Acute exhaustive exercise does not alter lipid peroxidation levels and antioxidant enzyme activities in rat hippocampus, prefrontal cortex and striatum

Although regular physical exercise is beneficial to the body, it is well known that exhaustive exercise causes oxidative stress in muscle. Recent studies suggest that regular moderate physical exercise has the beneficial effects on brain. However, there is little information regarding whether or not exhaustive exercise could generate oxidative stress in brain and the findings are conflicting. The aim of this study was to investigate the effects of exhaustive exercise on thiobarbituric acid reactive substances, as an indicator of lipid peroxidation, in the hippocampus, prefrontal cortex and striatum. Additionally we examined antioxidant enzymes activities, superoxide dismutase and glutathione peroxidase, to assess the effects of reactive oxygen species. Exhaustive exercise did not change superoxide dismutase and glutathione peroxidase enzyme activities and thiobarbituric acid reactive substances levels neither immediately (0 min) nor at 3, 6, 12, 24 and 48 h after the cessation of exercise in the brain. These results indicate that acute exhaustive exercise may not cause significant lipid peroxidation in the hippocampus, prefrontal cortex and striatum during the post-exercise period.     

Swimming exercise effects on the expression of HSP70 and iNOS in hippocampus and prefrontal cortex in combined stress

Exercise could play a beneficial role in stress, but its underlying mechanism especially about heat shock protein 70 (HSP70) and inducible nitric oxide synthase (iNOS) in brain has not been fully clarified. Moreover, few studies have investigated swimming exercise and its effects on the combined stress of both chronic and acute stress. In this study we tried to investigate the role of swimming exercise in combined stress and whether its biological mechanism was related to the HSP70 and iNOS in hippocampus and prefrontal cortex. 32 Wistar rats were enrolled and divided into four groups: control, CUMS, labetalol and exercise. After the animal model of chronic unpredicted mild stress (CUMS) was built in the latter three groups, all the rats were given the novel acute stress of inescapable footshock. The behavioral changes were measured by open field test. Radioimmunoassay (RIA) was adopted to test the change of serum corticosterone (CORT). The expression of HSP70 and iNOS in hippocampus and prefrontal cortex was analyzed by Western blot. The results demonstrated that swimming exercise could not only improve the behavior changes and protect the function of HPA axis stable in CUMS animals exposed to novel acute stress, but also increase the HSP70 expression and decrease the iNOS expression in hippocampus and prefrontal cortex. In conclusion, swimming exercise could play a beneficial role in combined stress by up-regulating HSP70 level and down-regulating iNOS level in brain.     

Inhibition of brain creatine kinase activity after renal ischemia is attenuated by N-acetylcysteine and deferoxamine administration

Encephalopathy may accompany acute or chronic renal failure, and the mechanisms responsible for neurological complications in patients with renal failure are poorly known. Considering that creatine kinase (CK) is important for brain energy homeostasis and is inhibited by free radicals, and that oxidative stress is probably involved in the pathogenesis of uremic encephalopathy, we measured CK activity (hippocampus, striatum, cerebellum, cerebral cortex and prefrontal cortex) in brain if rats submitted to renal ischemia and the effect of administration of antioxidants (N-acetylcysteine, NAC and deferoxamine, DFX) on this enzyme. We verified that CK activity was not altered in cerebellum and striatum of rats. CK activity was inhibited in prefrontal cortex and hippocampus of rats 12h after renal ischemia. The treatment with antioxidants prevented such effect. Cerebral cortex was also affected, but in this area CK activity was inhibited 6 and 12h after renal ischemia. Moreover, only NAC or NAC plus DFX were able to prevent the inhibition on the enzyme. Although it is difficult to extrapolate our findings to the human condition, the inhibition of brain CK activity after renal failure may be associated to neuronal loss and may be involved in the pathogenesis of uremic encephalopathy.     

Treatment with olanzapine, fluoxetine and olanzapine/fluoxetine alters citrate synthase activity in rat brain

A growing body of evidence has indicated that energy metabolism impairment may be involved in pathophysiology of some neuropsychiatric disorders. In this study, we evaluated the effect of acute and chronic administration of fluoxetine, olanzapine and the combination of fluoxetine/olanzapine on citrate synthase activity in brain of rats. For acute treatment, Wistar rats received one single injection of olanzapine (3 or 6mg/kg) and/or fluoxetine (12.5 or 25mg/kg). For chronic treatment, rats received daily injections of olanzapine (3 or 6mg/kg) and/or fluoxetine (12.5 or 25mg/kg) for 28 days. In the present study we observed that acute administration of olanzapine inhibited citrate synthase activity in cerebellum and prefrontal cortex. The acute administration of olanzapine increased citrate synthase activity in prefrontal cortex, hippocampus and striatum and fluoxetine increased citrate synthase activity in striatum. Olanzapine 3mg/kg and fluoxetine 12.5mg/kg in combination increased citrate synthase activity in prefrontal cortex, hippocampus and striatum. In the chronic treatment we did not observed any effect on citrate synthase activity. Our results showed that olanzapine and fluoxetine increased citrate synthase activity after acute, but not chronic treatment.     

Oxidative damage and sensitivity to nociceptive stimulus and opioids in aging rats

Oxidative stress contributes to aging and may cause alterations in pain and analgesia. Knowledge about effects of oxidative stress on the opioid system is very limited. This project was designed to determine the relationship between age-related oxidative damage and opioid antinociception. Three age groups of male Fischer 344 rats were tested for pain sensitivity and responses to morphine and fentanyl using the hot plate method. Oxidative stress markers in various brain regions were measured. With advancing age, nociceptive threshold and antinociceptive effects of opioids decreased significantly. There was a significant negative correlation between morphine antinociception and protein oxidation in cortex, striatum, and midbrain (r(2)=0.73, 0.87, and 0.77, respectively), and lipid peroxidation in cerebral cortex, hippocampus, and striatum (r(2)=0.73, 0.61, and 0.71, respectively). Similar correlation was observed between oxidative stress markers and fentanyl antinociception. These findings demonstrate that the age-related increase in oxidative damage in brain is associated with a significant decrease in the antinociceptive effects of opioids.     

Age-related changes in Cu,Zn superoxide dismutase, Se-dependent and -independent glutathione peroxidase and catalase activities in specific areas of rat brain.

Oxidative injury of tissues involves both accumulation of damage due to persistent oxidative stress and loss of the proper balance of antioxidative enzymes. These events may produce a faster rate of tissue senescence. In this regard, we have assayed the antioxidative enzyme activities (Cu,Zn superoxide dismutase, glutathione peroxidase and catalase), in various areas of rat brain (prefrontal cortex, parietal cortex, hippocampus, hypothalamus, caudate nucleus, mesencephalon and lower brain stem) for the age groups of 3, 6, 12, 24 months. The results obtained show that the levels of antioxidant enzyme activities differed considerably in the various brain parts studied. Furthermore, changes in the specific activities of superoxide dismutase, catalase, and glutathione peroxidase did not follow the same pattern as a function of aging. In particular, in prefrontal cortex and caudate nucleus, superoxide dismutase and glutathione peroxidase activities did not change, while catalase activity decreased. In parietal cortex and mesencephalon, superoxide dismutase and glutathione peroxidase activities increased, but the catalase activity decreased in parietal cortex and did not change in mesencephalon. In lower brain stem, the activities of glutathione peroxidase and catalase decreased in 3-12-month-old rats. The activity of glutathione peroxidase was increased in the hippocampus and was decreased in hypothalamus during aging. In this area the catalase activity was also significantly diminished.     

Effects of moderate exercise on cigarette smoke exposure-induced hippocampal oxidative stress values and neurological behaviors in mice

The objective of the present study was to investigate the effects of exercise training on behavior and neurochemical parameters in mice exposed to cigarette smoke. To this aim, mice (C57 BL6) male (30–35 g) were exposed to cigarette smoke 60 consecutive days three times a day and they were subjected to treadmill training 8 weeks for 5 days/week. For behavior assessment, mice were tested in the open-field and forced to a swim test. The superoxide anion, thiobarbituric acid reactive substances and protein carbonyl formation were measured as markers of oxidative stress in hippocampus of mice. In addition, the brain-derived neurotrophic factor (BDNF) levels were measured in the hippocampus samples. Cigarette smoke group and cigarette smoke plus exercise group, increased immobility time in forced swimming test in rats compared to the control group, without affecting spontaneous locomotor activity. There was an increase in the levels of superoxide, TBARS and of protein carbonyl and a decreased in BDNF levels in the hippocampus of rats exposed to cigarette smoke and cigarette smoke plus exercise. Exercise alone did not change any of the parameters evaluated in this study. In conclusion, we observed that physical training improves the oxidative stress parameters, but does not alter depressive-like behavior neither prevent the decreases in BDNF levels in hippocampus induced by cigarette smoke.     

Haloperidol and clozapine, but not olanzapine, induces oxidative stress in rat brain

Typical and atypical antipsychotic drugs have been shown to have different clinical and behavioral profiles. Haloperidol (HAL) is a typical neuroleptic that acts primarily as a D2 dopamine receptor antagonist. It has been proposed that reactive oxygen species play a causative role in neurotoxic effects induced by HAL. We evaluated oxidative damage in rat brain induced by chronic HAL, clozapine (CLO) or olanzapine (OLZ) administration. Adult male Wistar rats received daily injections of Hal (1.5mg/kg), CLO (25mg/kg) or OLZ (2.5, 5.0 or 10.0mg/kg). Control animals were given saline (SAL; NaCl 0.9%). Thiobarbituric acid reactive substances (TBARS) and protein carbonylation were measured in the hippocampus (HP), striatum (ST) and cortex (CX). TBARS was increased in the striatum after HAL treatment. In contrast, there was a decrease of TBARS levels induced by HAL, CLO and OLZ treatments in the cortex. Protein carbonyls after HAL and CLO treatment was increased in the hippocampus, compared to control. In hippocampus, OLZ did not show significant difference to control in both oxidative parameters. Our findings demonstrated that atypical antipsychotic CLO produced less oxidative damage than HAL and we did not find oxidative damage induced by OLZ.     

Disruption of brain redox homeostasis in glutaryl-CoA dehydrogenase deficient mice treated with high dietary lysine supplementation

Deficiency of glutaryl-CoA dehydrogenase (GCDH) activity or glutaric aciduria type I (GA I) is an inherited neurometabolic disorder biochemically characterized by predominant accumulation of glutaric acid and 3-hydroxyglutaric acid in the brain and other tissues. Affected patients usually present acute striatum necrosis during encephalopathic crises triggered by metabolic stress situations, as well as chronic leukodystrophy and delayed myelination. Considering that the mechanisms underlying the brain injury in this disease are not yet fully established, in the present study we investigated important parameters of oxidative stress in the brain (cerebral cortex, striatum and hippocampus), liver and heart of 30-day-old GCDH deficient knockout (Gcdh^?/?) and wild type (WT) mice submitted to a normal lysine (Lys) (0.9% Lys), or high Lys diets (2.8% or 4.7% Lys) for 60 h. It was observed that the dietary supplementation of 2.8% and 4.7% Lys elicited noticeable oxidative stress, as verified by an increase of malondialdehyde concentrations (lipid oxidative damage) and 2-7-dihydrodichlorofluorescein (DCFH) oxidation (free radical production), as well as a decrease of reduced glutathione levels and alteration of various antioxidant enzyme activities (antioxidant defenses) in the cerebral cortex and the striatum, but not in the hippocampus, the liver and the heart of Gcdh^?/? mice, as compared to WT mice receiving the same diets. Furthermore, alterations of oxidative stress parameters in the cerebral cortex and striatum were more accentuated in symptomatic, as compared to asymptomatic Gcdh^?/? mice exposed to 4.7% Lys overload. Histopathological studies performed in the cerebral cortex and striatum of these animals exposed to high dietary Lys revealed increased expression of oxidative stress markers despite the absence of significant structural damage. The results indicate that a disruption of redox homeostasis in the cerebral cortex and striatum of young Gcdh^?/? mice exposed to increased Lys diet may possibly represent an important pathomechanism of brain injury in GA I patients under metabolic stress.     

Age-dependent effects of maternal deprivation on oxidative stress in infant rat brain

Developing brain is much more sensitive to all kind of stressors than the developed brain. Early maternal deprivation causes some behavioural and physiological effects on rats. After the birth, there is no endocrinological response to stressors between post-natal 4 and 14th days, which is called stress-hyporesponsive period (SHRP) in rats. This hypo-responsiveness is time- and stressor-specific, as some more severe stressors have been shown to induce a stress response. The present study examined the effects of maternal deprivation on oxidative stress in the hippocampus, prefrontal cortex (PFC) and striatum regions of the brain both during and after SHRP of the infant rats. The results showed that maternal deprivation in SHRP increased antioxidant enzyme activities and reduced lipid peroxidation in infant rat brain. However, by the termination of SHRP, maternal deprivation reduced enzyme activities and increased lipid peroxidation. The results indicated that infant brain might be protected in SHRP from maternal deprivation-induced oxidative stress.     

Physiology and neurobiology of stress and adaptation: central role of the brain

The brain is the key organ of the response to stress because it determines what is threatening and, therefore, potentially stressful, as well as the physiological and behavioral responses which can be either adaptive or damaging. Stress involves two-way communication between the brain and the cardiovascular, immune, and other systems via neural and endocrine mechanisms. Beyond the "flight-or-fight" response to acute stress, there are events in daily life that produce a type of chronic stress and lead over time to wear and tear on the body ("allostatic load"). Yet, hormones associated with stress protect the body in the short-run and promote adaptation ("allostasis"). The brain is a target of stress, and the hippocampus was the first brain region, besides the hypothalamus, to be recognized as a target of glucocorticoids. Stress and stress hormones produce both adaptive and maladaptive effects on this brain region throughout the life course. Early life events influence life-long patterns of emotionality and stress responsiveness and alter the rate of brain and body aging. The hippocampus, amygdala, and prefrontal cortex undergo stress-induced structural remodeling, which alters behavioral and physiological responses. As an adjunct to pharmaceutical therapy, social and behavioral interventions such as regular physical activity and social support reduce the chronic stress burden and benefit brain and body health and resilience.     

Alpha-lipoic acid differently affects the reserpine-induced oxidative stress in the striatum and prefrontal cortex of rat brain

Antioxidative properties of alpha-lipoic acid (LA) are widely investigated in different in vivo and in vitro models. The aim of this study was to examine whether LA attenuates oxidative stress induced in rats by reserpine, a model substance frequently used to produce Parkinsonism in animals. Male Wistar rats were treated with reserpine (5 mg/kg) and LA (50 mg/kg) separately or in combination. The levels of reduced glutathione (GSH), glutathione disulfide (GSSG), nitric oxide (NO) and S-nitrosothiols as well as activities of glutathione peroxidase (GPx), glutathione-S-transferase (GST) and L-gamma-glutamyl transpeptidase (gamma-GT) were determined in the striatum and prefrontal cortex homogenates. In the striatum and prefrontal cortex a single dose of reserpine significantly enhanced levels of GSSG and NO but not that of S-nitrosothiols when compared with control. In the striatum, LA administered jointly with reserpine markedly increased the concentration of GSH and decreased GSSG level. In the prefrontal cortex, such treatment produced only an increasing tendency in GSH level but caused no changes in GSSG content. In both structures LA injected jointly with reserpine markedly decreased NO concentrations but did not cause significant changes in S-nitrosothiol levels when compared with control. Enzymatic activities of GPx and GST were intensified by LA in the striatum. In the prefrontal cortex, GPx activity was not altered, while that of GST was decreased. Gamma-GT activity was attenuated by reserpine in the striatum while LA reversed this effect. Such changes were not observed in the prefrontal cortex. The mode of LA action in the striatum during the reserpine-evoked oxidative stress strongly suggests that this compound may be of therapeutic value in the treatment of Parkinson's disease.     

Neuroprotective and anti-stress effect of A68930 in acute and chronic unpredictable stress model in rats

The neurorescuing effect of A68930 (a potent selective D₁ agonist) and its role on the regulation of hypothalamus-pituitary-adrenal (HPA)-axis have been investigated. Acute (AS) and chronic unpredictable (CUS) stress models were used to evaluate the effect of A68930 on HPA-axis regulation in relation to the change in the fiber density and number of immunoreactive (ir) neurons of tyrosine hydroxylase (TH) and glucocorticoid receptor (GR) in the dopamine (DA) and GR rich brain regions in rats. CUS caused a significant decrease in the number of TH ir neurons in the striatum, medial forebrain bundle, ventral tegmental area and substansia nigra and GR in the cortex, striatum and hippocampus as compared to the non-stress controls (NS). Administration of A68930 (0.25 mg/kg i.p.) significantly normalized these CUS-induced alterations. We also examined the role of A68930 on stress-induced brain oxidative status. AS enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the cortex and striatum, while CUS reduced the activities of SOD and catalase (CAT) in the cortex, striatum and hippocampus, when compared with NS. Increased GSH-Px activity, with reduced glutathione and increased lipid peroxidation was observed in both AS and CUS in selected brain regions as compared to NS. Administration of A68930 normalized the antioxidant enzyme activities, replenished GSH and decreased the extent of lipid peroxidation. In conclusion, present findings suggest that the stress-induced immunoreactivity of TH and GR in distinct brain regions are modulated by A68930 leading to the normalization of HPA-axis response. Ours results show the therapeutic importance of DA D₁ agonist in stress-induced dopaminergic-related neurological disorders. A68930 also influenced the brain antioxidant machinery probably through the restoration of stress-induced changes in the dopaminergic system and its crosstalk with GR.     

Nylon filament coated with paraffin for intraluminal permanent middle cerebral artery occlusion in rats

Decreased dopamine (DA) release in the hippocampus may be caused by dysfunctional mastication, although the mechanisms involved remain unclear. The present study examined the effects of soft- and hard-food diets on oxidative stress in the brain, and the relationship between these effects and hippocampal DA levels. The present study showed that DA release in the hippocampus was decreased in rats fed a soft-food diet. Electron spin resonance studies using the nitroxyl spin probe 3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl directly demonstrated a high level of oxidative stress in the rat brain due to soft-food diet feeding. In addition, we confirmed that DA directly react with reactive oxygen species such as hydroxyl radical and superoxide. These observations suggest that soft-food diet feeding enhances oxidative stress, which leads to oxidation and a decrease in the release of DA in the hippocampus of rats.     

Jobelyn® ameliorates neurological deficits in rats with ischemic stroke through inhibition of release of pro-inflammatory cytokines and NF-κB signaling pathway

The effects of Jobelyn® (JB) on neurological deficits and biochemical alterations associated with ischemic stroke induced by bilateral common carotid artery occlusion (BCCAO) in rats were investigated in this study. Male Wistar rats were divided into five groups (n?=?8): group 1 served as Sham control; group 2, which served as negative control received normal saline while groups 3–5 were given JB (25, 50 and 100?mg/kg, p.o) daily for 28 days. Then, rats in groups 2–5 were subjected to BCCAO for 30?min and reperfusion afterwards. Neurological deficits were assessed 3?h post-reperfusion using a 9-point neurological scoring scale. The levels of biomarkers of oxidative stress and pro-inflammatory cytokines (tumour necrotic factor-α and interleukin-6), expressions of immunopositive cells of nuclear factor-kappa B (NF-κB) and acetyl-cholinesterase (AChE) activity were determined in brain tissues. Histology of the striatum, prefrontal cortex (PFC) and hippocampus (CA1) was also evaluated. JB improved BCCAO-induced neurological deficits and attenuated increased oxidative stress and AChE activity in rats subjected to BCCAO (p?<?0.05). Increased brain levels of tumour necrotic factor-α and interleukin-6 as well as expressions of immunopositive cells of NF-κB were decreased by JB. JB reduced brain damage and also increased population of viable neurons in the striatum, PFC and hippocampus of ischemic stroke rats. These findings suggest that the positive effect of JB on neurological function in rats with ischemic stroke may be related to inhibition of oxidative stress, release of pro-inflammatory cytokines and expressions of immunopositive cells of NF-κB.     

Maternal exercise decreases maternal deprivation induced anxiety of pups and correlates to increased prefrontal cortex BDNF and VEGF

Maternal deprivation (MD) may cause neuropsychiatric disorders such as anxiety disorder by negatively affecting the cognitive functions and behavior in pups. The aim of this study is to investigate whether maternal exercise during pregnancy has beneficial effects on anxiety that increases with MD, and on the levels of VEGF and BDNF which have anxiolytic effects on the prefrontal cortex, the anxiety-related region of the brain. The anxiety level in the deprivation group was greater than the control group and found more in male than female pups. The prefrontal cortex VEGF and BDNF levels were decreased in the deprivation group compared to control group while serum corticosterone levels were increased in the deprivation group. Anxiety and serum corticosterone levels were decreased in maternally exercised female and male pups, while the prefrontal cortex VEGF and BDNF levels were increased, compared to sedentary mother's pups. These results indicate that maternal exercise may attenuate the negative effect of stresses such as maternal deprivation that can be encountered early in life.     

The effects of regular aerobic exercise in adolescent period on hippocampal neuron density, apoptosis and spatial memory

It is known that positive effects of regular aerobic exercise on cognitive functions in humans and also animals; but how to the effects of aerobic exercise in adolescent period is unknown. The present study examined the effects of regular aerobic exercise on spatial memory using the Morris water maze, cell density and apoptosis of hippocampus in adolescent rats. Twenty-two days of age male rats were run on a treadmill for 30 min/session at a speed of 8m/min and 0 degrees slope, five times a week for 8 weeks. The present study showed that exercise induced significant cognitive improvement throughout brain maturation in rats. The number of hippocampal CA1 and CA3 neurons, and gyrus dentatus neurons were significantly increased in the exercised rats. There was no significant difference of CA2 neuron density between exercise and control groups. There was no significantly differences in any groups according to the results of apoptosis that account of TUNEL positive cells. The present results suggest that regular moderate aerobic treadmill exercise benefit in cognitive functions. This result may derive from treadmill exercise-induced increase cell density without altering of apoptosis in the hippocampus and dentate gyrus of adolescent rats.     

Catalase activity in cerebellum, hippocampus, frontal cortex and striatum after status epilepticus induced by pilocarpine in Wistar rats

The mechanism underlying the vulnerability of the brain to status epilepticus (SE) induced by pilocarpine remains unknown. Oxidative stress has been implicated in a variety of acute and chronic neurologic conditions, including SE. The present study was aimed at was investigating the changes in catalase activity after pilocarpine-induced seizures and SE. The Control group was treated with 0.9% saline (NaCl, subcutaneously (s.c.)) and sacrificed 1h after the treatment. Another group was treated with pilocarpine (400 mg/kg, s.c., Pilocarpine group) and sacrificed 1h after treatment. The catalase activity in the cerebellum, hippocampus, frontal cortex and striatum of Wistar rats was determined. The results have shown that pilocarpine administration and resulting SE produced a significant increase in the catalase activity in the hippocampus (36%), striatum (31%) and frontal cortex (15%) of treated adult rats. Nevertheless, in the adult rat cerebellum after SE induced by pilocarpine no change was observed in the catalase activity. Our results demonstrated a direct evidence of an increase in the activity of the scavenging enzyme (catalase) in different cerebral structures during seizure activity that could be responsible for eliminating oxygen free radicals and might be one of the compensatory mechanisms to avoid the development of oxidative stress during the establishment of SE induced by pilocarpine. Our reports also indicate clear regional differences in the catalase activity caused by pilocarpine-induced seizures and SE and the hippocampus might be the principal area affected and cerebellum does not modify for this parameter studied during epileptic activity.     

Induction of oxidative stress in brain of glutaryl-CoA dehydrogenase deficient mice by acute lysine administration

In the present work we evaluated a variety of indicators of oxidative stress in distinct brain regions (striatum, cerebral cortex and hippocampus), the liver, and heart of 30-day-old glutaryl-CoA dehydrogenase deficient (Gcdh(-/-)) mice. The parameters evaluated included thiobarbituric acid-reactive substances (TBA-RS), 2-7-dihydrodichlorofluorescein (DCFH) oxidation, sulfhydryl content, and reduced glutathione (GSH) concentrations. We also measured the activities of the antioxidant enzymes glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), superoxide dismutase (SOD) and glucose-6-phosphate dehydrogenase (G6PD). Under basal conditions glutaric (GA) and 3-OH-glutaric (3OHGA) acids were elevated in all tissues of the Gcdh(-/-) mice, but were essentially absent in WT animals. In contrast there were no differences between WT and Gcdh(-/-) mice in any of the indicators or oxidative stress under basal conditions. Following a single intra-peritoneal (IP) injection of lysine (Lys) there was a moderate increase of brain GA concentration in Gcdh(-/-) mice, but no change in WT. Lys injection had no effect on brain 3OHGA in either WT or Gcdh(-/-) mice. The levels of GA and 3OHGA were approximately 40% higher in striatum compared to cerebral cortex in Lys-treated mice. In the striatum, Lys administration provoked a marked increase of lipid peroxidation, DCFH oxidation, SOD and GR activities, as well as significant reductions of GSH levels and GPx activity, with no alteration of sulfhydryl content, CAT and G6PD activities. There was also evidence of increased lipid peroxidation and SOD activity in the cerebral cortex, along with a decrease of GSH levels, but to a lesser extent than in the striatum. In the hippocampus only mild increases of SOD activity and DCFH oxidation were observed. In contrast, Lys injection had no effect on any of the parameters of oxidative stress in the liver or heart of Gcdh(-/-) or WT animals. These results indicate that in Gcdh(-/-) mice cerebral tissue, particularly the striatum, is at greater risk for oxidative stress than peripheral tissues following Lys administration.     

N-acetyl cysteine restores brain glutathione loss in combined 2-cyclohexene-1-one and d-amphetamine-treated rats: relevance to schizophrenia and bipolar disorder

Oxidative stress and reduced brain levels of glutathione have been implicated in schizophrenia and bipolar disorder. N-acetyl cysteine (NAC) is a precursor of glutathione and has additional effects on glutamate neurotransmission, neurogenesis and inflammation. While NAC treatment has shown benefits in both schizophrenia and bipolar disorder, the mechanisms of action are largely unknown. Similarly, the interaction between oxidative stress and altered dopaminergic activities in psychiatric illness is not yet characterized. This study investigated the capacity of NAC in restoring brain glutathione depletion in rats that received 2-cyclohexene-1-one (CHX, 75 mg/kg), d-amphetamine (2.5mg/kg) or both. CHX, but not amphetamine, induced significant depletion of glutathione levels in the striatum and frontal cortex. Glutathione depletion was reversed by NAC (1000 mg/kg) in saline-treated and amphetamine-treated (frontal cortex only) rats. While NAC was shown to be beneficial in this model, the lack of additional glutathione depletion by amphetamine in combination with CHX does not support a summative interaction between oxidative stress and altered dopamine transmission.