when compared to sham. Our results suggest that fornix DBS improves memory functions independent of hippocampal neurogenesis, possibly through other mechanisms such as synaptic plasticity and acute neurotransmitter release.

  1. Different protocols of treadmill exercise induce distinct neuroplastic effects in rat brain motor areas.

    Science.gov (United States)

    Real, Caroline C; Garcia, Priscila C; Britto, Luiz R G; Pires, Raquel S

    2015-10-22

    A variety of exercise protocols have been used to promote experimental neuroplasticity. However, the plastic brain responses generated by several aspects of training (types, frequency, regimens, duration) remain undetermined. The aim of this study was to compare the plastic changes in the glutamatergic system and synaptic proteins in motor cortex, striatum and cerebellum promoted by two different treadmill exercise regimens. The present study analyzed by immunohistochemistry and Western blotting the expression of the subunits of AMPA receptors (GluA1 and GluA2/3) and synaptic proteins (synapsin I and synaptophysin) in adult male Wistar rat brains. The animals were divided into animals subjected to two different frequencies of aerobic exercise groups and sedentary animals. The exercise groups were: intermittent treadmill exercise (ITE) - animals that exercised 3 times a week (every other day) during four weeks, and continuous treadmill exercise (CTE) - animals that exercised every day during four weeks. Our results reveal that different protocols of treadmill exercise were able to promote distinct synaptic reorganization processes among the exercised groups. In general, the intermittent exercise regimen induced a higher expression of presynaptic proteins, whereas the continuous exercise regimen increased postsynaptic GluA1 and GluA2/3 receptors. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. High resolution mapping of modafinil induced changes in glutamate level in rat brain.

    Science.gov (United States)

    Haris, Mohammad; Singh, Anup; Cai, Kejia; Nath, Kavindra; Verma, Gaurav; Nanga, Ravi Prakash Reddy; Hariharan, Hari; Detre, John A; Epperson, Neill; Reddy, Ravinder

    2014-01-01

    Modafinil is marketed in the United States for the treatment of narcolepsy and daytime somnolence due to shift-work or sleep apnea. Investigations of this drug in the treatment of cocaine and nicotine dependence in addition to disorders of executive function are also underway. Modafinil has been known to increase glutamate levels in rat brain models. Proton magnetic resonance spectroscopy (1HMRS) has been commonly used to detect the glutamate (Glu) changes in vivo. In this study, we used a recently described glutamate chemical exchange saturation transfer (GluCEST) imaging technique to measure Modafinil induced regional Glu changes in rat brain and compared the results with Glu concentration measured by single voxel 1HMRS. No increases in either GluCEST maps or 1HMRS were observed after Modafinil injection over a period of 5 hours. However, a significant increase in GluCEST (19 ± 4.4%) was observed 24 hours post Modafinil administration, which is consistent with results from previous biochemical studies. This change was not consistently seen with 1HMRS. GluCEST mapping allows regional cerebral Glu changes to be measured and may provide a useful clinical biomarker of Modafinil effects for the management of patients with sleep disorders and addiction.

  3. Constraint-induced movement therapy for children with acquired brain injury

    DEFF Research Database (Denmark)

    Pedersen, Kristina Schmidt; Pallesen, Hanne; Kristensen, Hanne Kaae

    2016-01-01

    An estimated 125–137 Danish children with acquired brain injury (ABI) require rehabilitation annually, 30–40 of these at a highly specialized level. Constraint-induced movement therapy (CIMT) has shown significant effects in increasing function in children with cerebral palsy. More knowledge of how...... CIMT can be adapted for the rehabilitation of children with ABI is needed. The primary purpose of the study was to generate new knowledge about the pedagogical initiatives and frameworks involved in children’s participation in and activities during CIMT. Four children with ABI participated in the 60 h...... intervention. Data generation consisted of qualitative research through participant observations and healthcare professional evaluations. A didactical approach with individualization and a solid structural framework enhanced the possibility of securing the children’s motivation for and participation...

  4. Constraint-induced movement therapy for children with acquired brain injury

    DEFF Research Database (Denmark)

    Schmidt Pedersen, Kristina; Pallesen, H.; Kristensen, H. K.

    2016-01-01

    An estimated 125-137 Danish children with acquired brain injury (ABI) require rehabilitation annually, 30-40 of these at a highly specialized level. Constraint-induced movement therapy (CIMT) has shown significant effects in increasing function in children with cerebral palsy. More knowledge of how...... CIMT can be adapted for the rehabilitation of children with ABI is needed. The primary purpose of the study was to generate new knowledge about the pedagogical initiatives and frameworks involved in childrens participation in and activities during CIMT. Four children with ABI participated in the 60 h...... intervention. Data generation consisted of qualitative research through participant observations and healthcare professional evaluations. A didactical approach with individualization and a solid structural framework enhanced the possibility of securing the childrens motivation for and participation...

  5. Downregulated Brain-Derived Neurotrophic Factor-Induced Oxidative Stress in the Pathophysiology of Diabetic Retinopathy.

    Science.gov (United States)

    Behl, Tapan; Kotwani, Anita

    2017-04-01

    Brain-derived neurotrophic factor (BDNF), a member of neurotrophin growth factor family, physiologically mediates induction of neurogenesis and neuronal differentiation, promotes neuronal growth and survival and maintains synaptic plasticity and neuronal interconnections. Unlike the central nervous system, its secretion in the peripheral nervous system occurs in an activity-dependent manner. BDNF improves neuronal mortality, growth, differentiation and maintenance. It also provides neuroprotection against several noxious stimuli, thereby preventing neuronal damage during pathologic conditions. However, in diabetic retinopathy (a neuromicrovascular disorder involving immense neuronal degeneration), BDNF fails to provide enough neuroprotection against oxidative stress-induced retinal neuronal apoptosis. This review describes the prime reasons for the downregulation of BDNF-mediated neuroprotective actions during hyperglycemia, which renders retinal neurons vulnerable to damaging stimuli, leading to diabetic retinopathy. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  6. [Permeability of blood-brain barrier oxygen-glucose deprivation induced by tetramethylpyrazine-puerarin in vitro].

    Science.gov (United States)

    Li, Jinhui; Che, Lingyan; Wang, Yu; Zhang, Yuyan; Wan, Haitong; Yang, Jiehong

    2010-10-01

    To explore permeability of artificial blood-brain barrier (aBBB) by oxygen-glucose deprivation combined (OGD)-induced using tetramethylpyrazine combined with puerarin in vitro. Rats were divided into normal control group, model group, tetramethylpyrazine group, puerarin group, tetramethylpyrazine-puerarin group and nimodipine group. Culture rat brain microvascular endothelial cells and astrocytes in vitro and build the OGD-induced aBBB damage model. Evaluate aBBB damage characteristics by TEER, gamma-GT, AKP and LDH. Determine contents of tetramethylpyrazine, puerarin, nimodipine and calculate drug permeating concentration of OGD-induced aBBB model by HPLC. Compared with the model, the level of TEER was lower than the control group with significant difference (P permeability of the OGD-induced aBBB.

  7. Dimethyl fumarate attenuates neuroinflammation and neurobehavioral deficits induced by experimental traumatic brain injury.

    Science.gov (United States)

    Casili, Giovanna; Campolo, Michela; Paterniti, Irene; Lanza, Marika; Filippone, Alessia; Cuzzocrea, Salvatore; Esposito, Emanuela

    2018-01-23

    TBI is a serious neuropathology that causes secondary injury mechanisms, including dynamic interplay between ischemic, inflammatory and cytotoxic processes. Fumaric acid esters (FAEs) showed beneficial effects in preclinical models of neuroinflammation and toxic oxidative stress, so the aim of the present work was to evaluate the potential beneficial effects of dimethyl fumarate (DMF), the most pharmacologically effective molecules among the FAEs, in a mouse model of TBI induced by controlled cortical impact (CCI). Mice were orally administered with DMF at the doses of 1, 10 and 30 mg/Kg, 1h and 4h after CCI. We performed histological, molecular, and immunohistochemistry analysis on the traumatic penumbral areas of the brain 24 hours after CCI. DMF treatment notably reduced histological damage and behavioral impairments, reducing neurodegeneration as evidenced by assessments of neuronal loss, Fluoro-jade C and TUNEL staining; also, treatment with DMF blocked apoptosis process increasing B-cell lymphoma 2 (Bcl-2) expression in injured cortex. Furthermore, DMF treatment up-regulated antioxidant Kelch-like ECH-associated protein 1/ Nuclear factor erythroid 2- related factor (Keap-1/Nrf-2) pathway, inducing activation of manganese superoxide dismutase (Mn-SOD) and heme-oxygenase-1 (HO-1) and reducing 4-hydroxy-2-nonenal (4-HNE) staining. Also, regulating NF-κB pathway, DMF treatment decreased the severity of inflammation through a modulation of neuronal nitrite oxide synthase (nNOS), interleukin 1 (Il-1β), tumor necrosis factor (TNF-α), cyclooxygenase 2 (COX-2) and myeloperoxidase (MPO) activity, reducing ionized calcium-binding adapter molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) expression. Our results support the thesis that DMF may be an effective neuroprotectant after brain trauma and warrants further study.

  8. Dietary supplementation with decaffeinated green coffee improves diet-induced insulin resistance and brain energy metabolism in mice.

    Science.gov (United States)

    Ho, Lap; Varghese, Merina; Wang, Jun; Zhao, Wei; Chen, Fei; Knable, Lindsay Alexis; Ferruzzi, Mario; Pasinetti, Giulio M

    2012-01-01

    There is accumulating evidence that coffee consumption may reduce risk for type 2 diabetes, a known risk factor for Alzheimer's and other neurological diseases. Coffee consumption is also associated with reduced risk for Alzheimer's disease and non-Alzheimer's dementias. However, preventive and therapeutic development of coffee is complicated by the cardiovascular side effects of caffeine intake. As coffee is also a rich source of chlorogenic acids and many bioactive compounds other than caffeine, we hypothesized that decaffeinated coffee drinks may exert beneficial effects on the brain. We have investigated whether dietary supplementation with a standardized decaffeinated green coffee preparation, Svetol®, might modulate diet-induced insulin resistance and brain energy metabolism dysfunction in a high-fat diet mouse model. As expected, dietary supplementation with Svetol® significantly attenuated the development of high-fat diet-induced deficits in glucose-tolerance response. We have also found that Svetol®) treatment improved brain mitochondrial energy metabolism as determined by oxygen consumption rate. Consistent with this evidence, follow-up gene expression profiling with Agilent whole-genome microarray revealed that the decaffeinated coffee treatment modulated a number of genes in the brain that are implicated in cellular energy metabolism. Our evidence is the first demonstration that dietary supplementation with a decaffeinated green coffee preparation may beneficially influence the brain, in particular promoting brain energy metabolic processes.

  9. Obesity-induced hepatic steatosis is mediated by endoplasmic reticulum stress in the subfornical organ of the brain.

    Science.gov (United States)

    Horwath, Julie A; Hurr, Chansol; Butler, Scott D; Guruju, Mallikarjun; Cassell, Martin D; Mark, Allyn L; Davisson, Robin L; Young, Colin N

    2017-04-20

    Nonalcoholic fatty liver disease (NAFLD), characterized by an excess accumulation of hepatic triglycerides, is a growing health epidemic. While ER stress in the liver has been implicated in the development of NAFLD, the role of brain ER stress - which is emerging as a key contributor to a number of chronic diseases including obesity - in NAFLD remains unclear. These studies reveal that chemical induction of ER stress in the brain caused hepatomegaly and hepatic steatosis in mice. Conversely, pharmacological reductions in brain ER stress in diet-induced obese mice rescued NAFLD independent of body weight, food intake, and adiposity. Evaluation of brain regions involved revealed robust activation of ER stress biomarkers and ER ultrastructural abnormalities in the circumventricular subfornical organ (SFO), a nucleus situated outside of the blood-brain-barrier, in response to high-fat diet. Targeted reductions in SFO-ER stress in obese mice via SFO-specific supplementation of the ER chaperone 78-kDa glucose-regulated protein ameliorated hepatomegaly and hepatic steatosis without altering body weight, food intake, adiposity, or obesity-induced hypertension. Overall, these findings indicate a novel role for brain ER stress, notably within the SFO, in the pathogenesis of NAFLD.

  10. Neck Flexion Induces Larger Deformation of the Brain Than Extension at a Rotational Acceleration, Closed Head Trauma

    Directory of Open Access Journals (Sweden)

    Hans-Arne Hansson

    2014-01-01

    Full Text Available A closed head trauma induces incompletely characterized temporary movement and deformation of the brain, contributing to the primary traumatic brain injury. We used the pressure patterns recorded with light-operated miniature sensors in anaesthetized adult rabbits exposed to a sagittal plane rotational acceleration of the head, lasting 1 ms, as a measure of brain deformation. Two exposure levels were used and scaled to correspond to force levels reported to cause mild and moderate diffuse injury in an adult man, respectively. Flexion induced transient, strong, extended, and predominantly negative pressures while extension generated a short positive pressure peak followed by a minor negative peak. Low level flexion caused as strong, extended negative pressures as did high level extension. Time differences were demonstrated between the deformation of the cerebrum, brainstem, and cerebellum. Available X-ray and MRI techniques do not have as high time resolution as pressure recordings in demonstrating complex, sequential compression and stretching of the brain during a trauma. The exposure to flexion caused more protracted and extensive deformation of the brain than extension, in agreement with a published histopathological report. The severity and extent of the brain deformation generated at a head trauma thus related to the direction at equal force.

  11. Withania somnifera (Ashwagandha) in neurobehavioural disorders induced by brain oxidative stress in rodents: a systematic review and meta-analysis.

    Science.gov (United States)

    Durg, Sharanbasappa; Dhadde, Shivsharan B; Vandal, Ravichandra; Shivakumar, Badamaranahalli S; Charan, Chabbanahalli S

    2015-07-01

    Withania somnifera has been in use for several thousand years in Ayurveda to treat various neurological disorders. There is, however, not much scientific data on its protective role in neuronal pathology specifically against brain oxidative stress. Hence, an attempt is made in this work for systematic review and meta-analysis of W. somnifera on neurobehavioural disorders induced by brain oxidative stress in rodents. A systematic search of the effect of W. somnifera on brain oxidative stress-induced neuronal pathology was performed using electronic databases. The systematic review was performed on neurobehavioural parameters, whereas meta-analysis of W. somnifera effect was done on oxidative stress markers (superoxide dismutase, catalase, glutathione peroxidase, glutathione and lipid peroxidation), nitrite, protein carbonyl, AchE, ChAT and Ach of rodent brain. Data were analysed using Review Manager Software. Twenty-eight studies were selected based upon the inclusion and exclusion criteria. W. somnifera appreciably inhibited the neurological abnormalities due to oxidative stress in rodent brain produced by different physical and chemical stimuli. W. somnifera also significantly restored the altered oxidative and other stress markers in different parts of rodent brain. The systematic review provides scientific evidence for the traditional claim of W. somnifera use in different neurological aliments. However, future clinical trials are mandated to establish the therapeutic efficacy and safety in human beings. © 2015 Royal Pharmaceutical Society.

  12. Traumatic Brain Injury Induces Genome-Wide Transcriptomic, Methylomic, and Network Perturbations in Brain and Blood Predicting Neurological Disorders

    Directory of Open Access Journals (Sweden)

    Qingying Meng

    2017-02-01

    Full Text Available The complexity of the traumatic brain injury (TBI pathology, particularly concussive injury, is a serious obstacle for diagnosis, treatment, and long-term prognosis. Here we utilize modern systems biology in a rodent model of concussive injury to gain a thorough view of the impact of TBI on fundamental aspects of gene regulation, which have the potential to drive or alter the course of the TBI pathology. TBI perturbed epigenomic programming, transcriptional activities (expression level and alternative splicing, and the organization of genes in networks centered around genes such as Anax2, Ogn, and Fmod. Transcriptomic signatures in the hippocampus are involved in neuronal signaling, metabolism, inflammation, and blood function, and they overlap with those in leukocytes from peripheral blood. The homology between genomic signatures from blood and brain elicited by TBI provides proof of concept information for development of biomarkers of TBI based on composite genomic patterns. By intersecting with human genome-wide association studies, many TBI signature genes and network regulators identified in our rodent model were causally associated with brain disorders with relevant link to TBI. The overall results show that concussive brain injury reprograms genes which could lead to predisposition to neurological and psychiatric disorders, and that genomic information from peripheral leukocytes has the potential to predict TBI pathogenesis in the brain.

  13. Blood-Brain Barrier Disruption Induced by Chronic Sleep Loss: Low-Grade Inflammation May Be the Link

    Directory of Open Access Journals (Sweden)

    G. Hurtado-Alvarado

    2016-01-01

    Full Text Available Sleep is a vital phenomenon related to immunomodulation at the central and peripheral level. Sleep deficient in duration and/or quality is a common problem in the modern society and is considered a risk factor to develop neurodegenerative diseases. Sleep loss in rodents induces blood-brain barrier disruption and the underlying mechanism is still unknown. Several reports indicate that sleep loss induces a systemic low-grade inflammation characterized by the release of several molecules, such as cytokines, chemokines, and acute-phase proteins; all of them may promote changes in cellular components of the blood-brain barrier, particularly on brain endothelial cells. In the present review we discuss the role of inflammatory mediators that increase during sleep loss and their association with general disturbances in peripheral endothelium and epithelium and how those inflammatory mediators may alter the blood-brain barrier. Finally, this manuscript proposes a hypothetical mechanism by which sleep loss may induce blood-brain barrier disruption, emphasizing the regulatory effect of inflammatory molecules on tight junction proteins.

  14. Blood-Brain Barrier Disruption Induced by Chronic Sleep Loss: Low-Grade Inflammation May Be the Link.

    Science.gov (United States)

    Hurtado-Alvarado, G; Domínguez-Salazar, E; Pavon, L; Velázquez-Moctezuma, J; Gómez-González, B

    2016-01-01

    Sleep is a vital phenomenon related to immunomodulation at the central and peripheral level. Sleep deficient in duration and/or quality is a common problem in the modern society and is considered a risk factor to develop neurodegenerative diseases. Sleep loss in rodents induces blood-brain barrier disruption and the underlying mechanism is still unknown. Several reports indicate that sleep loss induces a systemic low-grade inflammation characterized by the release of several molecules, such as cytokines, chemokines, and acute-phase proteins; all of them may promote changes in cellular components of the blood-brain barrier, particularly on brain endothelial cells. In the present review we discuss the role of inflammatory mediators that increase during sleep loss and their association with general disturbances in peripheral endothelium and epithelium and how those inflammatory mediators may alter the blood-brain barrier. Finally, this manuscript proposes a hypothetical mechanism by which sleep loss may induce blood-brain barrier disruption, emphasizing the regulatory effect of inflammatory molecules on tight junction proteins.

  15. Fatty acid–induced gut-brain signaling attenuates neural and behavioral effects of sad emotion in humans

    OpenAIRE

    Van Oudenhove, Lukas; Mckie, Shane; Lassman, Daniel; Uddin, Bilal; Paine, Peter; Coen, Steven; Gregory, Lloyd; Tack, Jan; Aziz, Qasim

    2011-01-01

    Although a relationship between emotional state and feeding behavior is known to exist, the interactions between signaling initiated by stimuli in the gut and exteroceptively generated emotions remain incompletely understood. Here, we investigated the interaction between nutrient-induced gut-brain signaling and sad emotion induced by musical and visual cues at the behavioral and neural level in healthy nonobese subjects undergoing functional magnetic resonance imaging. Subjects received an in...

  16. Task-induced frequency modulation features for brain-computer interfacing.

    Science.gov (United States)

    Jayaram, Vinay; Hohmann, Matthias; Just, Jennifer; Schölkopf, Bernhard; Grosse-Wentrup, Moritz

    2017-10-01

    Task-induced amplitude modulation of neural oscillations is routinely used in brain-computer interfaces (BCIs) for decoding subjects' intents, and underlies some of the most robust and common methods in the field, such as common spatial patterns and Riemannian geometry. While there has been some interest in phase-related features for classification, both techniques usually presuppose that the frequencies of neural oscillations remain stable across various tasks. We investigate here whether features based on task-induced modulation of the frequency of neural oscillations enable decoding of subjects' intents with an accuracy comparable to task-induced amplitude modulation. We compare cross-validated classification accuracies using the amplitude and frequency modulated features, as well as a joint feature space, across subjects in various paradigms and pre-processing conditions. We show results with a motor imagery task, a cognitive task, and also preliminary results in patients with amyotrophic lateral sclerosis (ALS), as well as using common spatial patterns and Laplacian filtering. The frequency features alone do not significantly out-perform traditional amplitude modulation features, and in some cases perform significantly worse. However, across both tasks and pre-processing in healthy subjects the joint space significantly out-performs either the frequency or amplitude features alone. This result only does not hold for ALS patients, for whom the dataset is of insufficient size to draw any statistically significant conclusions. Task-induced frequency modulation is robust and straight forward to compute, and increases performance when added to standard amplitude modulation features across paradigms. This allows more information to be extracted from the EEG signal cheaply and can be used throughout the field of BCIs.

  17. Task-induced frequency modulation features for brain-computer interfacing

    Science.gov (United States)

    Jayaram, Vinay; Hohmann, Matthias; Just, Jennifer; Schölkopf, Bernhard; Grosse-Wentrup, Moritz

    2017-10-01

    Objective. Task-induced amplitude modulation of neural oscillations is routinely used in brain-computer interfaces (BCIs) for decoding subjects’ intents, and underlies some of the most robust and common methods in the field, such as common spatial patterns and Riemannian geometry. While there has been some interest in phase-related features for classification, both techniques usually presuppose that the frequencies of neural oscillations remain stable across various tasks. We investigate here whether features based on task-induced modulation of the frequency of neural oscillations enable decoding of subjects’ intents with an accuracy comparable to task-induced amplitude modulation. Approach. We compare cross-validated classification accuracies using the amplitude and frequency modulated features, as well as a joint feature space, across subjects in various paradigms and pre-processing conditions. We show results with a motor imagery task, a cognitive task, and also preliminary results in patients with amyotrophic lateral sclerosis (ALS), as well as using common spatial patterns and Laplacian filtering. Main results. The frequency features alone do not significantly out-perform traditional amplitude modulation features, and in some cases perform significantly worse. However, across both tasks and pre-processing in healthy subjects the joint space significantly out-performs either the frequency or amplitude features alone. This result only does not hold for ALS patients, for whom the dataset is of insufficient size to draw any statistically significant conclusions. Significance. Task-induced frequency modulation is robust and straight forward to compute, and increases performance when added to standard amplitude modulation features across paradigms. This allows more information to be extracted from the EEG signal cheaply and can be used throughout the field of BCIs.

  18. Relationship Between Non-invasive Brain Stimulation-induced Plasticity and Capacity for Motor Learning.

    Science.gov (United States)

    López-Alonso, Virginia; Cheeran, Binith; Fernández-del-Olmo, Miguel

    2015-01-01

    Cortical plasticity plays a key role in motor learning (ML). Non-invasive brain stimulation (NIBS) paradigms have been used to modulate plasticity in the human motor cortex in order to facilitate ML. However, little is known about the relationship between NIBS-induced plasticity over M1 and ML capacity. NIBS-induced MEP changes are related to ML capacity. 56 subjects participated in three NIBS (paired associative stimulation, anodal transcranial direct current stimulation and intermittent theta-burst stimulation), and in three lab-based ML task (serial reaction time, visuomotor adaptation and sequential visual isometric pinch task) sessions. After clustering the patterns of response to the different NIBS protocols, we compared the ML variables between the different patterns found. We used regression analysis to explore further the relationship between ML capacity and summary measures of the MEPs change. We ran correlations with the "responders" group only. We found no differences in ML variables between clusters. Greater response to NIBS protocols may be predictive of poor performance within certain blocks of the VAT. "Responders" to AtDCS and to iTBS showed significantly faster reaction times than "non-responders." However, the physiological significance of these results is uncertain. MEP changes induced in M1 by PAS, AtDCS and iTBS appear to have little, if any, association with the ML capacity tested with the SRTT, the VAT and the SVIPT. However, cortical excitability changes induced in M1 by AtDCS and iTBS may be related to reaction time and retention of newly acquired skills in certain motor learning tasks. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Arsenic induced blood and brain oxidative stress and its response to some thiol chelators in rats.

    Science.gov (United States)

    Flora, Swaran J S; Bhadauria, Smrati; Pant, Satish C; Dhaked, Ram K

    2005-09-16

    corresponding decline in its substrate i.e. glutathione. Among all the three chelators, MiADMSA showed maximum reduction in the level of ROS in brain. Additionally, administration of MiADMSA was most effective in counteracting arsenic induced inhibition in brain ALAD, SOD and GPx activity. Based on these results and in particular higher metal decorporation from blood and brain, we suggest MiADMSA to be a potential drug of choice for the treatment of chronic arsenic poisoning. However, further studies are required for the choice of appropriate dose, duration of treatment and possible effects on other major organs.

  20. Stereotactic laser induced thermotherapy (LITT): a novel treatment for brain lesions regrowing after radiosurgery.

    Science.gov (United States)

    Torres-Reveron, Juan; Tomasiewicz, Hilarie C; Shetty, Anil; Amankulor, Nduka M; Chiang, Veronica L

    2013-07-01

    Since the inception of radiosurgery, the management of brain metastases has become a common problem for neurosurgeons. Although the use of stereotactic radiosurgery and/or whole brain radiation therapy serves to control the majority of disease burden, patients who survive longer than 6-8 months sometimes face the problem of symptomatic radiographically regrowing lesions with few treatment options. Here we investigate the feasibility of use of MRI-guided stereotactic laser induced thermotherapy (LITT) as a novel treatment option for these lesions. Six patients who had previously undergone gamma knife stereotactic radiosurgery for brain metastases were selected. All patients had an initial favorable response to radiosurgery but subsequently developed regrowth of at least one lesion associated with recurrent edema and progressive neurological symptoms requiring ongoing steroids for symptom control. All lesions were evaluated for craniotomy, but were deemed unresectable due to deep location or patient's comorbidities. Stereotactic biopsies were performed prior to the thermotherapy procedure in all cases. LITT was performed using the Visualase system and follow-up MRI imaging was used to determine treatment response. In all six patients biopsy results were negative for tumor and consistent with adverse radiation effects also known as radiation necrosis. Patients tolerated the procedure well and were discharged from the hospital within 48 h of the procedure. In 4/6 cases there was durable improvement of neurological symptoms until death. In all cases steroids were weaned off within 2 months. One patient died from systemic causes related to his cancer a month after the procedure. One patient had regrowth of the lesion 3 months after the procedure and required re-initiation of steroids and standard craniotomy for surgical resection. There were no complications directly related to the thermocoagulation procedure. Stereotactic laser induced thermotherapy is a feasible

  1. Ischemic conditioning-induced endogenous brain protection: Applications Pre-, Per- or Post-Stroke

    Science.gov (United States)

    Wang, Yuechun; Reis, Cesar; Applegate, Richard; Stier, Gary; Martin, Robert; Zhang, John H.

    2015-01-01

    In the area of brain injury and neurodegenerative diseases, a plethora of experimental and clinical evidence strongly indicates the promise of therapeutically exploiting the endogenous adaptive system at various levels like triggers, mediators and the end-effectors to stimulate and mobilize intrinsic protective capacities against brain injuries. It is believed that ischemic pre- or post-conditioning are actually the strongest known interventions to stimulate the innate neuroprotective mechanism to prevent or reverse neurodegenerative diseases including stoke and traumatic brain injury. Recently, studies showed the effectiveness of ischemic per-conditioning in some organs. Therefore the term ischemic conditioning, including all interventions applied pre-, per- and post- ischemia, which spans therapeutic windows in 3 time periods, has recently been broadly accepted by scientific communities. In addition, it is extensively acknowledged that ischemia-mediated protection not only affects the neurons but also all the components of the neurovascular network (consisting of neurons, glial cells, vascular endothelial cells, pericytes, smooth muscle cells, and venule/veins). The concept of cerebroprotection has been widely used in place of neuroprotection. Intensive studies on the cellular signaling pathways involved in ischemic conditioning have improved the mechanistic understanding of tolerance to cerebral ischemia. This has added impetus to exploration for potential pharmacologic mimetics, which could possibly induce and maximize inherent protective capacities. However, most of these studies were performed in rodents, and the efficacy of these mimetics remains to be evaluated in human patients. Several classical signaling pathways involving apoptosis, inflammation, or oxidation have been elaborated in the past decades. Newly characterized mechanisms are emerging with the advances in biotechnology and conceptual renewal. In this review we are going to focus on those

  2. An isogenic blood-brain barrier model comprising brain endothelial cells, astrocytes, and neurons derived from human induced pluripotent stem cells.

    Science.gov (United States)

    Canfield, Scott G; Stebbins, Matthew J; Morales, Bethsymarie Soto; Asai, Shusaku W; Vatine, Gad D; Svendsen, Clive N; Palecek, Sean P; Shusta, Eric V

    2017-03-01

    The blood-brain barrier (BBB) is critical in maintaining a physical and metabolic barrier between the blood and the brain. The BBB consists of brain microvascular endothelial cells (BMECs) that line the brain vasculature and combine with astrocytes, neurons and pericytes to form the neurovascular unit. We hypothesized that astrocytes and neurons generated from human-induced pluripotent stem cells (iPSCs) could induce BBB phenotypes in iPSC-derived BMECs, creating a robust multicellular human BBB model. To this end, iPSCs were used to form neural progenitor-like EZ-spheres, which were in turn differentiated to neurons and astrocytes, enabling facile neural cell generation. The iPSC-derived astrocytes and neurons induced barrier tightening in primary rat BMECs indicating their BBB inductive capacity. When co-cultured with human iPSC-derived BMECs, the iPSC-derived neurons and astrocytes significantly elevated trans-endothelial electrical resistance, reduced passive permeability, and improved tight junction continuity in the BMEC cell population, while p-glycoprotein efflux transporter activity was unchanged. A physiologically relevant neural cell mixture of one neuron: three astrocytes yielded optimal BMEC induction properties. Finally, an isogenic multicellular BBB model was successfully demonstrated employing BMECs, astrocytes, and neurons from the same donor iPSC source. It is anticipated that such an isogenic facsimile of the human BBB could have applications in furthering understanding the cellular interplay of the neurovascular unit in both healthy and diseased humans. Read the Editorial Highlight for this article on page 843. © 2016 International Society for Neurochemistry.

  3. Vagotomy attenuates brain cytokines and sleep induced by peripherally administered tumor necrosis factor-α and lipopolysaccharide in mice.

    Science.gov (United States)

    Zielinski, Mark R; Dunbrasky, Danielle L; Taishi, Ping; Souza, Gianne; Krueger, James M

    2013-08-01

    Systemic tumor necrosis factor-α (TNF-α) is linked to sleep and sleep altering pathologies in humans. Evidence from animals indicates that systemic and brain TNF-α have a role in regulating sleep. In animals, TNF-α or lipopolysaccharide (LPS) enhance brain pro-inflammatory cytokine expression and sleep after central or peripheral administration. Vagotomy blocks enhanced sleep induced by systemic TNF-α and LPS in rats, suggesting that vagal afferent stimulation by TNF-α enhances pro-inflammatory cytokines in sleep-related brain areas. However, the effects of systemic TNF-α on brain cytokine expression and mouse sleep remain unknown. We investigated the role of vagal afferents on brain cytokines and sleep after systemically applied TNF-α or LPS in mice. Spontaneous sleep was similar in vagotomized and sham-operated controls. Vagotomy attenuated TNF-α- and LPS-enhanced non-rapid eye movement sleep (NREMS); these effects were more evident after lower doses of these substances. Vagotomy did not affect rapid eye movement sleep responses to these substances. NREMS electroencephalogram delta power (0.5-4 Hz range) was suppressed after peripheral TNF-α or LPS injections, although vagotomy did not affect these responses. Compared to sham-operated controls, vagotomy did not affect liver cytokines. However, vagotomy attenuated interleukin-1 beta (IL-1β) and TNF-α mRNA brain levels after TNF-α, but not after LPS, compared to the sham-operated controls. We conclude that vagal afferents mediate peripheral TNF-α-induced brain TNF-α and IL-1β mRNA expressions to affect sleep. We also conclude that vagal afferents alter sleep induced by peripheral pro-inflammatory stimuli in mice similar to those occurring in other species.

  4. Changes in Brain Activation Induced by the Training of Hypothesis Generation Skills: An fMRI Study

    Science.gov (United States)

    Kwon, Yong-Ju; Lee, Jun-Ki; Shin, Dong-Hoon; Jeong, Jin-Su

    2009-01-01

    The aim of the present study is to investigate the learning-related changes in brain activation induced by the training of hypothesis generation skills regarding biological phenomena. Eighteen undergraduate participants were scanned twice with functional magnetic resonance imaging (fMRI) before and after training over a period of 2 months. The…

  5. The Acute Phase Response and Soman-Induced Status Epilepticus: Temporal, Regional and Cellular Changes in Rat Brain Cytokine Concentrations

    Science.gov (United States)

    2010-07-22

    factors such as IL-1is not surprising. Fur- thermore, IL-6 expression begins the synthesis of corti- cotrophin and glucocorticoids [50], initiating an...L, Cassel G: Effects of HI 6, diazepam and atropine on soman-induced IL-1 beta protein in rat brain. Neurotoxicology 2005, 26:173-181. 24. Shih TM

  6. Effects of metformin on learning and memory behaviors and brain mitochondrial functions in high fat diet induced insulin resistant rats.

    Science.gov (United States)

    Pintana, Hiranya; Apaijai, Nattayaporn; Pratchayasakul, Wasana; Chattipakorn, Nipon; Chattipakorn, Siriporn C

    2012-10-05

    Metformin is a first line drug for the treatment of type 2 diabetes mellitus (T2DM). Our previous study reported that high-fat diet (HFD) consumption caused not only peripheral and neuronal insulin resistance, but also induced brain mitochondrial dysfunction as well as learning impairment. However, the effects of metformin on learning behavior and brain mitochondrial functions in HFD-induced insulin resistant rats have never been investigated. Thirty-two male Wistar rats were divided into two groups to receive either a normal diet (ND) or a high-fat diet (HFD) for 12weeks. Then, rats in each group were divided into two treatment groups to receive either vehicle or metformin (15mg/kg BW twice daily) for 21days. All rats were tested for cognitive behaviors using the Morris water maze (MWM) test, and blood samples were collected for the determination of glucose, insulin, and malondialdehyde. At the end of the study, animals were euthanized and the brain was removed for studying brain mitochondrial function and brain oxidative stress. We found that in the HFD group, metformin significantly attenuated the insulin resistant condition by improving metabolic parameters, decreasing peripheral and brain oxidative stress levels, and improving learning behavior, compared to the vehicle-treated group. Furthermore, metformin completely prevented brain mitochondrial dysfunction caused by long-term HFD consumption. Our findings suggest that metformin effectively improves peripheral insulin sensitivity, prevents brain mitochondrial dysfunction, and completely restores learning behavior, which were all impaired by long-term HFD consumption. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy.

    Science.gov (United States)

    Mladenović, Dušan; Hrnčić, Dragan; Petronijević, Nataša; Jevtić, Gordana; Radosavljević, Tatjana; Rašić-Marković, Aleksandra; Puškaš, Nela; Maksić, Nebojša; Stanojlović, Olivera

    2014-11-01

    Neurosteroids are involved in the pathogenesis of hepatic encephalopathy (HE). This study evaluated the effects of finasteride, inhibitor of neurosteroid synthesis, on motor, EEG, and cellular changes in rat brain in thioacetamide-induced HE. Male Wistar rats were divided into the following groups: 1) control; 2) thioacetamide-treated group, TAA (300 mg·kg(-1)·day(-1)); 3) finasteride-treated group, FIN (50 mg·kg(-1)·day(-1)); and 4) group treated with FIN and TAA (FIN + TAA). Daily doses of TAA and FIN were administered in three subsequent days intraperitoneally, and in the FIN + TAA group FIN was administered 2 h before every dose of TAA. Motor and reflex activity was determined at 0, 2, 4, 6, and 24 h, whereas EEG activity was registered about 24 h after treatment. The expressions of neuronal (NeuN), astrocytic [glial fibrilary acidic protein (GFAP)], microglial (Iba1), and oligodendrocyte (myelin oligodendrocyte glycoprotein) marker were determined 24 h after treatment. While TAA decreased all tests, FIN pretreatment (FIN + TAA) significantly improved equilibrium, placement test, auditory startle, head shake reflex, motor activity, and exploratory behavior vs. the TAA group. Vital reflexes (withdrawal, grasping, righting and corneal reflex) together with mean EEG voltage were significantly higher (P EEG changes in TAA-induced HE and completely prevents the development of hepatic coma. Copyright © 2014 the American Physiological Society.

  8. Anaesthetics-Induced Neurotoxicity in Developing Brain: An Update on Preclinical Evidence

    Directory of Open Access Journals (Sweden)

    Zhaowei Zhou

    2014-03-01

    Full Text Available Every year millions of young people are treated with anaesthetic agents for surgery and sedation in a seemingly safe manner. However, growing and convincing preclinical evidence in rodents and nonhuman primates, together with recent epidemiological observations, suggest that exposure to anaesthetics in common clinical use can be neurotoxic to the developing brain and lead to long-term neurological sequelae. These findings have seriously questioned the safe use of general anaesthetics in obstetric and paediatric patients. The mechanisms and human applicability of anaesthetic neurotoxicity and neuroprotection have remained under intense investigation over the past decade. Ongoing pre-clinical investigation may have significant impact on clinical practice in the near future. This review represents recent developments in this rapidly emerging field. The aim is to summarise recently available laboratory data, especially those being published after 2010, in the field of anaesthetics-induced neurotoxicity and its impact on cognitive function. In addition, we will discuss recent findings in mechanisms of early-life anaesthetics-induced neurotoxicity, the role of human stem cell-derived models in detecting such toxicity, and new potential alleviating strategies.

  9. Single pulse TMS-induced modulations of resting brain neurodynamics encoded in EEG phase.

    Science.gov (United States)

    Stamoulis, Catherine; Oberman, Lindsay M; Praeg, Elke; Bashir, Shahid; Pascual-Leone, Alvaro

    2011-06-01

    Integration of electroencephalographic (EEG) recordings and transcranial magnetic stimulation (TMS) provides a useful framework for quantifying stimulation-induced modulations of neural dynamics. Amplitude and frequency modulations by different TMS protocols have been previously investigated, but the study of stimulation-induced effects on EEG phase has been more limited. We examined changes in resting brain dynamics following single TMS pulses, focusing on measures in the phase domain, to assess their sensitivity to stimulation effects. We observed a significant, approximately global increase in EEG relative phase following prolonged (>20 min) single-pulse TMS. In addition, we estimated higher rates of phase fluctuation from the slope of estimated phase curves, and higher numbers of phase resetting intervals following TMS over motor cortex, particularly in frontal and centro-parietal/parietal channels. Phase changes were only significantly different from their pre-TMS values at the end of the stimulation session, which suggests that prolonged single-pulse TMS may result in cumulative changes in neural activity reflected in the phase of the EEG. This is a novel result, as prior studies have reported only transient stimulation-related effects in the amplitude and frequency domains following single-pulse TMS.

  10. Role of Hypoxia-Induced Brain Derived Neurotrophic Factor in Human Pulmonary Artery Smooth Muscle.

    Directory of Open Access Journals (Sweden)

    William Hartman

    Full Text Available Hypoxia effects on pulmonary artery structure and function are key to diseases such as pulmonary hypertension. Recent studies suggest that growth factors called neurotrophins, particularly brain-derived neurotrophic factor (BDNF, can influence lung structure and function, and their role in the pulmonary artery warrants further investigation. In this study, we examined the effect of hypoxia on BDNF in humans, and the influence of hypoxia-enhanced BDNF expression and signaling in human pulmonary artery smooth muscle cells (PASMCs.48h of 1% hypoxia enhanced BDNF and TrkB expression, as well as release of BDNF. In arteries of patients with pulmonary hypertension, BDNF expression and release was higher at baseline. In isolated PASMCs, hypoxia-induced BDNF increased intracellular Ca2+ responses to serotonin: an effect altered by HIF1α inhibition or by neutralization of extracellular BDNF via chimeric TrkB-Fc. Enhanced BDNF/TrkB signaling increased PASMC survival and proliferation, and decreased apoptosis following hypoxia.Enhanced expression and signaling of the BDNF-TrkB system in PASMCs is a potential mechanism by which hypoxia can promote changes in pulmonary artery structure and function. Accordingly, the BDNF-TrkB system could be a key player in the pathogenesis of hypoxia-induced pulmonary vascular diseases, and thus a potential target for therapy.

  11. Postictal MRI abnormalities and seizure-induced brain injury: notions to be challenged.

    Science.gov (United States)

    Grillo, Eugenio

    2015-03-01

    This was a bibliographic search to address the quality of evidence in clinical reports supporting the assertion that brain MRI signal abnormalities are a direct consequence of seizures. The search on PubMed was performed by applying the following inclusion criteria: a) original case reports, b) in humans, c) as single case reports or series of patients, d) of visually detected acute MRI signal abnormalities, e) attributable directly to seizures, and f) published in English. Bibliographic references of initially selected publications were reviewed for additional articles. Full texts of selected publications were read for information regarding clinical, EEG, and MRI features. Moreover, claimed evidence supporting seizure-induced excitotoxicity was assessed. The search resulted in 91 publications corresponding to 413 cases. There was a wide range of clinical features and EEG and MRI abnormalities. Premorbid or comorbid conditions were present in many cases, and some of them are potential causes of MRI changes. Claimed evidence for MRI signal abnormalities as a direct consequence of ictal activity was mostly based on the similarity with previous reports, animal models, reversibility, congruent EEG, MRI changes not respecting vascular territories, and ruling out other etiologies. Evidence supporting the notion of seizure-induced excitotoxicity is questionable in the studied reports of postictal MRI abnormalities. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Histamine Induces Alzheimer's Disease-Like Blood Brain Barrier Breach and Local Cellular Responses in Mouse Brain Organotypic Cultures

    Science.gov (United States)

    Sedeyn, Jonathan C.; Wu, Hao; Hobbs, Reilly D.; Levin, Eli C.; Nagele, Robert G.; Venkataraman, Venkat

    2015-01-01

    Among the top ten causes of death in the United States, Alzheimer's disease (AD) is the only one that cannot be cured, prevented, or even slowed down at present. Significant efforts have been exerted in generating model systems to delineate the mechanism as well as establishing platforms for drug screening. In this study, a promising candidate model utilizing primary mouse brain organotypic (MBO) cultures is reported. For the first time, we have demonstrated that the MBO cultures exhibit increased blood brain barrier (BBB) permeability as shown by IgG leakage into the brain parenchyma, astrocyte activation as evidenced by increased expression of glial fibrillary acidic protein (GFAP), and neuronal damage-response as suggested by increased vimentin-positive neurons occur upon histamine treatment. Identical responses—a breakdown of the BBB, astrocyte activation, and neuronal expression of vimentin—were then demonstrated in brains from AD patients compared to age-matched controls, consistent with other reports. Thus, the histamine-treated MBO culture system may provide a valuable tool in combating AD. PMID:26697497

  13. Novel monoamine transporter ligands reduce cocaine-induced enhancement of brain stimulation reward.

    Science.gov (United States)

    Trzcińska, M; Pimentel, P; Stellar, J R; Hanson, R N; Choi, S W; Elmaleh, D R; Zhang, J; Prakash, K R; Tamiz, A P; Kozikowski, A P; Johnson, K M; Smith, M P; Babich, J W

    2001-01-01

    Six novel monoamine reuptake inhibitors were screened for their intrinsic effects on brain stimulation reward (BSR), as well as for their potential to reduce cocaine-induced reward-enhancement in that paradigm. Two of the compounds, nocaine-3B and 5-ara-74A (disubstituted piperidines) significantly reduced locus of rise (LOR), threshold measure of reward, at some doses. One compound, 1-RV-96A (a hybrid of the GBR and WIN-like agents) significantly reduced reward (increased LOR), but only at the highest dose tested. No effect of dose was found for MC9-20 (a GBR-like acyclic analogue of the N-bisarylmethoxyethyl-N'-phenylpropyl piperazine), nocaine-250B or 4-ara-42C (disubstituted piperidines). When cocaine (10 mg/kg, ip) and selected, hedonically neutral doses of novel compounds were combined, the following findings were obtained: MC9-20 (2.5 mg/kg, ip) showed a significant increase in cocaine-induced reward enhancement (0.2 log units or 53%). In contrast, nocaine-250B and 1-RV-96A (both at 10 mg/kg, ip) demonstrated a significant reduction (0.13 log units or 41%) in cocaine-induced reward enhancement (P<.01 and P<.05, respectively), as measured by changes in LOR. There were no differences in the maximum behavioral output (MAX) at either dose of each of the six drugs, or when selected doses were combined with cocaine. These results indicate that nocaine-250B and 1-RV-96A constitute two potential anticocaine compounds worthy of further behavioral and biochemical evaluation.

  14. MR imaging findings of generalized tonic clonic seizure induced brain changes

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jeong Ah; Chung, Jin Il; Yonn, Pyeong Ho; Kim, Dong Ik; Chung, Tae Sub; Kim, Joo Hee [College of Medicine, Yonsei Unversity, Seoul (Korea, Republic of)

    2000-03-01

    To evaluate MRI signal changes in the brain induced by generalized tonic clonic seizure. Six patients who underwent MRI within three days of generalized tonic clonic seizure were retrospectively reviewed. Diffusion -weighted images were added in three patients during initial examination, and in six, the follow-up MRI was performed nine days to five months after the onset of seizure. We evaluated the patterns of signal change, location of the lesion and degree of contrast enhancement, and the signal change seen on diffusion weighted images. We also compared the signal changes seen on initial and follow-up MRI. In all six patients, MR images showed focally increased T2 signal intensity, and swelling and increased volume of the involved cortical gyrus. In five, the lesion was mainly located in the cortical gray matter and subcortical white matter; namely, in the bilateral cingulate gyri, and the bilateral parieto-occipital, left parietal, left frontoparietal, and left temporal lobe. In the remaining patient, the lesion was located in the right hippocampus. Two patients showed bilateral lesions and one showed multiple lesions. In four patients, T1-weighted images revealed decreased signal intensity of the same location, and in one, gyral contrast enhancement was noted. On diffusion-weighted images, three patients showed increased signal intensity. Follow-up MRI demonstrated complete resolution of the abnormal signal change (n=3D5), or a decrease (n=3D1). A transient increase in MR signal intensity with increased volume was noted in cortical and subcortical white matter after generalized tonic clonic seizure. This finding reflects the vasogenic and cytotoxic edema induced by seizure and can help exclude etiologic lesions such as tumors, inflammation and demyelinating disease that induce epilepsy. (author)

  15. Zingiber Officinale Alters 3,4-methylenedioxymethamphetamine-Induced Neurotoxicity in Rat Brain

    Science.gov (United States)

    Mehdizadeh, Mehdi; Dabaghian, Fataneh; Nejhadi, Akram; Fallah-huseini, Hassan; Choopani, Samira; Shekarriz, Nima; Molavi, Nima; Basirat, Arghavan; Mohammadzadeh Kazorgah, Farzaneh; Samzadeh-Kermani, Alireza; Soleimani Asl, Sara

    2012-01-01

    Objective: The spice Zingiber officinale or ginger possesses antioxidant activity and neuroprotective effects. The effects of this traditional herbal medicine on 3,4-methylenedioxymethamphetamine (MDMA) induced neurotoxicity have not yet been studied. The present study considers the effects of Zingiber officinale on MDMA-induced spatial memory impairment and apoptosis in the hippocampus of male rats. Materials and Methods: In this experimental study, 21 adult male Sprague Dawley rats (200-250 g) were classified into three groups (control, MDMA, and MDMA plus ginger). The groups were intraperitoneally administered 10 mg/kg MDMA, 10 mg/kg MDMA plus 100 mg/kg ginger extract, or 1 cc/kg normal saline as the control solution for one week (n=7 per group). Learning memory was assessed by Morris water maze (MWM) after the last administration. Finally, the brains were removed to study the cell number in the cornu ammonis (CA1) hippocampus by light microscope, Bcl-2 by immunoblotting, and Bax expression by reverse transcription polymerase chain reaction (RT-PCR). Data was analyzed using SPSS 16 software and a one-way ANOVA test. Results: Escape latency and traveled distances decreased significantly in the MDMA plus ginger group relative to the MDMA group (p<0.001). Cell number increased in the MDMA plus ginger group in comparison to the MDMA group. Down-regulation of Bcl-2 and up-regulation of Bax were observed in the MDMA plus ginger group in comparison to the MDMA group (p<0.05). Conclusion: Our findings suggest that ginger consumption may lead to an improvement of MDMA-induced neurotoxicity. PMID:23508562

  16. The Responses of Tissues from the Brain, Heart, Kidney, and Liver to Resuscitation following Prolonged Cardiac Arrest by Examining Mitochondrial Respiration in Rats.

    Science.gov (United States)

    Kim, Junhwan; Villarroel, José Paul Perales; Zhang, Wei; Yin, Tai; Shinozaki, Koichiro; Hong, Angela; Lampe, Joshua W; Becker, Lance B

    2016-01-01

    Cardiac arrest induces whole-body ischemia, which causes damage to multiple organs. Understanding how each organ responds to ischemia/reperfusion is important to develop better resuscitation strategies. Because direct measurement of organ function is not practicable in most animal models, we attempt to use mitochondrial respiration to test efficacy of resuscitation on the brain, heart, kidney, and liver following prolonged cardiac arrest. Male Sprague-Dawley rats are subjected to asphyxia-induced cardiac arrest for 30 min or 45 min, or 30 min cardiac arrest followed by 60 min cardiopulmonary bypass resuscitation. Mitochondria are isolated from brain, heart, kidney, and liver tissues and examined for respiration activity. Following cardiac arrest, a time-dependent decrease in state-3 respiration is observed in mitochondria from all four tissues. Following 60 min resuscitation, the respiration activity of brain mitochondria varies greatly in different animals. The activity after resuscitation remains the same in heart mitochondria and significantly increases in kidney and liver mitochondria. The result shows that inhibition of state-3 respiration is a good marker to evaluate the efficacy of resuscitation for each organ. The resulting state-3 respiration of brain and heart mitochondria following resuscitation reenforces the need for developing better strategies to resuscitate these critical organs following prolonged cardiac arrest.

  17. The Responses of Tissues from the Brain, Heart, Kidney, and Liver to Resuscitation following Prolonged Cardiac Arrest by Examining Mitochondrial Respiration in Rats

    Directory of Open Access Journals (Sweden)

    Junhwan Kim

    2016-01-01

    Full Text Available Cardiac arrest induces whole-body ischemia, which causes damage to multiple organs. Understanding how each organ responds to ischemia/reperfusion is important to develop better resuscitation strategies. Because direct measurement of organ function is not practicable in most animal models, we attempt to use mitochondrial respiration to test efficacy of resuscitation on the brain, heart, kidney, and liver following prolonged cardiac arrest. Male Sprague-Dawley rats are subjected to asphyxia-induced cardiac arrest for 30 min or 45 min, or 30 min cardiac arrest followed by 60 min cardiopulmonary bypass resuscitation. Mitochondria are isolated from brain, heart, kidney, and liver tissues and examined for respiration activity. Following cardiac arrest, a time-dependent decrease in state-3 respiration is observed in mitochondria from all four tissues. Following 60 min resuscitation, the respiration activity of brain mitochondria varies greatly in different animals. The activity after resuscitation remains the same in heart mitochondria and significantly increases in kidney and liver mitochondria. The result shows that inhibition of state-3 respiration is a good marker to evaluate the efficacy of resuscitation for each organ. The resulting state-3 respiration of brain and heart mitochondria following resuscitation reenforces the need for developing better strategies to resuscitate these critical organs following prolonged cardiac arrest.

  18. Effect of locally tailored labour management guidelines on intrahospital stillbirths and birth asphyxia at the referral hospital of Zanzibar

    DEFF Research Database (Denmark)

    Maaløe, N.; Housseine, N.; Meguid, T.

    2018-01-01

    Objective: To evaluate effect of locally tailored labour management guidelines (PartoMa guidelines) on intrahospital stillbirths and birth asphyxia. Design: Quasi-experimental pre-post study investigating the causal pathway through changes in clinical practice. Setting: Tanzanian low-resource...... diagnosis) fell from 120 minutes (IQR 60–240) to 74 minutes (IQR 30-130) (Mann–Whitney test for difference, P human resources and substandard care remain major challenges...

  19. Dopaminergic activation of estrogen receptors induces fos expression within restricted regions of the neonatal female rat brain.

    Directory of Open Access Journals (Sweden)

    Kristin M Olesen

    2008-05-01

    Full Text Available Steroid receptor activation in the developing brain influences a variety of cellular processes that endure into adulthood, altering both behavior and physiology. Recent data suggests that dopamine can regulate expression of progestin receptors within restricted regions of the developing rat brain by activating estrogen receptors in a ligand-independent manner. It is unclear whether changes in neuronal activity induced by dopaminergic activation of estrogen receptors are also region specific. To investigate this question, we examined where the dopamine D1-like receptor agonist, SKF 38393, altered Fos expression via estrogen receptor activation. We report that dopamine D1-like receptor agonist treatment increased Fos protein expression within many regions of the developing female rat brain. More importantly, prior treatment with an estrogen receptor antagonist partially reduced D1-like receptor agonist-induced Fos expression only within the bed nucleus of the stria terminalis and the central amygdala. These data suggest that dopaminergic activation of estrogen receptors alters neuronal activity within restricted regions of the developing rat brain. This implies that ligand-independent activation of estrogen receptors by dopamine might organize a unique set of behaviors during brain development in contrast to the more wide spread ligand activation of estrogen receptors by estrogen.

  20. Dopaminergic Activation of Estrogen Receptors Induces Fos Expression within Restricted Regions of the Neonatal Female Rat Brain

    Science.gov (United States)

    Olesen, Kristin M.; Auger, Anthony P.

    2008-01-01

    Steroid receptor activation in the developing brain influences a variety of cellular processes that endure into adulthood, altering both behavior and physiology. Recent data suggests that dopamine can regulate expression of progestin receptors within restricted regions of the developing rat brain by activating estrogen receptors in a ligand-independent manner. It is unclear whether changes in neuronal activity induced by dopaminergic activation of estrogen receptors are also region specific. To investigate this question, we examined where the dopamine D1-like receptor agonist, SKF 38393, altered Fos expression via estrogen receptor activation. We report that dopamine D1-like receptor agonist treatment increased Fos protein expression within many regions of the developing female rat brain. More importantly, prior treatment with an estrogen receptor antagonist partially reduced D1-like receptor agonist-induced Fos expression only within the bed nucleus of the stria terminalis and the central amygdala. These data suggest that dopaminergic activation of estrogen receptors alters neuronal activity within restricted regions of the developing rat brain. This implies that ligand-independent activation of estrogen receptors by dopamine might organize a unique set of behaviors during brain development in contrast to the more wide spread ligand activation of estrogen receptors by estrogen. PMID:18478050

  1. Concepts and strategies for clinical management of blast-induced traumatic brain injury and posttraumatic stress disorder.

    Science.gov (United States)

    Chen, Yun; Huang, Wei; Constantini, Shlomi

    2013-01-01

    After exposure of the human body to blast, kinetic energy of the blast shock waves might be transferred into hydraulic energy in the cardiovascular system to cause a rapid physical movement or displacement of blood (a volumetric blood surge). The volumetric blood surge moves through blood vessels from the high-pressure body cavity to the low-pressure cranial cavity, causing damage to tiny cerebral blood vessels and the blood-brain barrier (BBB). Large-scale cerebrovascular insults and BBB damage that occur globally throughout the brain may be the main causes of non-impact, blast-induced brain injuries, including the spectrum of traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD). The volumetric blood surge may be a major contributor not only to blast-induced brain injuries resulting from physical trauma, but may also be the trigger to psychiatric disorders resulting from emotional and psychological trauma. Clinical imaging technologies, which are able to detect tiny cerebrovascular insults, changes in blood flow, and cerebral edema, may help diagnose both TBI and PTSD in the victims exposed to blasts. Potentially, prompt medical treatment aiming at prevention of secondary neuronal damage may slow down or even block the cascade of events that lead to progressive neuronal damage and subsequent long-term neurological and psychiatric impairment.

  2. Metformin induces up-regulation of blood-brain barrier functions by activating AMP-activated protein kinase in rat brain microvascular endothelial cells.

    Science.gov (United States)

    Takata, Fuyuko; Dohgu, Shinya; Matsumoto, Junichi; Machida, Takashi; Kaneshima, Shuji; Matsuo, Mai; Sakaguchi, Shinya; Takeshige, Yuki; Yamauchi, Atsushi; Kataoka, Yasufumi

    2013-04-19

    Blood-brain barrier (BBB) disruption occurs frequently in CNS diseases and injuries. Few drugs have been developed as therapeutic candidates for facilitating BBB functions. Here, we examined whether metformin up-regulates BBB functions using rat brain microvascular endothelial cells (RBECs). Metformin, concentration- and time-dependently increased transendothelial electrical resistance of RBEC monolayers, and decreased RBEC permeability to sodium fluorescein and Evans blue albumin. These effects of metformin were blocked by compound C, an inhibitor of AMP-activated protein kinase (AMPK). AMPK stimulation with an AMPK activator, AICAR, enhanced BBB functions. These findings indicate that metformin induces up-regulation of BBB functions via AMPK activation. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Low dose X-irradiation mitigates diazepam induced depression in rat brain.

    Science.gov (United States)

    Kaur, Amandeep; Singla, Neha; Dhawan, D K

    2016-10-01

    Depression is considered as one of the most prevalent health ailments. Various anti-depressant drugs have been used to provide succour to this ailment, but with little success and rather have resulted in many side effects. On the other hand, low dose of ionizing radiations are reported to exhibit many beneficial effects on human body by stimulating various biological processes. The present study was conducted to investigate the beneficial effects of low doses of X-rays, if any, during diazepam induced depression in rats. Female Sprague Dawley rats were segregated into four different groups viz: Normal control, Diazepam treated, X-irradiated and Diazepam + X-irradiated. Depression model was created in rats by subjecting them to diazepam treatment at a dosage of 2 mg/kg b.wt./day for 3 weeks. The skulls of animals belonging to X-irradiated and Diazepam + X-irradiated rats were X-irradiated with a single fraction of 0.5 Gy, given twice a day for 3 days, thereby delivered dose of 3 Gy. Diazepam treated animals showed significant alterations in the neurobehavior and neuro-histoarchitecture, which were improved after X-irradiation. Further, diazepam exposure significantly decreased the levels of neurotransmitters and acetylcholinesterase activity, but increased the monoamine oxidase activity in brain. Interestingly, X-rays exposure to diazepam treated rats increased the levels of neurotransmitters, acetylcholinesterase activity and decreased the monoamine oxidase activity. Further, depressed rats also showed increased oxidative stress with altered antioxidant parameters, which were normalized on X-rays exposure. The present study, suggests that low dose of ionizing radiations, shall prove to be an effective intervention and a novel therapy in controlling depression and possibly other brain related disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Moringa oleifera phytochemicals protect the brain against experimental nicotine-induced neurobehavioral disturbances and cerebellar degeneration.

    Science.gov (United States)

    Omotoso, Gabriel Olaiya; Gbadamosi, Ismail Temitayo; Olajide, Olayemi Joseph; Dada-Habeeb, Shakirat Opeyemi; Arogundade, Tolulope Timothy; Yawson, Emmanuel Olusola

    2018-01-04

    Nicotine is a neuro-stimulant that has been implicated in the pathophysiology of many brain diseases. The need to prevent or alleviate the resulting dysfunction is therefore paramount, which has also given way to the use of medicinal plants in the management of brain conditions. This study was designed to determine the histomorphological and neurobehavioural changes in the cerebellum of Wistar rats following nicotine insult and how such injuries respond to Moringa intervention. Twenty-four adult male Wistar rats were divided into 4 groups. Group A and B were orally treated with normal saline and Moringa oleifera respectively for twenty-eight days; Group C was treated with nicotine while group D was treated orally with Moringa oleifera and intraperitoneally with nicotine for twenty-eight days. Animals were subjected to the open field test on the last day of treatment. 24 h after last day treatment, the animals were anesthetized and perfusion fixation was carried out. The cerebellum was excised and post-fixed in 4% paraformaldehyde and thereafter put through routine histological procedures. Results revealed cytoarchitectural distortion and extreme chromatolysis in neuronal cells of the cerebellar cortical layers in the nicotine-treated group. The Purkinje cells of the cerebellum of animals in this group were degenerated. There were also reduced locomotor activities in the group. Moringa was able to prevent the chromatolysis, distortion of the cerebellar cortical cells and neurobehavioural deficit. Our result suggests that Moringa oleifera could prevent nicotine-induced cerebellar injury in Wistar rats, with the possibility of ameliorating the clinical features presented in associated cerebellar pathology. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. A multi-mode shock tube for investigation of blast-induced traumatic brain injury.

    Science.gov (United States)

    Reneer, Dexter V; Hisel, Richard D; Hoffman, Joshua M; Kryscio, Richard J; Lusk, Braden T; Geddes, James W

    2011-01-01

    Blast-induced mild traumatic brain injury (bTBI) has become increasingly common in recent military conflicts. The mechanisms by which non-impact blast exposure results in bTBI are incompletely understood. Current small animal bTBI models predominantly utilize compressed air-driven membrane rupture as their blast wave source, while large animal models use chemical explosives. The pressure-time signature of each blast mode is unique, making it difficult to evaluate the contributions of the different components of the blast wave to bTBI when using a single blast source. We utilized a multi-mode shock tube, the McMillan blast device, capable of utilizing compressed air- and compressed helium-driven membrane rupture, and the explosives oxyhydrogen and cyclotrimethylenetrinitramine (RDX, the primary component of C-4 plastic explosives) as the driving source. At similar maximal blast overpressures, the positive pressure phase of compressed air-driven blasts was longer, and the positive impulse was greater, than those observed for shockwaves produced by other driving sources. Helium-driven shockwaves more closely resembled RDX blasts, but by displacing air created a hypoxic environment within the shock tube. Pressure-time traces from oxyhydrogen-driven shockwaves were very similar those produced by RDX, although they resulted in elevated carbon monoxide levels due to combustion of the polyethylene bag used to contain the gases within the shock tube prior to detonation. Rats exposed to compressed air-driven blasts had more pronounced vascular damage than those exposed to oxyhydrogen-driven blasts of the same peak overpressure, indicating that differences in blast wave characteristics other than peak overpressure may influence the extent of bTBI. Use of this multi-mode shock tube in small animal models will enable comparison of the extent of brain injury with the pressure-time signature produced using each blast mode, facilitating evaluation of the blast wave components

  6. The impact of early aerobic exercise on brain microvascular alterations induced by cerebral hypoperfusion.

    Science.gov (United States)

    Leardini-Tristão, Marina; Borges, Juliana Pereira; Freitas, Felipe; Rangel, Raquel; Daliry, Anissa; Tibiriçá, Eduardo; Estato, Vanessa

    2017-02-15

    The therapeutic potential of early exercise training following cerebral hypoperfusion was investigated on brain perfusion and inflammation in rats with permanent bilateral occlusion of the common carotid arteries (2VO). Wistar rats were subjected to 2VO or sham surgery and each group was then subdivided randomly into sedentary or exercise groups. Early exercise training was initiated after three days of 2VO or sham surgery and consisted of seven days of treadmill training (30min/day at ∼60% of maximal exercise test), composing four groups: 1) Sham sedentary (Sham-Sed), 2) Sham exercised (Sham-Ex), 3) 2VO sedentary (2VO-Sed) and 4) 2VO exercised (2VO-Ex). Microvascular cerebral blood flow (MCBF) and NADPH oxidase and eNOS gene expression were evaluated by laser speckle contrast imaging and RT-PCR, respectively, and brain functional capillary density and endothelial-leukocyte interactions were evaluated by fluorescence intravital video-microscopy. The 2VO-Sed group presented a decrease in MCBF (Sham-Sed: 230.9±12.2 vs. 2VO-Sed: 183.6±10.6 arbitrary perfusion units, Pphysical exercise was able to prevent the cerebral microvascular inflammation by decreasing endothelial-leukocyte interactions (2VO-Ex: 0.9±0.3 vs. 2VO-Sed: 5±0.6cells/min/100μm, Pbrain NADPH oxidase gene expression (2VO-Ex: 1.7±0.1 arbitrary units, Pphysical exercise may represent a means of preventing the microvascular alterations induced by chronic cerebral hypoperfusion. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Alcohol-induced one-carbon metabolism impairment promotes dysfunction of DNA base excision repair in adult brain.

    Science.gov (United States)

    Fowler, Anna-Kate; Hewetson, Aveline; Agrawal, Rajiv G; Dagda, Marisela; Dagda, Raul; Moaddel, Ruin; Balbo, Silvia; Sanghvi, Mitesh; Chen, Yukun; Hogue, Ryan J; Bergeson, Susan E; Henderson, George I; Kruman, Inna I

    2012-12-21

    The brain is one of the major targets of chronic alcohol abuse. Yet the fundamental mechanisms underlying alcohol-mediated brain damage remain unclear. The products of alcohol metabolism cause DNA damage, which in conditions of DNA repair dysfunction leads to genomic instability and neural death. We propose that one-carbon metabolism (OCM) impairment associated with long term chronic ethanol intake is a key factor in ethanol-induced neurotoxicity, because OCM provides cells with DNA precursors for DNA repair and methyl groups for DNA methylation, both critical for genomic stability. Using histological (immunohistochemistry and stereological counting) and biochemical assays, we show that 3-week chronic exposure of adult mice to 5% ethanol (Lieber-Decarli diet) results in increased DNA damage, reduced DNA repair, and neuronal death in the brain. These were concomitant with compromised OCM, as evidenced by elevated homocysteine, a marker of OCM dysfunction. We conclude that OCM dysfunction plays a causal role in alcohol-induced genomic instability in the brain because OCM status determines the alcohol effect on DNA damage/repair and genomic stability. Short ethanol exposure, which did not disturb OCM, also did not affect the response to DNA damage, whereas additional OCM disturbance induced by deficiency in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR) in Mthfr(+/-) mice, exaggerated the ethanol effect on DNA repair. Thus, the impact of long term ethanol exposure on DNA repair and genomic stability in the brain results from OCM dysfunction, and MTHFR mutations such as Mthfr 677C→T, common in human population, may exaggerate the adverse effects of ethanol on the brain.

  8. Glucocorticoids regulation of FosB/ΔFosB expression induced by chronic opiate exposure in the brain stress system.

    Directory of Open Access Journals (Sweden)

    Daniel García-Pérez

    Full Text Available Chronic use of drugs of abuse profoundly alters stress-responsive system. Repeated exposure to morphine leads to accumulation of the transcription factor ΔFosB, particularly in brain areas associated with reward and stress. The persistent effects of ΔFosB on target genes may play an important role in the plasticity induced by drugs of abuse. Recent evidence suggests that stress-related hormones (e.g., glucocorticoids, GC may induce adaptations in the brain stress system that is likely to involve alteration in gene expression and transcription factors. This study examined the role of GC in regulation of FosB/ΔFosB in both hypothalamic and extrahypothalamic brain stress systems during morphine dependence. For that, expression of FosB/ΔFosB was measured in control (sham-operated and adrena