Quercetin and Omega 3 Ameliorate Oxidative Stress Induced by Aluminium Chloride in the Brain

Exposure to high levels of aluminum (Al) leads to neurodegeneration, which may be mediated through over-generation of free radicals. So, in the present study, we investigated the ability of both quercetin and omega 3 to ameliorate adverse effects of Al on brain antioxidants by monitoring the main brain antioxidant enzymes on molecular and cellular levels. The obtained results indicated that Al induced oxidative stress through induction of free radical production and inhibition of activity and expression of the antioxidant enzymes catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx); and at the same time induced superoxide dismutase (SOD) activity and gene expression. Both quercetin (QE) and omega 3 have the ability to overcome Al-induced oxidative stress, manifested by the significant reduction in free radical concentration and induction of the activity and gene expression of the brain antioxidant enzymes.     

Effects of selegiline on antioxidant systems in the nigrostriatum in rat

Summary. Selegiline, a therapeutic agent of Parkinson’s disease, is known to have neuroprotective properties that may involve its regulatory effects on antioxidant enzymes. We evaluated effects of selegiline on activities of catalase (CAT), Cu,Zn-superoxide dismutase (SOD1) and Mn-SOD (SOD2) in the striatum, cortex and hippocampus of 8- and 25-week-old rats, and on SOD activities and glutathione levels in mesencephalic slice cultures. Selegiline (2 mg/kg) significantly increased CAT and SOD2 activities in the striatum, but not in the cortex and hippocampus, of 25-week-old rats. In contrast, selegiline failed to increase CAT and SOD activities in three brain regions of 8-week-old rats, whereas L-dopa significantly increased SOD1 activity in the striatum. In slice cultures, selegiline increased SOD1 and SOD2 activities with a maximal effective concentration of 10⁻⁸ and 10⁻¹⁰ M, respectively. Moreover, selegiline significantly increased glutathione level. These results suggest that selegiline can decrease oxidative stress in nigrostriatum by augmenting various antioxidant systems, each of which responds optimally to different concentrations of selegiline.     

Antioxidant enzyme and malondialdehyde levels in patients with social phobia

A growing body of reports have indicated that free radicals are involved in the etiopathogenesis of some neuropsychiatric disorders. In the present study, we aimed to evaluate whether antioxidant enzymes (superoxide dismutase; SOD, glutathione peroxidase; GSH-Px, and catalase; CAT) activity levels and malondialdehyde (MDA), a product of lipid peroxidation, were associated with social phobia (SP). Eighteen patients diagnosed with SP and 18 healthy controls were enrolled. A clinical evaluation and measurements of MDA, SOD, GSH-Px and CAT were performed. Additionally, all patients were assessed with the Liebowitz Social Anxiety Scale (LSAC). The mean MDA, SOD, GSH-Px and CAT levels in the patient group were significantly higher than those in the control group. There was a positive correlation between LSAC scores and MDA, SOD, GSH-Px and LSAC levels, and between the duration of illness, and MDA, SOD and CAT levels in the patient group. In conclusion, our results suggest that there may be a relationship between increased antioxidant enzyme levels and MDA, and SP.     

Glucose-6-phosphate dehydrogenase and glutathione reductase support antioxidant enzymes in nerves and muscles of rats during nerve regeneration

The effects of the rat sciatic nerve crush on the activities of glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase (GR), glutathione peroxidase (GPX), superoxide dismutase (SOD) and catalase (CAT) were examined in regenerating nerve and in two reinnervating muscles: the slow twitch soleus and the fast twitch extensor digitorum longus (edl). The enzyme activities in the crushed side, were compared with the contralateral homologue tissues and basal values, determined in uncrushed animals. In the crushed side, the activity of G6PD, GR, GPX and CAT of the sciatic nerve and both muscles markedly increased in comparison with the uncrushed side. In the nerve and in both muscles, SOD activity decreased at 13 days, then rose to values higher than normal, but the pattern of the crushed side was not significantly different from that of the uncrushed. In the uncrushed side, we observed a significant increase of nerve G6PD, GPX and CAT activities compared to basal values, while in both muscles, values fluctuated around the normal without any significant variation. The mechanism of these enzymatic changes is unknown, however our work suggests that: (i) during nerve regeneration, an oxidative stress occurs in nerve and muscle, which causes adaptive responses in antioxidant enzymes; (ii) the maximum antioxidant power is expressed during the period of synaptic retraction; (iii) G6PD and GR activities are synergistically modulated with GPX and CAT, while SOD activity appears independently regulated.     

PCB (Aroclor 1254) enhances oxidative damage in rat brain regions: protective role of ascorbic acid

PCBs are one of the environmental toxicants and neurotoxic compounds which induce the production of free radicals leading to oxidative stress. Oxidative stress is a contributing factor to alteration caused in neurodegenerative processes. The ability of Vitamin C to retard oxidative processes has been recognized for many years. Therefore, the present experiment was carried out to determine the antioxidant role of ascorbate on Aroclor 1254 induced oxidative stress in brain regions of albino rats. One group of rats received corn oil as vehicle for 30 days as control. The other group of rats were administered Aroclor 1254 at a dose of 2 mg/kg bw/day intraperitoneally for 30 days. One group of rats received Vitamin C (100 mg/kg bw/day) orally simultaneously with Aroclor 1254 for 30 days. The brain was dissected to cerebral cortex (Cc), cerebellum (C) and hippocampus (H). Enzymatic and non-enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), reduced glutathione (GSH) and Vitamin C were estimated. Hydrogen peroxide (H(2)O(2)), lipid peroxidation (LPO) and acetylcholine esterase activity (AchE) were determined. Activities of SOD, CAT, GPx, GST, AchE and the concentration of GSH, Vitamin C were decreased while an increase in H(2)O(2) and LPO were observed in brain regions of PCB treated animals. Vitamin C administration retrieved all the parameters except GST, significantly. These results suggest that PCB induces oxidative stress in rat brain by decreasing the activities of antioxidant enzymes, which can be protected by Vitamin C treatment.     

Antioxidant intervention attenuates oxidative stress in children and teenagers with Down syndrome

We previously demonstrated that systemic oxidative stress is present in Down syndrome (DS) patients. In the present study we investigated the antioxidant status in the peripheral blood of DS children and teenagers comparing such status before and after an antioxidant supplementation. Oxidative stress biomarkers were evaluated in the blood of DS patients (n = 21) before and after a daily antioxidant intervention (vitamin E 400 mg, C 500 mg) during 6 months. Healthy children (n = 18) without DS were recruited as control group. The activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), gamma-glutamyltransferase (GGT), glucose-6-phosphate dehydrogenase (G6PD) and myeloperoxidase (MPO), as well as the contents of reduced glutathione (GSH), uric acid, vitamin E, thiobarbituric acid reactive substances (TBARS), and protein carbonyls (PC) were measured. Before the antioxidant therapy, DS patients presented decreased GST activity and GSH depletion; elevated SOD, CAT, GR, GGT and MPO activities; increased uric acid levels; while GPx and G6PD activities as well as vitamin E and TBARS levels were unaltered. After the antioxidant supplementation, SOD, CAT, GPx, GR, GGT and MPO activities were downregulated, while TBARS contents were strongly decreased in DS. Also, the antioxidant therapy did not change G6PD and GST activities as well as uric acid and PC levels, while it significantly increased GSH and vitamin E levels in DS patients. Our results clearly demonstrate that the antioxidant intervention with vitamins E and C attenuated the systemic oxidative damage present in DS patients.     

Antioxidant enzyme and malondialdehyde levels in patients with panic disorder

There is evidence of an etiopathogenetic role of free radicals (FRs) in some neuropsychiatric disorders. The aim of the present study was to determine whether the activity levels of some antioxidant enzymes [glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT)] and malondialdehyde (MDA), a product of lipid peroxidation, were associated with panic disorder (PD). Twenty patients diagnosed with PD and 20 healthy controls were enrolled in this study. A clinical evaluation and measurements of GSH-Px SOD, CAT and MDA were performed. Additionally, all patients were assessed by the Panic Agoraphobia Scale (PAS). The mean GSH-Px, SOD and MDA levels of the patient group were significantly higher than those of the controls. There was a significant positive correlation between PAS scores and GSH-Px, SOD and MDA levels and between the duration of illness and SOD, CAT and MDA levels in the patient group. In conclusion, our results suggest that FRs may be involved in PD.     

Antioxidant enzyme activities and malondialdehyde levels in patients with obsessive-compulsive disorder

To examine the importance of free radicals in the pathogenesis of obsessive-compulsive disorder (OCD), we aimed to evaluate whether malondialdehyde (MDA), a product of lipid peroxidation, and antioxidant enzyme [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT)] activity levels were associated with OCD. The patients were divided into two subgroups according to whether DSM-IV major depressive disorder (MDD) was accompanied (OCD + MDD) or not (OCD - MDD). The MDA and antioxidant enzyme levels both in patients and controls were determined. SOD activity levels were significantly higher in the OCD + MDD group compared with the control and the OCD - MDD group. Although the OCD - MDD group had slightly higher SOD activity levels as compared with the controls, the difference was not statistically significant. GSH-Px activity levels were statistically significantly higher in both groups compared with controls. Likewise, there was a significant difference in GSH-Px activity levels between the OCD + MDD and OCD - MDD group. CAT activity levels were slightly higher in the OCD + MDD group compared with the OCD - MDD and control group. MDA levels in both groups were significantly higher than in controls. In addition, the difference in MDA levels between both groups was statistically significant. In conclusion, our results suggest that OCD is associated with free radicals and that it may be a heterogeneous subtype including some biological indications of anxiety and affective disorders. More comprehensive and detailed studies are needed to decipher the exact role of free radicals in OCD.     

Effects of oral aluminum exposure on behavior and neurogenesis in a transgenic mouse model of Alzheimer's disease

The effects of a very low oral dose of Al on spatial learning and neurogenesis were evaluated in a transgenic mouse (Tg 2576) model of Alzheimer disease. At 5 months of age, wild and Tg 2576 mice received a diet supplemented with Al lactate at 0 and 1 mg/g of diet for 120 days. The experimental groups (n =  7–8) were: control wild, Al-treated wild, control transgenic, and Al-treated transgenic. After 3 months of Al exposure, activity in an open-field and learning in a water maze were evaluated. At the end of the behavioral testing, in order to study cell proliferation and differentiation in the hippocampus, mice were injected with 5-bromo-2-deoxyuridine (BrdU) and sacrificed 1 or 28 days after the last BrdU injection. Tg 2576 mice were impaired in both acquisition and retention of the water maze task, showing higher amounts of β-amyloid fragments in brain. Aluminum exposure impaired learning and memory in wild mice and increased the total number of proliferating cells in the dentate gyrus of hippocampus. The low Al doses here experimented suggest that this element might impair cognition in the general population at doses comparable to current levels of human exposure. Although these doses are not enough to interact with the amyloidogenic pathway, an increase in cell proliferation can indicate a reactive response of the brain to Al insult. Further investigations should be performed to corroborate the effects observed at very low doses of Al and to study the potential effects derived from a longer exposure period.     

Persistence of the benefit of an antioxidant therapy in children and teenagers with Down syndrome

This study examined the effect of an antioxidant intervention in biomarkers of inflammation and oxidative stress (OS) in the blood of Down syndrome (DS) children and teenagers during four different stages. A control group was composed by healthy children (n = 18), assessed once, and a Down group composed by DS patients (n = 21) assessed at the basal period (t₀), as well as after 6 months of antioxidant supplementation (t₁), after 12 months (after interruption of the antioxidant intervention for 6 months) (t₂), and again after further 6 months of antioxidant supplementation (t₃). Biomarkers of inflammation (myeloperoxidase activity – MPO and levels of IL-1β and TNF-α) and OS (thiobarbituric acid reactive substances – TBARS, protein carbonyls – PC), reduced glutathione (GSH), uric acid (UA) and vitamin E levels, as well as antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST) and gamma-glutamyltransferase (GGT) activities, were measured after each period. After the antioxidant supplementation, the activities of SOD, CAT, GPx, GR, GGT and MPO were downregulated, while TBARS contents were strongly decreased, the contents of GSH and vitamin E were significantly increased, and no changes in G6PD and GST activity as well as in UA and PC levels were detected. After the interruption of the antioxidant therapy for 6 months, DS patients showed elevated GPx and GGT activities and also elevated UA and TBARS levels. No changes in SOD, CAT, GR, GST, G6PD and MPO activities as well as in GSH, vitamin E, PC, TNF-α and IL-1β levels were detected. The results showed that the antioxidant intervention persistently attenuated the systemic oxidative damage in DS patients even after a relatively long period of cessation of the antioxidant intervention.     

Serum selenium and plasma malondialdehyde levels and antioxidant enzyme activities in patients with obsessive-compulsive disorder

There is mounting evidence indicating that reactive free radical species are involved in initiation and development of many different forms of human pathologies including psychiatric disorders. In the present study, we aimed to determine whether serum selenium (Se), antioxidant enzyme (glutathione peroxidase, GSH-Px, superoxide dismutase, SOD, and catalase, CAT) activities, and plasma malondialdehyde (MDA) levels, a product of lipid peroxidation, were associated with obsessive-compulsive disorder (OCD). The participants were 28 patients with OCD that were drug-free at least for a month and a control group (n=28) of healthy subjects, matched with respect to age and sex. In both groups, the levels of the erythrocyte MDA, GSH-Px, SOD, Se, and the CAT were measured. The levels of MDA and SOD were statistically significantly higher (p<0.01, p<0.05 respectively) in patients than controls. The activities of CAT, GSH-Px, and serum Se levels were statistically significantly lower (p<0.0001, p<0.001, and p<0.001 respectively) in patients than controls. There was a positive correlation in patients between plasma GSH-Px activity and Se concentration (r=52, p=0.001). However, in patients with OCD, CAT and SOD activities were significantly and negatively correlated with MDA levels (r=-0.45, p=0.017 for CAT and r=-0.54, p=0.020 for SOD). The study shows the presence of a significant relationship of OCD and oxidative stress, and consequently, an involvement of free radicals and of the antioxidant defence.     

Chronic Immobilization in the malpar1 Knockout Mice Increases Oxidative Stress in the Hippocampus

ABSTRACT The lysophosphatidic acid LPA(1) receptor has recently been involved in the adaptation of the hippocampus to chronic stress. The absence of LPA(1) receptor aggravates the chronic stress-induced impairment of both hippocampal neurogenesis and apoptosis that were accompanied with hippocampus-dependent memory deficits. Apoptotic death and neurogenesis in the hippocampus are regulated by oxidative stress. In the present work, we studied the involvement of LPA(1) receptor signaling pathway in the regulation of the hippocampal redox after chronic stress. To this end, we used malpar1 knockout (KO) and wild-type mice assigned to either chronic stress (21?days of restraint, 3?h/day) or control conditions. Lipid peroxidation, the activity of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX), as well as mitochondrial function stimulation, monitored through the activity of cytochrome c oxidase (COX), were studied in the hippocampus. Our results showed that chronic immobilization stress enhanced lipid peroxidation as well as the activity of the antioxidant enzymes studied (CAT, SOD, and GPX). This effect was only observed in absence of LPA(1) receptor. Furthermore, only malpar1 KO mice submitted to chronic stress exhibited a severe downregulation of the COX activity, suggesting the presence of mitochondrial damage. Altogether, these results suggest that malpar1 KO mice display enhanced oxidative stress in the hippocampus after chronic stress. This may be involved in the hippocampal abnormalities observed in this genotype after chronic immobilization, including memory, neurogenesis, and apoptosis.     

Effect of ingested sulfite on hippocampus antioxidant enzyme activities in sulfite oxidase competent and deficient rats

Animal tissues are exposed to sulfite used as a preservative in food and drugs, and generated from the catabolism of sulfur-containing amino acids. Sulfite, which is a very reactive and potentially toxic molecule, is detoxified by the enzyme sulfite oxidase (SOX). Laboratory animals can be made deficient in SOX by the administration of a high-tungsten/low molybdenum regimen. It has been suggested that SOX deficient rats might be used as a model for the prediction of sulfite toxicity in humans. The aim of this study was to investigate the effects of ingested sulfite on hippocampus superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities in SOX competent and deficient rats. Hippocampus SOD, CAT and GPx activities were found to be significantly increased by sulfite treatment in SOX competent groups. On the other hand, exposure to sulfite had no effect on antioxidant status in hippocampus of SOX deficient rats. In conclusion, these results suggest that hippocampus antioxidant capacity where defense mechanism against the oxidative challenge is up regulated by sulfite in SOX competent rats. This up regulation mechanism in antioxidant enzymes against to sulfite related oxidative stress is not observed in SOX deficient rats and remains to be explained.     

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.     

Effects of haloperidol on antioxidant defense system enzymes in schizophrenia

Dysregulation of free radical metabolism as reflected by abnormal erythrocyte activities of three critical enzymes of the antioxidant defense system (AODS), i.e. superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), has been reported in schizophrenic patients. The present study examined the effects of haloperidol, a standard antipsychotic agent, on the AODS enzymes, using a within-subject, repeated-measures, on–off haloperidol treatment design. The mean drug free period was 40 days. At baseline, there were no significant differences for all three enzymes between patients and age and sex-matched normal volunteers. During the drug-free condition, SOD activity, but not GSH-Px and CAT activities, was significantly higher relative to normal control subjects. However, within-subjects both SOD and GSH-Px activities, but not CAT activity, were higher in the drug-free condition compared to the treatment condition. No significant correlation was observed between SOD activity and plasma haloperidol (or daily haloperidol dose) levels. Smoking status, as assessed by the cotinine level, was unrelated to enzyme activities. In addition, none of the major AODS enzymes showed significant differences between relapsed and clinically stable patients. These findings suggest that haloperidol may not have direct regulatory effect on AODS enzyme activities and that SOD and GSH-Px activities may change in response to other factors such as change in symptom severity.     

Total antioxidant capacity is impaired in different structures from aged rat brain

Our data support a disproportion between free radicals levels and scavenging systems activity in different cerebral regions of the aging rat. We investigated the total reactive antioxidant potential and reactivity levels, which represent the total antioxidant capacity, in different cerebral regions of the aging rat (cortex, striatum, hippocampus and the cerebellum). In addition, we have determined several oxidative stress parameters, specifically the free radicals levels, the macromolecules damage (lipid peroxidation and carbonyl content), as well as the antioxidant enzymes activities in different cerebral areas from young (2 months-old), mature adult (6 months-old) and old (24 months-old) male Wistar rats. Free radicals levels, determined by 2′,7′-dichlorofluorescein diacetate probe, were higher in striatum, cerebellum and hippocampus from aged rats. There was an age-related increase in lipoperoxidation in hippocampus and cerebral cortex. In the cerebellum, a high activity of superoxide dismutase and a decrease of catalase activity were observed. The striatum exhibited a significant catalase activity decrease; and glutathione peroxidase activity was diminished in the hippocampus of mature and aged rats. There was a marked decrease of total antioxidant capacity in hippocampus in both reactivity and potential levels, whereas striatum and cerebral cortex displayed a reduction on reactivity assay. We suggest that age-related variations of total antioxidant defenses in brain may predispose structures to oxidative stress-related neurodegenerative disorders.     

Risperidone reverses phencyclidine induced decrease in glutathione levels and alterations of antioxidant defense in rat brain

Perinatal phencyclidine (PCP) administration to rats represents one of the actual animal models of schizophrenia. Numerous data suggest redox dysregulation in this disease. We have previously demonstrated decreased content of the reduced glutathione (GSH) and complex disbalance of antioxidant enzymes in the brain of rats perinatally treated with PCP. The aim of this study was to elucidate whether chronic risperidone treatment can reverse these changes. The Wistar rats were perinatally treated with either PCP (10mg/kg; PCP, two groups) or saline (0.9% NaCl, two groups). At postnatal day (PN) 35, two groups of rats one NaCl and one PCP have started to receive risperidone in drinking water for nine weeks (NaCl-RSP and PCP-RSP groups). Animals were sacrificed on PN100 and the levels of GSH, the activities of γ-glutamate cysteine ligase (GCL), glutathione peroxidase (GPx), glutathione reductase (GR) and superoxide dismutase (SOD), as well as, the concentration of lipid peroxides were determined in the different brain structures. Risperidone restored decreased GSH levels, as well as decreased γ-GCL activity in cortex and hippocampus of animals perinatally treated with PCP. Alterations in GPx and GR activities caused by perinatal PCP treatment were also reversed by risperidone in most investigated brain structures. Furthermore, chronic risperidone treatment caused the decrease in SOD activity both in control and in PCP perinatally treated groups. Increased levels of lipid peroxides noticed in hippocampus and thalamus were reversed after chronic risperidone treatment. The results of the present study demonstrate that risperidone treatment restores GSH levels and to great measure reverses antioxidant defense alterations in the brain of perinatally PCP treated rats. Further studies are necessary in order to clarify the significance of risperidone influence on oxidative stress parameters in schizophrenia.     

Calcium and zinc supplementation protects lead (Pb)-induced perturbations in antioxidant enzymes and lipid peroxidation in developing mouse brain

Several studies have implicated oxidative stress as one of the important mechanisms of toxic effects of lead (Pb). In the present study we tested the beneficial effects of calcium (Ca²⁺) and zinc (Zn²⁺) in protecting the Pb-induced oxidative stress in the brains of developing and adult mice. Mice were lactationally exposed to 0.2% Pb and supplemented with either calcium (Ca²⁺) or zinc (Zn²⁺) and the mitochondrial antioxidant enzymes [superoxide dismutase (SOD), xanthine oxidase (XO) and catalase (CAT)] and lipid peroxidation (LP) were analyzed in cortex, hippocampus, cerebellum and medulla of brains excised on postnatal day (PND) 14, 21, 28 and 3 months. The levels of free radicals were measured using direct Electron Paramagnetic Resonance (EPR) spectroscopy. Exposure to Pb resulted a significant decrease in the activities of SOD, XO and CAT while the LP levels were significantly increased in different brain regions. Evaluation of EPR signals and g-values showed abundant accumulation of free radicals in different regions of the brain following Pb exposure. Interestingly the supplementation with Ca²⁺ or Zn²⁺ reversed the Pb-induced effects on antioxidant enzymes, LP and free radical formation; however Zn²⁺ supplementation appeared to be more protective. These findings strongly support that zinc and calcium supplementation significantly protect the Pb-induced oxidative stress, a major contributing factor to neurotoxicity.     

Ability of GDNF to diminish free radical production leads to protection against kainate-induced excitotoxicity in hippocampus

The primary aim of this study is to explore the protective mechanisms of glial-derived neurotrophic factor (GDNF) during excitotoxicity by kainate in the hippocampus. After a 15-min microinjection with kainate, excitotoxicity was induced in the rat hippocampus. The protective effect of GDNF in the hippocampus was evaluated by administering GDNF 14 min after injection of kainate. The resulting hydroxyl free radicals were quantified by microdialysis of the hippocampus. The results show that GDNF can effectively suppress the production of kainate-induced hydroxyl free radical production. In addition, histological observation indicated the ability of GDNF to decrease the damage level of pyramidal neurons in the CA3 and CA4 areas of the hippocampus. Superoxide dismutase (SOD) activity in the hippocampus was elevated significantly at 30 min and 7 days after kainate induction, while glutathione peroxidase (cGPx) activity did not increase significantly until the seventh day. With GDNF treatment, SOD and cGPx activity in the hippocampus was elevated significantly 7 days after kainate induction. We suggest that mechanisms including a decrease in free radical generation and scavenging of free radicals might be involved in GDNF protection against kainate-induced excitotoxicity.