The effects of oxidative stress on in vivo brain GSH turnover in young and mature mice

Glutathione (GSH) synthetase activities and GSH turnover rates were examined during severe oxidative stress in the mouse brain as induced byt-butylhydroperoxide (t-BuOOH). Brain GSH synthetase activities in 8-mo-old mice in the cortex, striatum, thalamus, hippocampus, midbrain, and cerebellum were found to increase followingt-BuOOH treatment. The effect of GSH synthesis on brain GSH turnover rates for 2- and 8-mo-old mice were determined after intracerebroventricular (icv) injection of [³⁵S]cysteine. Rate constants for GSH turnover were determined by least-squares iterative minimization from the specific activity data from 20 min to 108 h after [³⁵S]cysteine administration. GSH and glutathione disulfide (GSSG) specific activities were determined after separation by high-pressure liquid chromatography (HPLC). The half-life of GSH in the 2-mo-old mouse was 59.5 h and in the 8-mo-old mouse was 79.1 h. In summary, defense mechanisms against oxidative stress in the brain differ with age. Young mice can increase the cellular availability of GSH, whereas mature mice can increase GSH synthetase activity during oxidative stress. These differences make mature mice more susceptible to brain oxidative damage.     

Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain

Despite increasing evidence of oxidative stress in the pathophysiology of autism, most studies have not evaluated biomarkers within specific brain regions, and the functional consequences of oxidative stress remain relatively understudied. We examined frozen samples from the cerebellum and temporal cortex (Brodmann area 22 (BA22)) from individuals with autism and unaffected controls (n=15 and n=12 per group, respectively). Biomarkers of oxidative stress, including reduced glutathione (GSH), oxidized glutathione (GSSG) and glutathione redox/antioxidant capacity (GSH/GSSG), were measured. Biomarkers of oxidative protein damage (3-nitrotyrosine; 3-NT) and oxidative DNA damage (8-oxo-deoxyguanosine; 8-oxo-dG) were also assessed. Functional indicators of oxidative stress included relative levels of 3-chlorotyrosine (3-CT), an established biomarker of a chronic inflammatory response, and aconitase activity, a biomarker of mitochondrial superoxide production. Consistent with previous studies on plasma and immune cells, GSH and GSH/GSSG were significantly decreased in both autism cerebellum (P<0.01) and BA22 (P<0.01). There was a significant increase in 3-NT in the autism cerebellum and BA22 (P<0.01). Similarly, 8-oxo-dG was significantly increased in autism cerebellum and BA22 (P<0.01 and P=0.01, respectively), and was inversely correlated with GSH/GSSG in the cerebellum (P<0.01). There was a significant increase in 3-CT levels in both brain regions (P<0.01), whereas aconitase activity was significantly decreased in autism cerebellum (P<0.01), and was negatively correlated with GSH/GSSG (P=0.01). Together, these results indicate that decreased GSH/GSSG redox/antioxidant capacity and increased oxidative stress in the autism brain may have functional consequence in terms of a chronic inflammatory response, increased mitochondrial superoxide production, and oxidative protein and DNA damage.     

Time-course of changes in water,sodium, potassium and calcium contents of various brain regions in rats after systemic kainic acid administration

Summary The changes in the water, sodium, potassium and calcium content of the frontoparietal cortex, hippocampus, thalamus and cerebellum in rats were investigated 2, 4, 8, 12 and 24 h and 3 and 7 days after systemic kainic acid administration. The water content was significantly increased in the thalamus and hippocampus 4 and 8 h, respectively, after the kainic acid injection and remained elevated at each subsequent time point. No change was found in the water content of the frontoparictal cortex and cerebellum. The sodium content of the frontoparietal cortex, hippocampus and thalamus was increased 4 h after kainic acid administration, and that of the cerebellum after 8 h. These levels remained elevated throughout the 7 days, with the exception of that for the frontoparietal cortex. A significant potassium decrease was observed in all brain regions investigated. Calcium accumulation was found to begin 4 h after kainic acid administration and was the most pronounced on the 7th day in the thalamus and hippocampus. Electron microscope investigations revealed a mainly intramitochondrial calcium accumulation in these brain regions. Pretreatment with Verapamil did not prevent calcium accumulation. The ion shifts and the development of edema in the thalamus and hippocampus in the early period, and also the changes of the sodium and potassium contents in the frontoparietal cortex and cerebellum in the early and late (12 h and later) periods, can be regarded as concomitant events of epileptic activity. In the hippocampus and thalamus, severe secondary necrotic and hemorrhagic neuropathological damage was accompained by ion shifts and edema in the late period after systemic kainic acid administration.     

Effects of age and caloric intake on glutathione redox state in different brain regions of C57BL/6 and DBA/2 mice

The main purpose of the present study was to determine whether specific regions of the mouse brain exhibit different age-related changes in oxidative stress, as indicated by glutathione redox state and the level of protein-glutathionyl mixed disulfides. Comparison of 3- and 21-month-old mice indicated an age-related decrease in the ratio of reduced to oxidized glutathione (GSH/GSSG) as well as a pro-oxidizing shift in the calculated redox potential (ranging from 6 to 15 mV) in the cortex, hippocampus, striatum and cerebellum, whereas there was little change in the brainstem. This pro-oxidizing shift in redox state was due to a modest decrease in GSH content occurring in all the brain regions examined, and elevations in GSSG amount that were most pronounced in the striatum and cerebellum. The regional changes in glutathione redox state were paralleled by increases in the amounts of protein-mixed disulfides. A reduction of caloric intake by 40% for a short period (7 weeks), implemented in relatively old mice (17 months), increased the GSH/GSSG ratio and redox potential at 19 months in the same brain regions that exhibited age-related decreases. The effects of age and caloric restriction were qualitatively similar in C57BL/6 and DBA/2 mice. However, young DBA/2 mice, which do not show extension of life span in response to long-term caloric restriction, had lower GSH/GSSG ratios and higher protein-mixed disulfides than age-matched C57BL/6 mice. The current findings demonstrate that oxidative stress, as reflected by glutathione redox state, increases in the aging brain in regions linked to age-associated losses of function and neurodegenerative diseases.     

Protection against kainate neurotoxicity by ginsenosides: attenuation of convulsive behavior, mitochondrial dysfunction, and oxidative stress

We previously demonstrated that kainic acid (KA)-mediated mitochondrial oxidative stress contributed to hippocampal degeneration and that ginsenosides attenuated KA-induced neurotoxicity and neuronal degeneration. Here, we examined whether ginsenosides affected KA-induced mitochondrial dysfunction and oxidative stress in the rat hippocampus. Treatment with ginsenosides attenuated KA-induced convulsive behavior dose-dependently. KA treatment increased lipid peroxidation and protein oxidation and decreased the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio to a greater degree in the mitochondrial fraction than in the hippocampal homogenate. KA treatment resulted in decreased Mn-superoxide dismutase expression and diminished the mitochondrial membrane potential. Furthermore, KA treatment increased intramitochondrial Ca(2+) and promoted ultrastructural degeneration in hippocampal mitochondria. Treatment with ginsenosides dose-dependently attenuated convulsive behavior and the KA-induced mitochondrial effects. Protection appeared to be more evident in mitochondria than in tissue homogenates. Collectively, the results suggest that ginsenosides prevent KA-induced neurotoxicity by attenuating mitochondrial oxidative stress and mitochondrial dysfunction.     

Effect of pentylenetetrazol-induced epileptic seizure on thiol redox state in the mouse cerebral cortex

In the present study we examined the effects of pentylenetetrazol (PTZ) administration on the thiol redox state (TRS), lipid peroxidation and protein oxidation in left and right mouse cerebral cortex in order (a) to quantitate the major components of the thiol redox state and relate them with oxidative stress and cortical laterality, and (b) to investigate whether neuronal activation without synchronization, induced by subconvulsive doses of PTZ, can cause similar qualitative effects on the thiol redox state. Specifically, we examined the TRS components [glutathione (GSH), glutathione disulfide (GSSG), cysteine (CSH), protein (P) thiols (PSH) and protein and non-protein (NP) mixed/symmetric disulfides (PSSR, NPSSR, NPSSC, PSSP)]. At 15 min after seizure, GSH, GSSG, CSH, NPSSC, PSSR and PSSC levels are decreased in left (14-50%) and right (11-53%) cortex while PSSP levels are increased in both left (1400%) and right (1600%) cortex. At 30 min after seizure, GSSG, CSH, NPSSC, PSSR and PSSC levels are decreased in left (14-51%) and right (18-56%) cortex while PSSP and protein carbonyl levels are increased in left (2300% and 20%, respectively) and right (2800% and 21%, respectively) cortex. At 24 h after seizure, the TRS components return to normal and protein carbonyl levels are decreased in left (16%) and right (20%) cortex. The significant decrease in GSH, GSSG, CSH, NPSSC, PSSR and PSSC, as well as the increase in protein carbonyl and the high increase in PSSP levels after PTZ-induced seizure indicate increased oxidative stress in cerebral cortex of mice, and of similar magnitude and TRS-component profiles between left and right cerebral cortex.     

Protective effects of guanosine against sepsis-induced damage in rat brain and cognitive impairment

The development of cognitive impairment in sepsis is associated with neurotoxic effects caused by oxidative stress. We have assessed the effects of acute and extended administration of guanosine (GUA) on brain oxidative stress parameters and cognitive impairment in rats submitted to sepsis by cecal ligation and perforation (CLP). To achieve this goal, male Wistar rats underwent either sham operation or CLP with GUA. Rats subjected to CLP were treated with intraperitoneal injection of GUA (8 mg/kg after CLP) or vehicle. Twelve and 24 h after CLP, the rats were sacrificed, and samples from brain (hippocampus, striatum, cerebellum, prefrontal cortex and cortex) were obtained and assayed for thiobarbituric acid reactive species (TBARS) formation and protein carbonyls. On the 10th day, another group of rats was submitted to the behavioral tasks. GUA administration reduced TBARS and carbonyl levels in some brain regions between 12 and 24 h after CLP, and ameliorated cognitive impairment evaluated 10 days after CLP. Our data provide the first experimental demonstration that GUA was able to reduce the consequences of CLP-induced sepsis in rats, by decreasing oxidative stress parameters in the brain and recovering the memory impairment.     

Neuroprotective Effect of Hydrogen Sulfide in Hyperhomocysteinemia Is Mediated Through Antioxidant Action Involving Nrf2

Homocysteine (Hcy) is a sulfur-containing amino acid derived from methionine metabolism. Elevated plasma Hcy levels (>?15 µM) result in a condition called hyperhomocysteinemia (HHcy), which is an independent risk factor in the development of various neurodegenerative disorders. Reactive oxygen species (ROS) produced by auto-oxidation of Hcy have been implicated in HHcy-associated neurological conditions. Hydrogen sulfide (H₂S) is emerging as a potent neuroprotective and neuromodulator molecule. The present study was aimed to evaluate the ability of NaHS (a source of H₂S) to attenuate Hcy-induced oxidative stress and altered antioxidant status in animals subjected to HHcy. Impaired cognitive functions assessed by Y-maze and elevated plus maze in Hcy-treated animals were reversed on NaHS administration. Increased levels of ROS, lipid peroxidation, protein carbonyls, and 4-hydroxynonenal (4-HNE)-modified proteins were observed in the cortex and hippocampus of Hcy-treated animals suggesting accentuated oxidative stress. This increase in Hcy-induced oxidative stress was reversed following NaHS supplementation. GSH/GSSG ratio, activity of antioxidant enzymes viz; superoxide dismutase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase were decreased in Hcy-treated animals. NaHS supplementation, on the otherhand, restored redox ratio and activity of antioxidant enzymes in the brains of animals with HHcy. Further, NaHS administration normalized nuclear factor erythroid 2-related factor 2 expression and acetylcholinesterase (AChE) activity in the brain of Hcy-treated animals. Histopathological studies using cresyl violet indicated higher number of pyknotic neurons in the cortex and hippocampus of HHcy animals, which were reversed by NaHS administration. The results clearly demonstrate that NaHS treatment significantly ameliorates Hcy-induced cognitive impairment by attenuating oxidative stress, improving antioxidant status, and modulating AChE activity thereby suggesting potential of H₂S as a therapeutic molecule.     

Folic Acid Protects Rat Cerebellum Against Oxidative Damage Caused by Homocysteine: the Expression of Bcl-2, Bax,and Caspase-3 Apoptotic Genes

There is evidence that oxidative stress involves in homocysteine-induced pathogenesis. Considering the antioxidative properties of folic acid and its involvement as a cofactor for methionine synthase (MS) in the homocysteine-methionine cycle, the aim of this study was to evaluate the mechanism associated with homocysteine-induced toxicity and its prevention with folic acid supplementation. Male rat pups were divided into four groups including control, homocysteine (Hcy), Hcy + folic acid and folic acid groups. The Hcy group received Hcy 0.3–0.6 μmol/g body weight, while Hcy + folic acid group received folic acid orally as 0.011 μmol/g body weight along with Hcy on a postnatal day (PD) 4 until 25. The reduced and oxidized glutathione (GSH and GSSG) levels, GSH/GSSG ratio, protein carbonyl content, cystathionine β synthase (CBS), and MS activities in the cerebellum were measured 25 days after birth. Levels of malondialdehyde (MDA), marker of lipid peroxidation were measured. Also, Bcl2, Bax, and caspase-3 expression levels were measured by real-time quantitative PCR. Furthermore, caspase-3 protein level assay was performed by the ELISA test. Results indicated that Hcy administration could promote both lipid and protein oxidation, which was associated with increased amounts of caspase-3 mRNA and protein levels and Bax mRNA expression level in this group. Cerebellar MS, CBS enzyme activity, GSH, GSSG, and GSH/GSH ratio did not change following Hcy administration. Folic acid significantly reduced MDA level, protein carbonyl content, Bax, the caspase-3 mRNA, and protein expression levels in the cerebellum of Hcy-treated group. Moreover, cerebellar MS, CBS enzyme activity, GSH, and GSH/GSH ratio increased following folic acid treatment. We conclude that Hcy might cause apoptosis in the cerebellum. We suggest that folic acid, in addition of having antioxidant properties, can protect cerebellum against homocysteine-mediated neurotoxicity via modulating the expression of proteins that are contributed in regulation of apoptosis in the rat’s cerebellum.

     

Age-dependent and tissue-related glutathione redox status in a mouse model of Alzheimer's disease

Glutathione plays an essential role in the intracellular antioxidant defense against oxidant radicals, especially the ?OH radical. To understand the early and progressive cellular changes in the development of Alzheimer's disease (AD), we investigated reduced glutathione/oxidized glutathione (GSH/GSSG) status in a double mutated AD transgenic mouse model (B6.Cg-Tg), which carries Swedish amyloid-β protein precursor mutation (AβPPswe) and exon 9 deletion of the PSEN1 gene. In this study, we quantified and compared both GSH/GSSG and mixed-disulfide (Pr-SSG) levels in blood samples and three anatomic positions in brain (cerebrum, cerebellum, and hippocampus) at 3 age stages (1, 5, and 11 months) of AD transgenic (Tg)/wild type mice. The present study was designed to characterize and provide insight into the glutathione redox state of both brain tissues and blood samples at different disease stages of this Tg model. The level of Pr-SSG increased in all AD brain tissues and blood compared with controls regardless of age. The GSH/GSSG ratio in AD-Tg brain tissue started at a higher value at 1 month, fell at the transitional period of 5 months, right before the onset of amyloid plaques, followed by an increase in GSSG and associated decrease of GSH/GSSG at 11 months. These results suggest that formation of Pr-SSG may be an early event, preceding amyloid plaque appearance, and the data further implies that tissue thiol redox is tightly regulated. Notably, the high basal levels of mixed-disulfides in hippocampus suggest a potential for increased oxidative damage under oxidizing conditions and increased GSSG in this vulnerable region.     

Differential vulnerability of immature murine neurons to oxygen-glucose deprivation

In vivo studies support selective neuronal vulnerability to hypoxia-ischemia (HI) in the developing brain. Since differences in intrinsic properties of neurons might be responsible, pure cultures containing immature neurons (6-8 days in vitro) isolated from mouse cortex and hippocampus, regions chosen for their marked vulnerability to oxidative stress, were studied under in vitro ischemic conditions-oxygen-glucose deprivation (OGD). Twenty-four hours of reoxygenation after 2.5 h of OGD induced significantly greater cell death in hippocampal than in cortical neurons (67.8% vs. 33.4%, P = 0.0068). The expression of neuronal nitric oxide synthase (nNOS) protein, production of nitric oxide (NO), and reactive oxygen species (ROS), as well as glutathione peroxidase (GPx) activity and intracellular levels of reduced glutathione (GSH), were measured as indicators of oxidative stress. Hippocampal neurons had markedly higher nNOS expression than cortical neurons by 24 h of reoxygenation, which coincided with an increase in NO production, and significantly greater ROS accumulation. GPx activity declined significantly in hippocampal but not in cortical neurons at 4 and 24 h after OGD. The decrease in GSH level in hippocampal neurons correlated with the decline of GPx activity. Our data suggest that developing hippocampal neurons are more sensitive to OGD than cortical neurons. This finding supports our in vivo studies showing that mouse hippocampus is more vulnerable than cortex after neonatal HI. An imbalance between excess prooxidant production (increased nNOS expression, and NO and ROS production) and insufficient antioxidant defenses created by reduced GPx activity and GSH levels may, in part, explain the higher susceptibility to OGD of immature hippocampal neurons.     

Glutathione levels in specific brain regions of genetically epileptic (tg/tg) mice

The tottering (tg/tg) mouse is a genetic model of human generalized epilepsy; these mice exhibit spontaneous absence seizures accompanied by bilaterally synchronous spike-wave discharges (6). The mechanism(s) for seizure activity are unknown in these mice. Several recent studies have suggested that membrane lipid peroxidation may be causally involved in some forms of experimentally induced epilepsies (18). Since reduced glutathione (GSH) is the most important free radical scavenging compound in vivo that can prevent membrane lipid peroxidation, the objective of this study was to investigate GSH concentrations in specific central nervous system regions of genetically epileptic, tg/tg, mice as compared to age-matched controls. Three brain regions, cerebellum, hippocampus, and occipital cortex, were dissected, weighed and the concentrations of reduced and oxidized glutathione (GSH and GSSG, respectively) were measured in each of these tissues. GSH content was significantly lower in the occipital cortex of tg/tg mice compared to controls; no differences were observed in the other two brain regions examined. Total GSH content (GSH plus 2 x GSSG) paralleled GSH concentration differences. GSSG content from tg/tg mice was lower in the hippocampus and occipital cortex, compared to controls. This is the first report of an association between decreased central nervous system glutathione concentrations and seizure activity in animals exhibiting generalized seizures.     

Down-regulation of gamma-glutamylcysteine synthetase regulatory subunit gene expression in rat brain tissue during aging

The mechanism underlying age-related neurodegenerative diseases is still an area of significant controversy. Increased evidence suggests that oxidative stress contributes importantly to neuronal damage observed in the brains of aged animals and in neurodegenerative diseases. Glutathione (GSH), the most abundant intracellular nonprotein thiol, plays an important role in antioxidant defense. The concentration of this important antioxidant decreases with age in the brain, which is accompanied by an increase in oxidative damage to macromolecules. The mechanism underlying the age-associated decline in GSH content in the brain, however, is not clear. In this study, we demonstrate for the first time that the expression of the regulatory subunit of gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in de novo GSH synthesis, decreases with age in cerebellum, cerebral cortex, and hippocampus of Fisher 344 rats. This was accompanied by a decline in GCS activity and GSH content. There were no significant differences in either the concentrations of cysteine and glutathione disulfide (GSSG) or the activities of glutathione synthetase (GS), gamma-glutamyl traspeptidase (GGT), and glutathione reductase (GR) in the brains from different age groups. Our results suggest that the age-associated decrease in GSH in the brain may result from the down-regulation of GCS regulatory subunit and consequently a decrease in the activity of GCS.     

Levels of low molecular weight scavengers in the rat brain during focal ischemia.

Ascorbic acid, cysteine, glutathione, uric acid, tyrosine and tryptophan were quantified in samples of frontoparietal cortex, striatum, hippocampus and cerebellum from both sides of rat brain 0.5 h, 4 h and 24 h after focal ischemia. Cysteine, tyrosine and tryptophan were increased in cortex and striatum at 0.5 h, returning afterwards to normal. Uric acid was increased, whereas ascorbic acid and glutathione were correspondingly decreased. Although changes can be explained primarily by energy failure they are also consistent with free radical activity during early stages of ischemia.     

Alterations in glutathione levels of brain structures caused by acute restraint stress and by nitric oxide synthase inhibition but not by intraspecific agonistic interaction

Glutathione is the major non-protein thiol to which many different roles in the central nervous system (CNS) are attributed. To further investigate the glutathione response in the CNS, we tested the effect of three stress models on glutathione levels in the brain. We tested the effect of two models of repeated intraspecific agonistic interaction in mice. No influence was observed over the glutathione levels in the mice cerebral cortex, cerebellum, liver, and blood. Acute restraint stress in rats was found to induce an increase in glutathione levels in the cerebellum after 2 and 4 h of immobilization, an effect not observed in the cerebral cortex, striatum, and hippocampus. To investigate the interference of an inhibitor of nitric oxide synthase (NOS), N(omega)Nitro-L-arginine-methyl-ester (L-NAME, 50 mg/kg) was applied i.p. at the beginning of restraint stress. L-NAME alone did not lead to a change in glutathione levels although, in combination with restraint stress, it induced an increase in such levels. This effect was observed in all four structures studied, i.e. cortex, hippocampus, striatum, and cerebellum. The values returned to basal levels after 6h of immobilization. In conclusion, the pattern of dominance, after repeated intraspecific agonistic interaction, was ineffective in producing alterations in brain glutathione, whereas acute restraint stress led to an increase in glutathione levels within a window of 2-4 h, and the inhibition of NOS increased glutathione levels in all studied rat brain structures, suggesting a specificity interference of acute restraint stress with the glutathione system.     

Alterations in brain glutathione homeostasis induced by the nerve gas soman

Public awareness of the dangers of chemical and biological warfare has been heightened in recent times. In particular, chemical nerve agents such as soman and its analogs have been developed and used in war as well as recent incidents, such as in Iraq and Japan. Soman, a rapid acting acetylcholinesterase inhibitor, produces a status epilepticus that leads to extensive neuropathology in vulnerable brain regions (eg. piriform cortex and hippocampus). This study was undertaken to determine whether oxidative mechanisms are involved in brain pathology during soman toxicity. Intracellular thiols such as glutathione (GSH) and protein sulfhydryls (PrSH) are among the most critical antioxidants used to combat oxidative stress. Here we report that during the seizure phase (1 h post soman exposure), PrSH levels in piriform cortex and hippocampus were decreased without changes in glutathione (GSH) levels. However, by 24 h post somam exposure (pathology phase), GSH levels were decreased by nearly 50% in the piriform cortex with a corresponding decrease in PrSH groups. The shift to a more oxidized thiol status indicates that oxygen free radicals likely participate in the neuropathoplgy associated with soman-induced seizures.     

Thiol redox state and lipid and protein oxidation in the mouse striatum after pentylenetetrazol-induced epileptic seizure

PURPOSE: In the present study, we examined the effects of pentylenetetrazol (PTZ) administration on the thiol redox state (TRS), lipid peroxidation, and protein oxidation in the mouse striatum to (a) quantitate the major components of TRS and relate them to oxidative stress, and (b) investigate whether neuronal activation without synchronization, induced by subconvulsive doses of PTZ, can cause similar qualitative effects on TRS in this brain area. Specifically, we examined the TRS components glutathione (GSH), glutathione disulfide (GSSG), cysteine (CSH), protein thiols (PSH), and the protein (P) and nonprotein (NP/R) disulfides PSSR, NPSSR, NPSSC, and PSSP. METHODS: TRS components were measured photometrically (GSSG enzymatically) as were lipid peroxidation and protein oxidation. RESULTS: GSH, GSSG, and NPSSC levels are decreased by 45%, 38% and 26%, respectively, at 15 min after seizure; PSSP and PSSR levels and lipid peroxidation are increased by 47%, 200% and 22%, respectively, whereas CSH, NPSSR, PSH, PSSC, and protein carbonyl levels do not change. At 30 min after seizure, GSH, GSSG, CSH, NPSSC, and protein carbonyl levels are decreased by 26%, 62%, 25%, 40%, and 13%, respectively. PSSP and NPSSR levels are increased by 30% and 42%, respectively, whereas PSH, PSSC, PSSR, and lipid peroxidation remain unchanged. At 24 h after seizure, GSH, NPSSR, PSSR, and lipid-peroxidation levels return to normal; GSSG, CSH, NPSSC, and protein carbonyl levels are decreased by 44%, 22%, 30%, and 27%, respectively. CONCLUSIONS: The significant decrease in GSH, GSSG, CSH, and NPSSC and the increase in PSSP, NPSSR, PSSR, and lipid peroxidation after PTZ-induced seizure strongly suggest increased oxidative stress in the mouse striatum.     

Glutathione levels in specific brain regions of genetically epileptic (tg/tg) mice

The tottering (tg/tg) mouse is a genetic model of human generalized epilepsy; these mice exhibit spontaneous absence seizures accompanied by bilaterally synchronous spike-wave discharges (6). The mechanism(s) for seizure activity are unknown in these mice. Several recent studies have suggested that membrane lipid peroxidation may be causally involved in some forms of experimentally induced epilepsies (18). Since reduced glutathione (GSH) is the most important free radical scavenging compound in vivo that can prevent membrane lipid peroxidation, the objective of this study was to investigate GSH concentrations in specific central nervous system regions of genetically epileptic, tg/tg, mice as compared to age-matched controls. Three brain regions, cerebellum, hippocampus, and occipital cortex, were dissected, weighed and the concentrations of reduced and oxidized glutathione (GSH and GSSG, respectively) were measured in each of these tissues. GSH content was significantly lower in the occipital cortex of tg/tg mice compared to controls; no differences were observed in the other two brain regions examined. Total GSH content (GSH plus 2 × GSSG) paralleled GSH concentration differences. GSSG content from tg/tg mice was lower in the hippocampus and occipital cortex, compared to controls. This is the first report of an association between decreased central nervous system glutathione concentrations and seizure activity in animals exhibiting generalized seizures.     

Increased on oxidative brain injury in the diabetic rats following sepsis

Diabetes has been the subject of recent research by increase susceptibility to infections, thus the aim of this study was to evaluate in animal model of diabetes induced by alloxan (ALX) and subjected to sepsis the parameters of oxidative stress on the brain. Diabetes was induced in Wistar rats by ALX (150 mg/kg), and 15 days after, sepsis was induced by cecal ligation and puncture (CLP). The myeloperoxidase activity (MPO), nitrite/nitrate, oxidative damage parameters, and the activity of superoxide dismutase (SOD) and catalase (CAT) were measured in the cerebellum, hippocampus, striatum, prefrontal, and cortex in 6, 12, and 24 h after CLP. The results showed the potentiation of diabetes with sepsis. We verified these potentiation on MPO levels in the cerebellum, hippocampus, and prefrontal and an increase of the nitrite/nitrate concentration in the hippocampus, striatum, prefrontal, and cortex in 24 h after sepsis surgery. To oxidative damage, we verified in 6 h an increase on lipid and protein damage parameters in the striatum and hippocampus in 24 h. When we associate sepsis and diabetes, the SOD and CAT activity not were altered. Thus, diabetes associated with sepsis exacerbates brain damage resulting from inflammation and oxidative stress in brain. Synapse, 2014 . © 2014 Wiley Periodicals, Inc.     

The Combined Effect of Sleep Deprivation and Western Diet on Spatial Learning and Memory: Role of BDNF and Oxidative Stress

Either sleep deprivation or Western diet can impair learning and memory via induction of oxidative stress, which results in neuronal damage and interference with the neurotransmission. In this study, we examined the combined effect of sleep deprivation and Western diet on hippocampus-dependent spatial learning and memory. In addition, possible molecular targets for sleep deprivation and Western diet-induced cognitive impairments were investigated. Sleep deprivation was induced in rats using the modified multiple platform model simultaneous with the administration of Western diet for 6 weeks. Thereafter, spatial learning and memory were tested using radial arm water maze. At the molecular level, BDNF protein and antioxidant markers including superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione (GSH), oxidized glutathione (GSSG), GSH/GSSG, and thiobarbituric acid reactive substances (TBARS) were assessed. The results of this study revealed that sleep deprivation, Western diet, or a combination of both impair short- and long-term memory (P?<?0.05). The magnitude of the impairment induced by the combined treatment at the 24-h long-term memory was higher than that caused by each factor alone (P?<?0.05). In addition, the combined treatment reduced the levels of hippocampal BDNF, a reduction that was not detected with each factor alone. Moreover, the combined treatment reduced the hippocampal activities of SOD, catalase, GPx, ratio of GSH/GSSG, and elevated TBARS level (P?<?0.05). In conclusion, the combination of sleep deprivation and Western diet decreases BDNF levels and increases oxidative stress in the hippocampus, thus inducing memory impairment that is greater than the impairment produced by each factor alone.