Brain Oxidative Stress Parameters Research Articles

The Potential Therapeutic Effect of Guanosine after Cortical Focal Ischemia in Rats

Background and PurposeStroke is a devastating disease. Both excitotoxicity and oxidative stress play important roles in ischemic brain injury, along with harmful impacts on ischemic cerebral tissue. As guanosine plays an important neuroprotective role in the central nervous system, the purpose of this study was to evaluate the neuroprotective effects of guanosine and putative cerebral events following the onset of permanent focal cerebral ischemia.MethodsPermanent focal cerebral ischemia was induced in rats by thermocoagulation. Guanosine was administered immediately, 1 h, 3 h and 6 h after surgery. Behavioral performance was evaluated by cylinder testing for a period of 15 days after surgery. Brain oxidative stress parameters, including levels of ROS/RNS, lipid peroxidation, antioxidant non-enzymatic levels (GSH, vitamin C) and enzymatic parameters (SOD expression and activity and CAT activity), as well as glutamatergic parameters (EAAC1, GLAST and GLT1, glutamine synthetase) were analyzed.ResultsAfter 24 h, ischemic injury resulted in impaired function of the forelimb, caused brain infarct and increased lipid peroxidation. Treatment with guanosine restored these parameters. Oxidative stress markers were affected by ischemic insult, demonstrated by increased ROS/RNS levels, increased SOD expression with reduced SOD activity and decreased non-enzymatic (GSH and vitamin C) antioxidant defenses. Guanosine prevented increased ROS/RNS levels, decreased SOD activity, further increased SOD expression, increased CAT activity and restored vitamin C levels. Ischemia also affected glutamatergic parameters, illustrated by increased EAAC1 levels and decreased GLT1 levels; guanosine reversed the decreased GLT1 levels and did not affect the EAAC1 levels.ConclusionThe effects of brain ischemia were strongly attenuated by guanosine administration. The cellular mechanisms involved in redox and glutamatergic homeostasis, which were both affected by the ischemic insult, were also modulated by guanosine. These observations reveal that guanosine may represent a potential therapeutic agent in cerebral ischemia by preventing oxidative stress and excitotoxicity.

Neuropharmacological evaluation of a novel 5-HT3 receptor antagonist (6g) on chronic unpredictable mild stress-induced changes in behavioural and brain oxidative stress parameters in mice.

Aim:The aim of the study was to evaluate a novel 5 HT3 receptor antagonist (6g) on chronic stress induced changes in behavioural and brain oxidative stress parameter in mice. A complicated relationship exists among stressful stimuli, body's reaction to stress and the onset of clinical depression. Chronic unpredictable stressors can produce a situation similar to human depression, and such animal models can be used for the preclinical evaluation of antidepressants.Materials and Methods:In the present study, a novel and potential 5-HT3 receptor antagonist (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone (6g) with good Log P (3.08) value and pA2(7.5) values, synthesized in our laboratory was investigated to study the effects on chronic unpredictable mild stress (CUMS)-induced behavioural and biochemical alterations in mice. Mice were subjected to different stress paradigms daily for a period of 28 days to induce depressive-like behaviour.Results:The results showed that CUMS caused depression-like behaviour in mice, as indicated by the significant (P < 0.05) decrease in sucrose consumption and locomotor activity and increase in immobility the forced swim test. In addition, it was found that lipid peroxidation and nitrite levels were significantly (P < 0.05) increased, whereas glutathione levels, superoxide dismutase and catalase activities decreased in brain tissue of CUMS-treated mice. ‘6g’ (1 and 2 mg/kg, p.o., 21 days) and fluoxetine treatment (20 mg/kg, p.o., 21 days) significantly (P < 0.05) reversed the CUMS-induced behavioural (increased immobility period, reduced sucrose preference and decreased locomotor activity) and biochemical (increased lipid peroxidation; decreased glutathione levels, superoxide dismutase and catalase activities). However fluoxetine treatment (20 mg/kg, p.o., 21 days) significantly decreased the nitrite level in the brain while ‘6g’ (1 and 2 mg/kg, p.o., 21 days) did not show significant (P < 0.05) effect on the nitrite levels in brain.Conclusion:Compound ‘6g’ exerted antidepressant-like effects in behavioural despair paradigm in chronically stressed mice by restoring antioxidant mechanisms.

Quercetin alleviates predator stress-induced anxiety-like and brain oxidative signs in pregnant rats and immune count disturbance in their offspring

This study was performed in rats to investigate the effect of a psychogenic stress during late gestation on the immediate behavior and brain oxidative status in dams as well as on the immune cell counts in their offspring up to weaning. Besides, the ability of quercetin (a natural flavonoid) to prevent stress effects was evaluated. Quercetin was orally administered for 6 consecutive days before the pregnant rats were acutely exposed to predator stress on gestational day 19. Post-stress corticosterone level, brain oxidative stress parameters and anxiety-like behavior were assessed in dams, whereas immune cell counts were postnatally determined in both male and female pups. Predator stress caused an oxidative stress in the brain and elicited an elevation in plasma corticosterone with concomitant behavioral impairment in dams. Prenatally-stressed pups mainly showed a decrease in total leukocytes and lymphocytes along with monocytosis and granulocytosis, but these changes were sex-dependent throughout the postnatal period studied. Quercetin pretreatment blocked the stress-induced corticosterone release and alleviated the brain oxidative stress with the maternal anxiety measures being slightly attenuated, whereas its effects on the offspring immune cell counts were mostly revealed at birth. Our findings suggest that late gestational exposure to traumatic events may cause anxiety symptoms in dams, in which corticosterone and brain oxidative stress play a certain role, and trigger negative immune changes in the early postnatal life of progeny. Notably, quercetin intake before such adverse events seems to be beneficial against negative outcomes in both dams and offspring.

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.

Pharmacokinetic and pharmacodynamic interactions of valproate, phenytoin, phenobarbitone and carbamazepine with curcumin in experimental models of epilepsy in rats

The present study investigates the interaction of curcumin with four antiepileptic drugs (AEDs) in male Wistar rats. In the first protocol, seizures were induced using pentylenetetrazole (PTZ) and valproate was injected intraperitoneally (i.p.) in therapeutic and sub-therapeutic doses 30min before PTZ administration. Curcumin was co-administered with sub-therapeutic dose of valproate 60min before PTZ injection. In the second protocol, seizures were induced by maximal-electroshock. Phenytoin, phenobarbitone and carbamazepine were injected in their therapeutic and sub-therapeutic doses 120, 60 and 30min, respectively, before seizure induction. Curcumin was administered along with sub-therapeutic doses of phenytoin, phenobarbitone and carbamazepine, 60min before induction of seizures. Behavioral parameters were assessed using elevated plus maze test and passive avoidance paradigm. Rat brain oxidative stress parameters were assessed and the serum levels of the AEDs were estimated. The AEDs in their therapeutic doses produced complete protection against seizures. However, sub-therapeutic doses of these AEDs failed to completely protect against seizures. Co-administration of curcumin with sub-therapeutic dose of valproate significantly increased the latency to myoclonic jerks. The percentage protection against seizures with sub-therapeutic doses of valproate, phenytoin, phenobarbitone and carbamazepine was also enhanced by concomitant curcumin administration. Both PTZ and MES induced seizures caused significant impairment of cognitive functions. Co-administration of curcumin with these AEDs in their sub-therapeutic doses prevented the impairment of learning and memory due to seizures whereas no such improvement was observed in the groups administered the sub-therapeutic doses of the AEDs alone. Additionally, curcumin reversed the oxidative stress due to seizures. However, curcumin co-administration did not cause any significant alteration in the serum levels of the AEDs. The results thus suggest the potential of curcumin as an adjunct to these AEDs in epilepsy with the advantage of increasing the efficacy, reducing the dose and side effects of the AEDs.

Role of Oxidative Stress and Inflammation in Hypoxia-Induced Cerebral Edema: A Molecular Approach

The present study reports the possible role of oxidative stress and inflammation (role of nuclear factor, NFkB) in hypoxia-induced transvascular leakage in brain of rats. The rats were exposed to a simulated altitude of 25,000 ft for different durations: 0, 3, 6, 12, 24, and 48h. Brain water content, transvascular leakage, oxidative stress, and proinflammatory parameters were studied at different durations of hypoxic exposure. The results revealed that maximum increase in transvascular leakage in brain of rats was observed at 24h of hypoxic exposure (240.16 ± 1.95 relative fluorescence units (r.f.u)/g tissue) compared with control (100.58 ± 1.79 r.f.u/g tissue). There was a significant increase in reactive oxygen species (ROS) and lipid peroxidation (MDA), with concomitant reduction in antioxidants. Hypoxic exposure resulted in a significant increase in NFκB protein expression levels and in the DNA binding activity in the 24-h hypoxic exposure (p<0.001) compared with control. There was a significant increase in proinflammatory cytokines, with concomitant upregulation of cell adhesion molecules. Simultaneously, to rule out the fact that inflammation causes cerebral edema, the rats were pretreated with curcumin (100 mg/kg body weight) 1h prior to 24-h hypoxia. Curcumin pretreatment significantly attenuated the hypoxia-induced cerebral transvascular leakage (p<0.05), with concomitant downregulation in the expression of brain NFκB levels (p<0.001). The present study therefore reveals that inflammation (NFκB) plays a significant role in hypoxia-induced cerebral edema.

Effects of inorganic selenium administration in methylmercury-induced neurotoxicity in mouse cerebral cortex

Selenium can counteract methylmercury (MeHg) neurotoxicity. However, data about the neuroprotective effects of sodium selenite (Na2SeO3) on the activity of mitochondrial complexes and creatine kinase (mtCK) are scarce. Therefore, this study investigated the effects of the chronic exposure to Na2SeO3 on brain energy metabolism and oxidative stress parameters in MeHg-poisoned mice. Adult male mice were orally treated with MeHg (40mgL−1 in drinking water, ad libitum) during 21 days and simultaneously administrated with daily subcutaneous injections of Na2SeO3 (5μmolkg−1), a potential neuroprotectant. Mitochondrial complexes I to IV and mtCK activities were measured in cerebral cortex mitochondria. The cerebro-cortical tissue was also used to evaluate the antioxidant enzymes glutathione peroxidase (GPx) and glutathione reductase (GR) activities, as well as lipid peroxidation. Metal deposition was followed autometalographically (AMG). Na2SeO3 partially prevented MeHg-induced inhibition of complexes II–III, IV and mtCK activities; however, it was unable to prevent MeHg-induced complex I and II inhibition. MeHg increased lipid peroxidation, GR activity and decreased GPx activity in the cerebral cortex; however, Na2SeO3 did not modify such events. Furthermore, Na2SeO3per se inhibited complexes I, II–III and IV and mtCK activities and increased GPx and GR activities and lipid peroxidation. These data show that inorganic selenium was ineffective in preventing most of the MeHg-induced brain biochemical alterations. However, the most prominent finding was the selenium-induced reduction of cells labelled for metal deposition. Although, the literature supports the beneficial effects of selenium against mercury toxicity, the toxic effects elicited by Na2SeO3, alone or in combination with mercury, should be considered when this compound is proposed as a potential protective therapy for MeHg poisoning.

Oxidative metabolism studies on thermal regulation‐Protective mechanism against free radical in zebrafish brain

Exposure of ectothermic vertebrates to fluctuated temperatures accelerates mitochondrial respiration and has been shown to increase the formation of mitochondrial reactive oxygen species (ROS), such as O2−, H2O2, and O2−·. Excess ROS production by intensively respiring mitochondria is held responsible for cellular damage. The present study was to test whether a protective oxidative‐stress pathway would be initiated in fish central nervous system upon cold stress.Effects of acute cold exposure (from 28 °C to 18 °C) on brain oxidative stress parameters were investigated in zebrafish (Danio rerio). Concentrations of cellular protein carbonyl groups (biomarkers of oxidative stress) were significantly increased after 1‐hour cold exposure. Increased levels of anti‐oxidative stress parameters, catalase (CAT) and superoxide dismutase (SOD) were observed at 1‐ and 6‐hour cold exposure, respectively. In spite of maintained anti‐oxidant capacity, the increment status of cellular oxidized protein accumulation was still observed. A neuronal defense pathway against ROS, peroxisome proliferator‐activated receptor (PPAR), acts with genes encoding uncoupling proteins (UCPs) was further monitored. Real‐time PCR analysis indicated that ppar‐1αb increased was transcriptionally regulated the expression of zucp2 and zucp2l. Mitochondrial biogenesis activation, mild uncoupling, and reduction of free radicals may result intracellular pO2 levels drop. Moreover, these protective mechanisms in fish brain have been found to cause hypoxia‐induced factor (HIF) stabilization that facilitates an increase in energy supply.

Estradiol valerate and tibolone: effects upon brain oxidative stress and blood biochemistry during aging in female rats

Estrogen compounds have been described as important brain protectors. This study investigated the effects of estradiol valerate (EV--0.3 mg/kg) and two concentrations of tibolone (TB1=0.5 mg/kg and TB2=1 mg/kg) on brain oxidative stress parameters and blood biochemistry in ovariectomized female rats, of three different age groups (young--2 months, adult--8 months, and old--20 months). In the brain cortex, young and old TB2-treated and old no-hormone-replacement (NR) females showed lower lipid hydroperoxide (LPO) levels compared to young Sham and adult TB1 animals (P<0.05). Also in the cortex, both tibolone doses produced higher (P<0.05) total antioxidant capacity (TOSC) levels compared to EV-treated adult females. Ovariectomized adult females (NR, EV, TB1 and TB2) showed lower (P<0.05) TOSC levels in the hippocampus compared to the Sham control. Reactive oxygen species (ROS) were higher (P<0.05) in old females compared to all younger ones. TB2-treated adults showed higher plasma glucose (P<0.05) levels compared to old animals. Regardless of age, TB2 treatment increased female (P<0.05) LDL levels compared to Sham and EV-treated animals. In old females, TB2 significantly increased HDL levels compared to Sham controls, and decreased triglyceride levels were shown in EV, TB1 and TB2 compared to Sham old females. The Atherogenic Index of Plasma was higher (P<0.05) in adult tibolone-treated females compared to both young and old TB2-treated females. These results suggest that the effects of gonad steroid on brain and blood physiology change significantly with aging, and that evaluating hormonal treatment types and doses could be the key factor in the potential use of a specific hormone therapy.

Oxidative stress parameters in different rat brain structures after electroconvulsive shock-induced seizures

Electroconvulsive therapy has been used in the treatment of psychiatric disorders since the 1930s, but little progress has been made in understanding the cellular mechanisms underlying its therapeutic and adverse effects. Electroconvulsive shock (ECS) in animals provides a common experimental model for studying the effects of electroconvulsive therapy in humans. In order to examine the changes of the brain oxidative stress parameters in several brain structures in the early time period after ECS-induced seizures, the levels of lipid peroxidation as well as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in the rat hippocampus, cerebellum, frontal cortex and the pons/medulla region were determined at different time points during the first 24 h after single ECS-induced seizures. In the hippocampus and cerebellum the levels of lipid peroxidation were unchanged, while the SOD and GSH-Px activities were significantly increased. Levels of lipid peroxidation and the activities of SOD and GSH-Px were not statistically changed in the pons/medulla region. Levels of lipid peroxidation in the frontal cortex were significantly higher in comparison to the control group at all time points examined while the SOD and GSH-Px activities were not statistically changed. In conclusion, the results of the present study indicate that single ECS causes the rat brain structure-specific alterations in the levels of lipid peroxidation as well as in the SOD and GSH-Px activities at different time points within the first 24 h after the seizures induction. Oxidative lipid damage was evident only in the frontal cortex, while the hippocampus, cerebellum and the pons/medulla region remained oxidatively unaffected in our experimental conditions.

Possible involvement of free radicals in the differential neurobehavioral responses to stress in male and female rats

The effect of restraint stress (RS) on neurobehavioral and brain oxidative stress parameters, and their modulation by antioxidants were evaluated in male and cycling female rats. Exposure to RS suppressed both open arm entries and open arm time in the elevated plus maze and these changes were more marked in males than in females. Assay of brain homogenates revealed that the behavioral suppression was associated with similar differential increases in malondialdehye (MDA) and decreases in glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels in males and females. Pretreatment with α-tocopherol (25 and 50 mg/kg) and N-acetylcysteine (100 and 200 mg/kg), attenuated the stress induced alteration of behavioral and oxidative stress markers in a consistent manner in both male and female rats. These findings suggest that males may be more susceptible than females to stress induced neurobehavioral changes and free radicals may exert a regulatory influence in such gender dependent responses to stress.