Brain Glutathione Levels Research Articles

Glutathione depletion in the brain disrupts short-term spatial memory in the Y-maze in rats and mice

Oxidative stress and reduced brain glutathione (GSH) levels have been reported in psychiatric illnesses including schizophrenia and bipolar disorder. However the role of GSH in cognitive impairment in the illness remains unclear. Treatment of Sprague-Dawley rats and C57Bl/6 mice with 2-cyclohexene-1-one (CHX) dose-dependently reduced striatal and frontal cortical GSH levels similar to those in schizophrenia. In both species, GSH depletion resulted in disruption of short-term spatial recognition memory in a Y-maze test. In conclusion, GSH depletion induces cognitive impairment, which may be relevant to the role of GSH in psychiatric illnesses.

Ceruloplasmin Alters the Tissue Disposition and Neurotoxicity of Manganese, but not its Loading onto Transferrin

Manganese (Mn) is a redox-active element, and whereas its uptake, disposition, and toxicity in mammals may depend in part on its oxidation state, the proteins affecting manganese oxidation state and speciation in vivo are not well known. Studies have suggested that the oxidase protein ceruloplasmin (Cp) mediates iron and manganese oxidation and loading onto plasma transferrin (Tf), as well as cellular iron efflux. We hypothesized that ceruloplasmin may also affect the tissue distribution and eventual neurotoxicity of manganese. To test this, aceruloplasminemic versus wild-type mice were treated with a single i.p. (54)Mn tracer dose, or elevated levels of manganese subchronically (0, 7.5, or 15 mg Mn/kg s.c., three doses per week for 4 weeks), and evaluated for transferrin-bound manganese, blood manganese partitioning, tissue manganese disposition, and levels of brain glutathione, thiobarbituric acid reactive substances (TBARS), and protein carbonyls as measures of oxidative stress, and open arena activity. Results show that ceruloplasmin does not play a role in the loading of manganese onto plasma transferrin in vivo, or in the partitioning of manganese between the plasma and cellular fractions of whole blood. Ceruloplasmin did, however, affect the retention of manganese in blood and its distribution to tissues, most notably kidney and to a lesser extent brain and lung. Results also indicate that ceruloplasmin interacted with chronic elevated manganese exposures to produce greater levels of brain oxidative stress. These results provide evidence that metal oxidase proteins play an important role in altering neurotoxicity arising from elevated manganese exposures.

N-Acetyl Cysteine as a Glutathione Precursor for Schizophrenia—A Double-Blind, Randomized, Placebo-Controlled Trial

Brain glutathione levels are decreased in schizophrenia, a disorder that often is chronic and refractory to treatment. N-acetyl cysteine (NAC) increases brain glutathione in rodents. This study was conducted to evaluate the safety and effectiveness of oral NAC (1 g orally twice daily [b.i.d.]) as an add-on to maintenance medication for the treatment of chronic schizophrenia over a 24-week period. A randomized, multicenter, double-blind, placebo-controlled study. The primary readout was change from baseline on the Positive and Negative Symptoms Scale (PANSS) and its components. Secondary readouts included the Clinical Global Impression (CGI) Severity and Improvement scales, as well as general functioning and extrapyramidal rating scales. Changes following a 4-week treatment discontinuation were evaluated. One hundred forty people with chronic schizophrenia on maintenance antipsychotic medication were randomized; 84 completed treatment. Intent-to-treat analysis revealed that subjects treated with NAC improved more than placebo-treated subjects over the study period in PANSS total [-5.97 (-10.44, -1.51), p = .009], PANSS negative [mean difference -1.83 (95% confidence interval: -3.33, -.32), p = .018], and PANSS general [-2.79 (-5.38, -.20), p = .035], CGI-Severity (CGI-S) [-.26 (-.44, -.08), p = .004], and CGI-Improvement (CGI-I) [-.22 (-.41, -.03), p = .025] scores. No significant change on the PANSS positive subscale was seen. N-acetyl cysteine treatment also was associated with an improvement in akathisia (p = .022). Effect sizes at end point were consistent with moderate benefits. These data suggest that adjunctive NAC has potential as a safe and moderately effective augmentation strategy for chronic schizophrenia.

Negative Correlation between Brain Glutathione Level and Negative Symptoms in Schizophrenia: A 3T 1H-MRS Study

BackgroundGlutathione (GSH), a major intracellular antioxidant, plays a role in NMDA receptor-mediated neurotransmission, which is involved in the pathophysiology of schizophrenia. In the present study, we aimed to investigate whether GSH levels are altered in the posterior medial frontal cortex of schizophrenic patients. Furthermore, we examined correlations between GSH levels and clinical variables in patients.Methods and FindingsTwenty schizophrenia patients and 16 age- and gender-matched normal controls were enrolled to examine the levels of GSH in the posterior medial frontal cortex by using 3T SIGNA EXCITE 1H-MRS with the spectral editing technique, MEGA-PRESS. Clinical variables of patients were assessed by the Global Assessment of Functioning (GAF), Scale for the Assessment of Negative Symptoms (SANS), Brief Psychiatric Rating Scale (BPRS), Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS), and five cognitive performance tests (Word Fluency Test, Stroop Test, Trail Making Test, Wisconsin Card Sorting Test and Digit Span Distractibility Test). Levels of GSH in the posterior medial frontal cortex of schizophrenic patients were not different from those of normal controls. However, we found a significant negative correlation between GSH levels and the severity of negative symptoms (SANS total score and negative symptom subscore on BPRS) in patients. There were no correlations between brain GSH levels and scores on any cognitive performance test except Trail Making Test part A.ConclusionThese results suggest that GSH levels in the posterior medial frontal cortex may be related to negative symptoms in schizophrenic patients. Therefore, agents that increase GSH levels in the brain could be potential therapeutic drugs for negative symptoms in schizophrenia.

Protection effects of S-adenosyl-L-methionine on lead-exposed rats during development and its mechanism of long-term potentiation

To explore the effects of S-adenosyl-L-methionine (SAM) on blood lead concentration and oxidative stress of tissue in prenatal and postnatal lead-exposed rats, and evaluate the potential reparation exerted by SAM on paired-pulse facilitation (PPF) and long-term potentiation (LTP) in lead-exposed rat. Pregnant Wistar rats were randomly divided into three groups: control, lead-exposed and lead-exposed with SAM treatment groups. Lead-exposed rats drank 1.5 g/L lead acetate solution through pregnancy until weaning and then the pups received 20 mg/kg SAM or saline daily intraperitoneally depending on their group. Control group rats drank tap water throughout the experiment. At the postnatal 44-60 days, all the pup rats were given an extracellular recording measured in dentate gyrus (DG) area of hippocampus. The blood lead concentration and oxidative stress in liver, brain and hippocampus were also detected. The blood lead concentration in lead-exposed group was higher (159. 3 +/- 10. 9 microg/L) in comparing with those of control group (27.5 +/-3.8 microg/L) and lead +SAM group (33.1 +/-9.5 microg/L) (F=213.5, P<0.01). A significant recovery of liver, brain glutathione (GSH) and malondialdehyde (MDA) level was clearly produced in lead-exposed rats after SAM treatment (P <0.05). Chronic lead exposure during development impaired LTP measured on field excitatory postsynaptic potential (EPSP) [(112 +/-2.1)%] compared with control rats [(131+/-4.5)%] and the impaired LTP could be significantly increased by SAM treatment [(120 +/- 2.6)%] (F = 26. 1, P <0. 05). SAM might be beneficial for treatment of lead intoxication, especially in the rescue of learning and memory impairment induced by lead and should deserve more detailed research.

Depletion of Liver Glutathione Levels in Rats: A Potential Confound of Nose-Only Inhalation

Nose-only inhalation exposure chambers offer key advantages to whole-body systems, particularly when aerosol or mixed aerosol-vapor exposures are used. Specifically, nose-only chambers provide enhanced control over the route of exposure and dose by minimizing the deposition of particles either on the subjects skin/fur or on surfaces of a whole-body exposure system. In the current series of experiments, liver, brain, and lung total glutathione (GSH) levels were assessed following either nose-only or whole-body exposures to either jet fuel or to clean, filtered air. The data were compared to untreated control subjects. Acute nose-only inhalation exposures of rats resulted in a significant depletion of liver GSH levels both in subjects that were exposed to clean, filtered air as well as those exposed to JP-8 jet fuel and to a synthetic jet fuel. Glutathione levels were not altered in lung or brain tissue. Whole-body inhalation exposure had no effect on GSH levels in any tissue for any of the treatment groups. A second experiment demonstrated that the loss of GSH did not occur if rats were anaesthetized prior to and during nose-only exposure to clean, filtered air or to mixed hydrocarbons. These data appear to be consistent with studies demonstrating depletion in liver GSH levels among rats subjected to restraint stress. Finally, the depletion of GSH that was observed in liver following a single acute exposure was reduced following five daily exposures to clean, filtered air, suggesting the possibility of habituation to restraint in the nose-only exposure chamber. The finding that placement in a nose-only exposure chamber per se yields liver GSH depletion raises the possibility of an interaction between this mode of toxicant exposure and the toxicological effects of certain inhaled test substances.

Glutathione Precursor, N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia Patients

In schizophrenia patients, glutathione dysregulation at the gene, protein and functional levels, leads to N-methyl-D-aspartate (NMDA) receptor hypofunction. These patients also exhibit deficits in auditory sensory processing that manifests as impaired mismatch negativity (MMN), which is an auditory evoked potential (AEP) component related to NMDA receptor function. N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients to determine whether increased levels of brain glutathione would improve MMN and by extension NMDA function. A randomized, double-blind, cross-over protocol was conducted, entailing the administration of NAC (2 g/day) for 60 days and then placebo for another 60 days (or vice versa). 128-channel AEPs were recorded during a frequency oddball discrimination task at protocol onset, at the point of cross-over, and at the end of the study. At the onset of the protocol, the MMN of patients was significantly impaired compared to sex- and age- matched healthy controls (p=0.003), without any evidence of concomitant P300 component deficits. Treatment with NAC significantly improved MMN generation compared with placebo (p=0.025) without any measurable effects on the P300 component. MMN improvement was observed in the absence of robust changes in assessments of clinical severity, though the latter was observed in a larger and more prolonged clinical study. This pattern suggests that MMN enhancement may precede changes to indices of clinical severity, highlighting the possible utility AEPs as a biomarker of treatment efficacy. The improvement of this functional marker may indicate an important pathway towards new therapeutic strategies that target glutathione dysregulation in schizophrenia.

P.3.c.040 Antipsychotic effectiveness based on early response in the treatment of schizophrenia

Brain glutathione levels are decreased in schizophrenia, a disorder that often is chronic and refractory to treatment. N-acetyl cysteine (NAC) increases brain glutathione in rodents. This study was conducted to evaluate the safety and effectiveness of oral NAC (1 g orally twice daily [b.i.d.]) as an add-on to maintenance medication for the treatment of chronic schizophrenia over a 24-week period.A randomized, multicenter, double-blind, placebo-controlled study. The primary readout was change from baseline on the Positive and Negative Symptoms Scale (PANSS) and its components. Secondary readouts included the Clinical Global Impression (CGI) Severity and Improvement scales, as well as general functioning and extrapyramidal rating scales. Changes following a 4-week treatment discontinuation were evaluated. One hundred forty people with chronic schizophrenia on maintenance antipsychotic medication were randomized; 84 completed treatment.Intent-to-treat analysis revealed that subjects treated with NAC improved more than placebo-treated subjects over the study period in PANSS total [−5.97 (−10.44, −1.51), p = .009], PANSS negative [mean difference −1.83 (95% confidence interval: −3.33, −.32), p = .018], and PANSS general [−2.79 (−5.38, −.20), p = .035], CGI-Severity (CGI-S) [−.26 (−.44, −.08), p = .004], and CGI-Improvement (CGI-I) [−.22 (−.41, −.03), p = .025] scores. No significant change on the PANSS positive subscale was seen. N-acetyl cysteine treatment also was associated with an improvement in akathisia (p = .022). Effect sizes at end point were consistent with moderate benefits.These data suggest that adjunctive NAC has potential as a safe and moderately effective augmentation strategy for chronic schizophrenia.

Melatonin ameliorates blood–brain barrier permeability, glutathione, and nitric oxide levels in the choroid plexus of the infantile rats with kaolin-induced hydrocephalus

Hydrocephalus is a disabling disease for children, but current data concerning the effects of melatonin on ventricular enlargement are still limited. We have investigated the changes in the choroid plexuses (CPs) of ventricles and blood–brain barrier (BBB) of hydrocephalic rats. Forty-five Swiss Albino rats at age 2 weeks were divided into three equal groups: control, hydrocephalus, and melatonin-treated hydrocephalus groups. Hydrocephalus was induced by kaolin injection into the cisterna magna of all pups except control group and melatonin was given at a daily dose of 0.5 mg/100 g body weight for 4 weeks. At the end of the study, one animal from each group was examined using a gamma camera to study the disruption of BBB due to hydrocephalus. All animals were then killed for assay of glutathione (GSH) and nitric oxide (NO), as well as histological study of the CPs during the hydrocephalus. We observed an increased BBB activity was found in hydrocephalus group, while melatonin reversed these changes. It was found that NO concentration was elevated in hydrocephalus group and melatonin partly abolished the increased levels of NO. In contrast, GSH levels were significantly decreased in hydrocephalus group, while melatonin increased the tissue GSH level ( p < 0.01). Histologically, there was a significant alteration in the CPs of the ventricles of hydrocephalic animals, but it was regressed after melatonin treatment in consistent with the gross morphological changes related to hydrocephalus. In conclusion, our results clearly demonstrated for the first time the neuroprotective effects of melatonin upon hydrocephalus-induced CP changes in infantile rats, but further studies are needed to suggest melatonin as a candidate protective drug in children.

Subchronic intoxication with chlorfenvinphos, an organophosphate insecticide, affects rat brain antioxidative enzymes and glutathione level

Organophosphate pesticides (OP) belong to the class of xenobiotics that are intentionally released to the environment. Toxicity of these compounds is mainly due to inhibition of acetylcholinesterase (AChE), but many authors postulate that OP in acute as well as in chronic intoxication disturb the redox processes, changing the activities of antioxidative enzymes and causing enhancement of lipid peroxidation in many organs. Epidemiological studies have demonstrated a relationship of certain human diseases with pesticide exposure and with changes in antioxidative enzymes. There is also evidence that oxidative stress is an important pathomechanism of neurological disorders such as Alzheimer disease and Parkinson disease, cardiovascular disorders and many others. The study objective was to investigate the activities of brain antioxidative enzymes and reduced glutathione level in rats subchronically intoxicated with chlorfenvinphos. In the rat brain the activities of such enzymes as superoxide dismutase, catalase, glutathione peroxidase and reductase were found to increase, while reduced glutathione level decreased in chlorfenvinphos intoxication. Based on experimental findings of this study, it can be suggested that subchronic administration of chlorfenvinphos leads to a change in the brain oxidative status and that the change occurs at a dose of 0.3 mg/kg/day, i.e., twice smaller than LOAEL level for rats.

Protective effect of selenium on protein-undernutrition-induced brain damage in rats

The effect of ad libitum ingestion of selenium (Se) in drinking water (0.15 mg SeO2/L) for 3 wk on the brain weight, total brain protein, glutathione (GSH) level, catalase activity, and lipid peroxidation in the brain of protein-undernourished (PU) rats was investigated, in an attempt to determine whether antioxidants alone can reverse some of the neuropathological changes associated with protein undernutrition in rats. Feeding on a normal diet (16% casein) by well-fed rats or a low-protein diet (5% casein) by PU rats and Se-treated PU rats lasted 14 wk. Se-treated PU rats were given Se in drinking water during the last 3 wk of the experiment. Results show that protein undernutrition induced significant reductions (p < 0.001) in brain weight, total brain protein, and catalase activity (p < 0.05) while it induced a significant increase (p < 0.05) in lipid peroxidation when compared with well-nourished rats; but no significant effect was observed for the GSH level. However, the ingestion of Se in drinking water by PU rats for 3 wk resulted in significant increases (p < 0.05) in brain weight, catalase activity, and total brain protein but induced a significant reduction (p < 0.05) in lipid peroxidation when compared with PU rats given water. The values obtained for Se-treated PU rats are comparable with those obtained for well-nourished rats. The GSH level was, however, not affected by Se ingestion. We suggest that Se, by inducing increases in the concentration of certain proteins, including catalase, in the brain, abolished some of the pathological changes associated with protein undernutrition in the brain, and appears as a promising antioxidant in the prevention and management of pro-oxidant-induced brain damage.

Quercetin attenuates spontaneous behavior and spatial memory impairment in d-galactose–treated mice by increasing brain antioxidant capacity

Quercetin, one of the flavonoids in fruits and vegetables, has a powerful antioxidant activity both in vitro and in vivo. To evaluate the antiaging effects of quercetin on the mouse brain, we investigated whether long-term intake of quercetin could improve spontaneous behavior and spatial memory in a mouse aging model. d-Galactose, known to induce age-related biochemical changes of the rodent brain, was used to develop the mouse aging model. In the present study, mice were subcutaneously injected with d-galactose (50 mg/kg) for 8 weeks and were administered quercetin via gastric intubation simultaneously. Animal behavior was observed in the open field and Morris water maze task. The results showed that quercetin significantly prevented changes of spontaneous behavior and spatial memory of d-galactose–treated mice. The antiaging effect of quercetin was found to be related to its ability to inhibit biochemical changes in hippocampi and cortices of d-galactose–treated mice. Quercetin increased brain glutathione level, hydroxy radical scavenging ability, and Na+,K+-adenosine triphosphatase activity, but decreased brain nitric oxide synthase activity and mitochondrial malondialdehyde content in d-galactose–treated mice. In conclusion, quercetin attenuated d-galactose-induced behavioral impairments, suggesting a potential antiaging effect of quercetin.

Glutathione elevation by γ‐glutamyl cysteine ethyl ester as a potential therapeutic strategy for preventing oxidative stress in brain mediated by in vivo administration of adriamycin: Implication for chemobrain

Oxidative stress in heart and brain by the cancer chemotherapeutic drug adriamycin (ADR), used for treating solid tumors, is well established. Long-term treatment with ADR in breast cancer patients has led to symptoms of cardiomyopathy. Less well recognized, but increasingly well documented, is cognitive dysfunction. After chemotherapy, free radical-mediated oxidative stress has been reported in both heart and brain. We recently showed a significant increase in protein oxidation and lipid peroxidation in brain isolated from mice injected intraperitonially (i.p) with ADR. Systemic administration of ADR also induces tumor necrosis factor-alpha (TNF-alpha), which leads to production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in brain. Circulating TNF also causes mitochondrial dysfunction, leading to apoptotic pathways in brain. Inducible nitric oxide synthase also plays a role in ADR-induced TNF-mediated neurotoxicity. In addition, we previously showed a significant decrease in glutathione (GSH) levels in brain isolated from ADR injected mice, along with increased expression of multidrug-resistant protein-1 (MRP-1), glutathione-S-transferase (GST), glutathione peroxidase (GPx), and glutathione reductase (GR). There was a significant decrease in activity of brain GST. The present study was designed to test the hypothesis that, by elevating brain levels of GSH, the brain would be protected against oxidative stress in ADR-injected mice. gamma-Glutamyl cysteine ethyl ester (GCEE), a precursor of glutathione, injected i.p. (150 mg/ kg body weight) 4 hr prior ADR injection (20 mg/kg body weight) led to significantly decreased protein oxidation and lipid peroxidation in subsequently isolated mice brain compared with brain isolated from ADR-injected mice without GCEE. The GSH levels were restored to the level of brain isolated from saline-injected mice. Furthermore, the enzyme activity of GST was increased in brain isolated from ADR-injected mice previously injected with GCEE compared with the brain isolated from ADR-injected mice previously injected with saline. These results are discussed with regard to potential pharmacological prevention of brain cognitive dysfunction in patients receiving ADR chemotherapy.

Spinal Morphine Administration Reduces the Fatty Acid Contents in Spinal Cord and Brain by Increasing Oxidative Stress

It is well known that oxidative stress damages biomolecules such as DNA and lipids. No study is available on the morphine-induced oxidative damage and fatty acids changes in brain and spinal tissues. The aim of this work was to determine the effects of morphine on the concentrations and compositions of fatty acid in spinal cord segments and brain tissues in rabbits as well as lipid peroxidation (LP) and glutathione (GSH) levels in cortex brain. Twelve New Zealand albino rabbits were used and they were randomly assigned to two groups of 6 rabbits each. First group used as control although morphine administrated to rats in second group. Cortex brain and (cervical, thoracic, lumbar) samples were taken. The fatty acids between n:18.0 and 21.0 were present in spinal cord sections and n:10 fatty acids in control animals were present in the brain tissues. Compared to n:20.0-24.0 fatty acids in spinal cord sections and 8.0 fatty acids in the brain tissues of drug administered animals. The concentration and composition of the fatty acid methyl esters in spinal cord and brain tissues was decreased by morphine treatments. LP levels in the cortex brain were increased although GSH levels were decreased by the morphine administration. In conclusion, unsaturated fatty acids contents in brain and spinal cord sections and GSH were reduced by administrating spinal morphine although oxidative stress as LP increased. The inhibition oxidative damage may be a useful strategy for the development of a new protection for morphine administration as well as opiate abuse.

Influence of ethanol on methanol‐induced oxidative stress and neurobehavioral deficits

The present study examines the efficacy of ethanol as an antidote in methanol neurotoxicity in terms of its effect on antioxidant defense system and behavior. It was observed that acute methanol exposure (7.5 g/kg body weight) led to an increase in lipid peroxidation in various regions of brain. Ethanol administration (7.5 g/kg body weight), on the other hand, was found to accentuate methanol-induced lipid peroxidation. Glutathione levels in brain were significantly reduced in methanol-exposed animals. However, in the coexposed animals, the levels of glutathione were comparable to those observed in controls. The activities of superoxide dismutase and catalase were decreased in the brain following methanol exposure, whereas in methanol- and ethanol-coexposed animals there was no significant effect on these enzymes as compared to methanol-exposed animals. The activity of acetylcholinesterase was significantly reduced in the methanol-exposed animals. On the other hand, acetylcholinesterase activity was not affected in the coexposed animals in comparison to methanol-treated group. Neurobehavioral studies revealed impaired motor and cognitive functions following methanol exposure. In contrast, ethanol exposure ameliorated the behavioral deficits induced by methanol. The findings from the present study suggest the beneficial effect of ethanol on neurobehavioral deficits induced by methanol along with intensification of methanol-induced oxidative stress.

The effects of dexfenfluramine administration on brain serotonin immunoreactivity and lipid peroxidation in mice

Obesity continues to be an increasing health problem in worldwide and antiobesity drugs have commonly been used by obese patients. During the use of anorectic drugs, the antioxidant defense may be affected, especially by reactive oxygen species. It was decided to investigate the effects of dexfenfluramine on body weight, daily food intake, brain thiobarbituric acid-reactive substances (TBARS), glutathione (GSH) and nitric oxide (NO) levels, and 5-HT immunoreactivity. Mice were divided into two groups each containing 8 Swiss Albino adult (6 months) mice. Group 1, untreated, was used as a control; group 2 was treated with dexfenfluramine 0.4 mg/kg per day intraperitoneally for 7 days. Brain TBARS and GSH levels were assayed spectrophotometrically. The stable end-products of NO, nitrite and nitrate, were analyzed spectrophotometrically. Brain tissue 5-HT immunoreactivity was observed using an immunohistochemical method. There were significant decreases in body weight in the dexfenfluramine group (p < 0.05). Although brain GSH and NO(x) levels decreased significantly, brain TBARS levels increased in the dexfenfluramine group (p < 0.05). Brain 5-HT immunoreactivity also increased in the dexfenfluramine-treated group compared to control. In conclusion, our findings show that dexfenfluramine is effective in achieving weight loss and also increases lipid peroxidation in mouse brain.

The Effect of Human Growth Hormone on Superoxide Dismutase Activity, Glutathione and Malondialdehyde Levels of Hypoxic-Ischemic Newborn Rat Brain

Objectives: We investigated the effect of human growth hormone (GH) on newborn rat brain superoxide dismutase, glutathione and malondialdehyde (MDA) levels in hypoxic-ischemic (H-I) newborn rats. Methods: Fourty-eight 7 days old newborn rats were randomized to a healthy (n: 15), H-I (n: 18) and GH administered H-I (GH-H-I, n: 15) group. Permanent, left common carotid ligation was performed in the H-I groups. In the GH-H-I group, 50 mg/kg human GH (Norditropin Simplex, Novo Nordisk A/S) was administered subcutaneously just before carotid artery ligation. Two hours after ligation, rats were subjected to 2 h of hypoxemia and then were decapitated. Right and left cerebral hemispheres (CHs) and cerebellum-brain stem (C-BS) were separated. Results: Glutathione levels of each region were not statistically different from each other in and between the groups. Superoxide dismutase levels were higher in C-BSs compared to CHs (for each comparison p < 0.01). CHs and C-BS MDA levels were similar in the control and H-I groups but MDA levels of both CHs of the GH-H-I group were significantly higher than the levels of the H-I group (p = 0.01; p = 0.024, respectively). Left CH MDA level of GH-H-I group was higher compared to left CH MDA of the control group (p = 0.045) while there was no difference between right CHs. In the GH-H-I group, left CH MDA level was higher than the C-BS (p = 0.03). MDA levels of the C-BSs did not differ between the groups (p > 0.05). Conclusion: Although we have not evaluated the effect of GH histopathologically, increased lipid peroxidation especially in the H-I (left) hemisphere of the GH treated rats might suggest that GH treatment may be harmful in H-I encephalopathy.

Chronic administration of pioglitazone attenuates intracerebroventricular streptozotocin induced-memory impairment in rats

Memory impairment induced by intracerebroventricular (ICV) injection of streptozotocin (STZ) in rats is associated with impaired brain glucose and energy metabolism, oxidative stress and impaired cholinergic neurotransmission. Treatment with antioxidants and cholinergic agonists has been reported to produce beneficial effect in this model. However, no reports are available on drugs that improve glucose utilization and metabolism. In the present study, we evaluated the effects of pioglitazone on cognitive performance, oxidative stress and glucose utilization in ICV STZ injected rats (3 mg/kg, on day 1 and 3). Pioglitazone (10 and 30 mg/kg) was administered per oral (p.o.) for 14 days, starting 5 days prior to STZ injection. Cognitive performance was assessed using step-through passive avoidance and Morris water maze task. Malondialdehyde (MDA) and glutathione levels in brain were estimated as parameters of oxidative stress. Glucose utilization by brain was assessed as the amount of glucose consumed from the media by the brain. ICV STZ injected rats showed a severe deficit in learning and memory associated with increased MDA levels (+ 67.5%), decreased glutathione levels (− 29.2%) and impaired cerebral glucose utilization (− 44.4%). In contrast pioglitazone treatment improved cognitive performance, lowered oxidative stress and improved cerebral glucose utilization in ICV STZ rats. The present study demonstrates the beneficial effects of pioglitazone in the ICV STZ induced cognitive deficits, which can be exploited for the dementia associated with diabetes and age-related neurodegenerative disorder, where oxidative stress and impaired glucose and energy metabolism are involved.

Fruit Extract of Emblica Officinalis (Amla) Protects Radiation Induced Biochemical Lesions In The Brain of Swiss Albino Mice

The alterations in enzymatic and biochemical activities were investigated in the brain of Swiss albino mice, with (experimental) or without (control) fruit extract before exposure to 5 Gy gamma radiation. The value of serum acid phosphatase activity were significantly higher in the irradiated group throughout the experiments compared to normal. However, this activity in Emblica officinalis pretreated irradiated animals showed a significant decline over untreated irradiated animals at all the autopsy intervals and attained the normal value by day 20th of treatment conversely, a marked decrease in serum alkaline phosphatase activity was noted in both the irradiated groups, but in the Emblica officinalis pretreated group an elevation in protein and cholesterol levels was observed. Furthermore, Emblica officinalis inhibited lipid peroxidation and increased glutathione (GSH) level in brain. doi; 10.5214/ans.0972.7531.2006.130302

Impairment in Consolidation of Learned Place Preference Following Dopaminergic Neurotoxicity in Mice is Ameliorated by N-acetylcysteine but not D1 and D2 Dopamine Receptor Agonists

Some of the major concerns related to methamphetamine (METH) abuse are the neuronal damage inflicted at dopamine (DA) nerve terminals and the cognitive deficits observed in human METH abusers. We have shown that a high dose of METH selectively depleted dopaminergic markers in striatum, frontal cortex and amygdala of Swiss Webster mice, and impaired learned place preference. In this study, we investigated whether deficits in consolidation of place learning, as a consequence of METH neurotoxicity, underlie the underperformance of cocaine conditioned place preference (CPP). Administration of METH (5 mg/kg x 3) to Swiss Webster mice decreased striatal tyrosine hydroxylase (TH) immunoreactive neurons and significantly increased glial fibrillary acidic protein (GFAP) expression, confirming the neurotoxic potential of METH in mice. This treatment significantly attenuated the establishment of cocaine (15 mg/kg) CPP compared to control. To investigate whether manipulation of the consolidation phase improves learned place preference, mice were trained by cocaine and received daily post-training injections of DA receptor agonists or N-acetylcysteine (NAC). As memory consolidation occurs shortly after training, drugs were administered either immediately or 2 h post-training. Immediate post-training administration of the D1 DA receptor agonist SKF38393 (5, 10, and 20 mg/kg) or the D2 DA receptor agonist quinpirole (0.25, 0.5, and 1.0 mg/kg) did not improve the establishment of CPP following METH neurotoxicity. However, immediate but not delayed NAC administration (50 and 100 mg/kg) enhanced cocaine CPP following METH neurotoxicity and had no effect on control CPP. The levels of the reduced form of glutathione (GSH) in striatum, amygdala, hippocampus and frontal cortex were significantly lower in METH-treated mice compared to control during the period of CPP training. Acute and repeated administration of NAC to METH-treated mice restored the decreased brain GSH but had no effect on controls. Results suggest that METH-induced dopaminergic neurotoxicity is associated with impairment of consolidation of learned place preference, and that this impairment is improved by immediate post-training administration of the glutathione precursor NAC and not by D1 or D2 DA receptor agonists. Restoration of brain glutathione levels immediately post-training may facilitate the consolidation process.