Malathion-induced Oxidative Stress in Rat Brain Regions

Malathion is a pesticide with high potential for human exposure. However, it is possible that during the malathion metabolism, there is generation of reactive oxygen species (ROS) and malathion may produce oxidative stress in intoxicated rats. The present study was therefore undertaken to determine malathion-induced lipid peroxidation (LPO), protein carbonylation and to determine whether malathion intoxication alters the antioxidant system in brain rats. Malathion was administered intraperitoneally in the acute and chronic protocols in the doses of 25, 50, 100 and 150 mg malathion/kg. The results showed that LPO in brain increased in both protocols. The increased oxidative stress resulted in an increased in the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT), observed in cortex, striatum in the acute malathion protocol and hippocampus in the chronic malathion protocol. Our results demonstrated that malathion induced oxidative stress and modulated SOD and CAT activity in selective brain regions.     

Evaluation of Fluoride-Induced Oxidative Stress in Rat Brain: A Multigeneration Study

Multigenerational evaluation was made in rats on exposure to high fluoride (100 and 200 ppm) to assess neurotoxic potential of fluoride in discrete areas of the brain in terms of lipid peroxidation and the activity of antioxidant enzyme system. The rats were given fluoride through drinking water (100 and 200 ppm) and maintained subsequently for three generations. Fluoride treatment significantly increased the lipid peroxidation and decreased the activity of antioxidant enzymes viz, catalase, superoxide dismutase, glutathione peroxidase, glutathione S-transferase, and glutathione level in first-generation rats and these alterations were more pronounced in the subsequent second and third-generation rats in both the doses tested. Decreased feed and water consumption, litter size and organ (brain) somatic index, marginal drop in body growth rate and mortality were observed in all three generations. Decreased antioxidant enzyme activity and increased malondialdehyde levels found in the present study might be related to oxidative damage that occurs variably in discrete regions of the brain. Results of this study can be taken as an index of neurotoxicity in rats exposed to water fluoridation over several generations.     

Venlafaxine Modulates Depression-Induced Oxidative Stress in Brain and Medulla of Rat

Venlafaxine is an approved antidepressant that is an inhibitor of both serotonin and norepinephrine transporters. Medical treatment with oral venlafaxine can be beneficial to depression due to reducing free radical production in the brain and medulla of depression- induced rats because oxidative stress may a play role in some depression. We investigated the effect of venlafaxine administration and experimental depression on lipid peroxidation and antioxidant levels in cortex brain, medulla and erythrocytes of rats. Thirty male wistar rats were used and were randomly divided into three groups. Venlafaxine (20 mg/kg) was orally supplemented to depression-induced rats constituting the first group for four week. Second group was depression-induced group although third group was used as control. Depressions in the first and second groups were induced on day zero of the study by chronic mild stress. Brain, medulla and erythrocytes samples were taken from all animals on day 28. Depression resulted in significant decrease in the glutathione peroxidase (GSH-Px) activity and vitamin C concentrations of cortex brain, glutathione (GSH) value of medulla although their levels were increased by venlafaxine administration to the animals of depression group. The lipid peroxidation levels in the three tissues and nitric oxide value in cortex brain elevated although their levels were decreased by venlafaxine administration. There were no significant changes in cortex brain vitamin A, erythrocytes vitamin C, GSH-Px and GSH, medulla vitamin A, GSH and GSH-Px values. In conclusion, cortex brain within the three tissues was most affected by oxidative stress although there was the beneficial effect of venlafaxine in the brain of depression-induced rats on investigated antioxidant defenses in the rat model. The treatment of depression by venlafaxine may also play a role in preventing oxidative stress. Abstract of the paper was submitted in 1st Ion Channels and Oxidative Stress Congress, 14–16 September 2006, Isparta, Turkey.     

Oxidative Parameters in the Rat Brain of Chronic Mild Stress Model for Depression: Relation to Anhedonia-Like Responses

The chronic mild stress (CMS) protocol is widely used to evoke depression-like behaviors in the laboratory. Some animals exposed to CMS are resistant to the development of anhedonia, whereas the remaining are responsive, CMS-resilient and CMS-sensitive, respectively. The aim of this study was to examine the effects of chronic stress on oxidative parameters in the rat brain. The consumption of sweet food, protein and lipid oxidation levels and superoxide dismutase and catalase activities in the rat hippocampus, cortex and cerebellum were assessed. We found a significant increase in protein peroxidation (hippocampus and cortex), a significant increase in catalase activity (cortex, hippocampus and cerebellum) and a decrease in superoxide dismutase activity (cortex, hippocampus and cerebellum) in the CMS-sensitive group compared to the CMS-resilient group and normal controls as well as an increase in lipid peroxidation (cerebellum) in the CMS-sensitive and CMS-resilient groups compared to normal controls. However, there was no significant difference in protein peroxidation (cerebellum) and lipid peroxidation (cortex and hippocampus) among the three groups. In conclusion, our results indicate that the segregation into CMS-sensitive and -resilient groups based on sucrose intake is paralleled by significant differences in oxidative parameters. CMS induces oxidative damage and alterations in the activity of antioxidants which may lead to increased oxidative damage, irrespective of the anhedonia-like status of the stressed animals.     

Oxidative Stress and Proinflammatory Cytokines Contribute to Demyelination and Axonal Damage in a Cerebellar Culture Model of Neuroinflammation

Background

Demyelination and axonal damage are critical processes in the pathogenesis of multiple sclerosis (MS). Oxidative stress and pro-inflammatory cytokines elicited by inflammation mediates tissue damage.

Methods/Principal Findings

To monitor the demyelination and axonal injury associated with microglia activation we employed a model using cerebellar organotypic cultures stimulated with lipopolysaccharide (LPS). Microglia activated by LPS released pro-inflammatory cytokines (IL-1β, IL-6 and TNFα), and increased the expression of inducible nitric oxide synthase (iNOS) and production of reactive oxygen species (ROS). This activation was associated with demyelination and axonal damage in cerebellar cultures. Axonal damage, as revealed by the presence of non-phosphorylated neurofilaments, mitochondrial accumulation in axonal spheroids, and axonal transection, was associated with stronger iNOS expression and concomitant increases in ROS. Moreover, we analyzed the contribution of pro-inflammatory cytokines and oxidative stress in demyelination and axonal degeneration using the iNOS inhibitor ethyl pyruvate, a free-scavenger and xanthine oxidase inhibitor allopurinol, as well as via blockage of pro-inflammatory cytokines using a Fc-TNFR1 construct. We found that blocking microglia activation with ethyl pyruvate or allopurinol significantly decreased axonal damage, and to a lesser extent, demyelination. Blocking TNFα significantly decreased demyelination but did not prevented axonal damage. Moreover, the most common therapy for MS, interferon-beta, was used as an example of an immunomodulator compound that can be tested in this model. In vitro, interferon-beta treatment decreased oxidative stress (iNOS and ROS levels) and the release of pro-inflammatory cytokines after LPS stimulation, reducing axonal damage.

Conclusion

The model of neuroinflammation using cerebellar culture stimulated with endotoxin mimicked myelin and axonal damage mediated by the combination of oxidative stress and pro-inflammatory cytokines. This model may both facilitate understanding of the events involved in neuroinflammation and aid in the development of neuroprotective therapies for the treatment of MS and other neurodegenerative diseases.     

Mitochondrial Oxidative Stress and Dysfunction in Rat Brain Induced by Carbofuran Exposure

Repeated low-dose exposure to carbofuran exerts its neurotoxic effects by non-cholinergic mechanisms. Emerging evidence indicates that oxidative stress plays an important role in carbofuran neurotoxicity after sub-chronic exposure. The purpose of the present study is to evaluate the role of mitochondrial oxidative stress and dysfunction as a primary event responsible for neurotoxic effects observed after sub-chronic carbofuran exposure. Carbofuran was administered to rats at a dose of 1 mg/kg orally for a period of 28 days. There was a significant inhibition in the activity of acetylcholinesterase (66.6%) in brain samples after 28 days of carbofuran exposure. Mitochondrial respiratory chain functions were assessed in terms of MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) reduction and activity of succinate dehydrogenase in isolated mitochondria. It was observed that carbofuran exposure significantly inhibited MTT reduction (31%) and succinate dehydrogenase activity (57%). This was accompanied by decrease in low-molecular weight thiols (66.6%) and total thiols (37.4%) and an increase in lipid peroxidation (43.7%) in the mitochondria isolated from carbofuran-exposed rat brain. The changes in mitochondrial oxidative stress and functions were associated with impaired cognitive and motor functions in the animals exposed to carbofuran as compared to the control animals. Based on these results, it is clear that carbofuran exerts its neurotoxicity by impairing mitochondrial functions leading to oxidative stress and neurobehavioral deficits.     

Effect of Mobile Phone Exposure on Apoptotic Glial Cells and Status of Oxidative Stress in Rat Brain

The aim of this study was to investigate the effects of mobile phone exposure on glial cells in brain. The study carried out on 31 Wistar Albino adult male rats. The rat heads in a carousel exposed to 900 MHz microwave. For the study group (n:14), rats exposed to the radiation 2h per day (7 days in a week) for 10 months. For the sham group (n:7), rats were placed into the carousel and the same procedure was applied except that the generator was turned off. For the cage control (n:10), nothing applied to rats in this group. In this study, rats were euthanized after 10 months of exposure periods and brains were removed.

Brain tissues were immunohistochemically stained for the active (cleaved) caspase-3, which is a well-known apoptosis marker, and p53. The expression of the proteins was evaluated by a semi-quantitative scoring system. However, total antioxidative capacity (TAC), catalase, total oxidant status (TOS), and oxidative stress index were measured in rat brain.

Final score for apoptosis in the exposed group was significantly lower than the sham (p < 0.001) and the cage control groups (p < 0.01). p53 was not significantly changed by the exposure (p > 0.05). The total antioxidant capacity and catalase in the experimental group was found higher than that in the sham group (p < 0.001, p < 0.05). In terms of the TOS and oxidative stress index, there was no statistically significant difference between exposure and sham groups (p > 0.05).

In conclusion, the final score for apoptosis, total antioxidant capacity and catalase in rat brain might be altered by 900 MHz radiation produced by a generator to represent exposure of global systems for mobile communication (GSM) cellular phones.     

Tannic Acid Attenuates Peripheral and Brain Changes in a Preclinical Rat Model of Glioblastoma by Modulating Oxidative Stress and Purinergic Signaling

Neurochemical Research - Glioblastoma (GB) is a highly aggressive and invasive brain tumor; its treatment remains palliative. Tannic acid (TA) is a polyphenol widely found in foods and possesses...     

Protective Effects of Curcumin against Fluoride-Induced Oxidative Stress in the Rat Brain

We examined effects of a plant polyphenolic compound, curcumin, against fluoride-induced oxidative stress in the rat brain. Five experimental groups of male rats (10 animals each) were compared. Animals of these experimental groups were treated with curcumin (10 and 20 mg/kg body mass), vitamin C (10 mg/kg), and sample solvent (0.5 ml) for a week prior to sodium fluoride intoxication. After treatment, rats of the experimental groups, except for the normal control group, were intoxicated with sodium fluoride (600 ppm through drinking water) for a week. Then, brains were collected and homogenized, and activities of superoxide dismutase and catalase and levels of reduced glutathione and lipid peroxidation final products were evaluated in the brain tissue homogenates. Treatment with curcumin prior to fluoride intoxication significantly normalized the above biochemical parameters; the intensity of protective effects of 20 mg/kg curcumin was close to that of vitamin C.     

Effect of Acute,Slightly Increased Intra-Abdominal Pressure on Intestinal Permeability and Oxidative Stress in a Rat Model

IntroductionIntra-abdominal hypertension (IAH) is known as a common, serious complication in critically ill patients. Bacterial translocation and permeability changes are considered the pathophysiological bases for IAH-induced enterogenic endotoxemia and subsequent multiorgan failure. Nevertheless, the effects of slightly elevated intra-abdominal pressures (IAPs) on the intestinal mucosa and the associated mechanisms remain unclear.MethodsTo investigate the acute effects of different nitrogen pneumoperitoneum grades on colonic mucosa, male Sprague-Dawley rats were assigned to six groups with different IAPs (0 [control], 4, 8, 12, 16, and 20 mmHg, n = 6/group). During 90 min of exposure, we dynamically monitored the heart rate and noninvasive hemodynamic parameters. After gradual decompression, arterial blood gas analyses were conducted. Thereafter, structural injuries to the colonic mucosa were identified using light microscopy. Colon permeability was determined using the expression of tight junction proteins, combined with fluorescein isothiocyanate dextran (FD-4) absorption. The pro-oxidant-antioxidant balance was determined based on the levels of malondialdehyde (MDA) and antioxidant enzymes.ResultsIAH significantly affected the histological scores of the colonic mucosa, tight junction protein expression, mucosal permeability, and pro-oxidant-antioxidant balance. Interestingly, elevations of IAP that were lower than the threshold for IAH also showed a similar, undesirable effect. In the 8 mmHg group, mild hyponatremia, hypocalcemia, and hypoxemia occurred, accompanied by reduced blood and abdominal perfusion pressures. Mild microscopic inflammatory infiltration and increased MDA levels were also detected. Moreover, an 8-mm Hg IAP markedly inhibited the expression of tight junction proteins, although no significant differences in FD-4 permeability were observed between the 0- and 8-mmHg groups.ConclusionsAcute exposure to slightly elevated IAP may result in adverse effects on intestinal permeability and the pro-oxidant-antioxidant balance. Therefore, in patients with critical illnesses, IAP should be dynamically monitored and corrected, as soon as possible, to prevent intestinal mucosal injury and subsequent gut-derived sepsis.     

Evidence that Plasmalogen is Protective Against Oxidative Stress in the Rat Brain

The antioxidant capabilities of phosphatidylethanolamine plasmalogen (PlsEtn), in vivo, against lipid peroxidation were investigated via acute phosphine (PH₃) administration in rats. Oxidative stress was assessed from measures of malondialdehyde and various enzyme activities, while NMR analyses of lipid and aqueous tissue extracts provided metabolic information in cerebellum, brainstem, and cortex. Brainstem had the highest basal [PlsEtn], and showed only moderate PH₃-induced oxidative damage with no loss of ATP. The lowest basal [PlsEtn] was observed in cortex, where PH₃ caused a 51% decrease in [ATP]. The largest oxidative effect occurred in cerebellum, but [ATP] was unaffected. Myo-inositol+ethanolamine pretreatment attenuated all PH₃ effects. Specifically, the pretreatment attenuated the ATP decrease in cortex, and elevated brain [PlsEtn] in the cerebellum, nearly abolishing the cerebellar oxidative effects. Our data suggest a high basal [PlsEtn], or the capacity to synthesize new ethanolamine lipids (particularly PlsEtn) may protect against PH₃ toxicity.     

Ubiquitin-Mediated Stress Response in a Rat Model of Brain Transient Ischemia/Hypoxia

Ubiquitin (Ub) is a small 76-residue protein, involved in intracellular protein degradation through a specific ATP-dependent system, which uses Ub as a tag to label proteins committed to be hydrolyzed by a specific 26 S protease. PGP-9.5 is another important component of the Ub system, i.e. a neuron-specific carboxyl-terminal hydrolase, which recycles Ub from Ub-polypeptide complexes. We have investigated the expression of Ub and PGP-9.5 in rat hippocampal neurons in an early phase of reperfusion in a model of transient global brain ischemia/hypoxia (bilateral occlusion of common carotid arteries for 10 min accompanied by mild hypoxia—15% O₂—for 20 min), by means of immunohistochemical methods using light and electron microscopy. The intensity of Ub and PGP-9.5 immunoreactivity was evaluated by image analysis. We have detected a marked increase of Ub immunoreactivity (UIR) in neurons of CA1, CA2, CA3, CA4, and dentate gyrus subfields 1 hr after ischemia/hypoxia (but not after hypoxia only), statistically significant as confirmed by image analysis. Such increase in immunoreactivity in ischemic/hypoxic rats was localized essentially in the nuclei of hippocampal neurons. There were no changes in PGP-9.5 immunoreactivity. The data suggest that in the present model of rat brain ischemia/hypoxia Ub is involved in the neuronal stress response.     

Ethanolic Extract of Astragali Radix and Salviae Radix Prohibits Oxidative Brain Injury by Psycho-Emotional Stress in Whisker Removal Rat Model

Myelophil, an ethanolic extract of Astragali Radix and Salviae Radix, has been clinically used to treat chronic fatigue and stress related disorders in South Korea. In this study, we investigated the protective effects of Myelophil on a whisker removal-induced psycho-emotional stress model. SD rats were subjected to whisker removal after oral administration of Myelophil or ascorbic acid for consecutive 4 days. Whisker removal considerably increased total reactive oxygen species in serum levels as well as cerebral cortex and hippocampal regions in brain tissues. Lipidperoxidation levels were also increased in the cerebral cortex, hippocampus regions, and brain tissue injuries as shown in histopathology and immunohistochemistry. However, Myelophil significantly ameliorated these alterations, and depletion of glutathione contents in both cerebral cortex and hippocampus regions respectively. Serum levels of corticosterone and adrenaline were notably altered after whisker removal stress, whereas these abnormalities were significantly normalized by pre-treatment with Myelophil. The NF-κB was notably activated in both cerebral cortex and hippocampus after whisker removal stress, while it was efficiently blocked by pre-treatment with Myelophil. Myelophil also significantly normalizes alterations of tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and interferon-γ in both gene expressions and protein levels. These results suggest that Myelophil has protective effects on brain damages in psycho-emotional stress, and the underlying mechanisms involve regulation of inflammatory proteins, especially NF-κB modulation.     

Evaluation of the Effects of Fructose on Oxidative Stress and Inflammatory Parameters in Rat Brain

Hereditary fructose intolerance is an autosomal recessive disorder characterized by the accumulation of fructose in tissues and biological fluids of patients. The disease results from a deficiency of aldolase B, responsible for metabolizing fructose in the liver, kidney, and small intestine. We investigated the effect of acute fructose administration on oxidative stress and neuroinflammatory parameters in the cerebral cortex of 30-day-old Wistar rats. Animals received subcutaneous injection of sodium chloride (0.9 %) (control group) or fructose solution (5 μmol/g) (fructose group). One hour later, the animals were euthanized and the cerebral cortex was isolated. Oxidative stress (levels of thiobarbituric acid-reactive substances (TBA-RS), carbonyl content, nitrate and nitrite levels, 2′,7′-dihydrodichlorofluorescein (DCFH) oxidation, glutathione (GSH) levels, as well as the activities of catalase (CAT) and superoxide dismutase (SOD)) and neuroinflammatory parameters (TNF-α, IL-1β, and IL-6 levels and myeloperoxidase (MPO) activity) were investigated. Acute fructose administration increased levels of TBA-RS and carbonyl content, indicating lipid peroxidation and protein damage. Furthermore, SOD activity increased, whereas CAT activity was decreased. The levels of GSH, nitrate, and nitrite and DCFH oxidation were not altered by acute fructose administration. Finally, cytokines IL-1β, IL-6, and TNF-α levels, as well as MPO activity, were not altered. Our present data indicate that fructose provokes oxidative stress in the cerebral cortex, which induces oxidation of lipids and proteins and changes of CAT and SOD activities. It seems therefore reasonable to propose that antioxidants may serve as an adjuvant therapy to diets or to other pharmacological agents used for these patients, to avoid oxidative damage to the brain.     

Protective Effects of Lamotrigine,Aripiprazole and Escitalopram on Depression-induced Oxidative Stress in Rat Brain

We investigated the effects of lamotrigine, aripiprazole and escitalopram administration and experimental depression on lipid peroxidation (LP) and antioxidant levels in cortex of the brain in rats. Forty male wistar rats were randomly divided into five groups. First group was used as control although second group was depression-induced group. Aripiprazole, lamotrigine and escitalopram per day were orally supplemented to chronic mild stress (CMS) depression-induced rats constituting the third, fourth and fifth groups for 28 days, respectively. Depression resulted in significant decrease in the glutathione peroxidase (GSH-Px) activity, reduced glutathione and vitamin C of cortex of the brain although their levels and beta-carotene concentrations were increased by the three drugs administrations to the animals of CMS induced depression group. The LP levels in the cortex of the brain and plasma of depression group were elevated although their levels were decreased by the administrations. The increases of antioxidant values in lamotrigine group were higher according to aripiprazole and escitalopram supplemented groups. Vitamin A level did not change in the five groups. In conclusion, the experimental depression is associated with elevated oxidative stress although treatment with lamotrigine has most protective effects on the oxidative stress within three medicines.     

Oxidative Stress Induces Dephosphorylation of τ in Rat Brain Primary Neuronal Cultures

Abstract: Oxidative stress and free radical damage have been implicated in the neurodegenerative changes characteristic of several neurodegenerative diseases, including Alzheimer's disease. There is experimental evidence that the neurotoxicity of β-amyloid is mediated via free radicals, and as the deposition of β-amyloid apparently precedes the formation of paired helical filaments (PHF) in Alzheimer's disease, we have investigated whether subjecting primary neuronal cultures to oxidative stress induces changes in the phosphorylation state of the principal PHF protein τ that resemble those found in PHF-τ. Contrary to causing an increase in τ phosphorylation, treatment of neurones with hydrogen peroxide caused a dephosphorylation of τ and so we conclude that oxidative stress is not the direct cause of τ hyperphosphorylation and hence of PHF formation.