Oxidative variables and antioxidant enzymes activities in the mdx mouse brain

Dystrophin is a protein found at the plasmatic membrane in muscle and postsynaptic membrane of some neurons, where it plays an important role on synaptic transmission and plasticity. Its absence is associated with Duchenne's muscular dystrophy (DMD), in which cognitive impairment is found. Oxidative stress appears to be involved in the physiopathology of DMD and its cognitive dysfunction. In this regard, the present study investigated oxidative parameters (lipid and protein peroxidation) and antioxidant enzymes activities (superoxide dismutase and catalase) in prefrontal cortex, cerebellum, hippocampus, striatum and cortex tissues from male dystrophic mdx and normal C57BL10 mice. We observed (1) reduced lipid peroxidation in striatum and protein peroxidation in cerebellum and prefrontal cortex; (2) increased superoxide dismutase activity in cerebellum, prefrontal cortex, hippocampus and striatum; and (3) reduced catalase activity in striatum. It seems by our results, that the superoxide dismutase antioxidant mechanism is playing a protective role against lipid and protein peroxidation in mdx mouse brain.     

Effects of chronic mild stress on the oxidative parameters in the rat brain

Major depression is characterized for symptoms at the psychological, behavioral and physiological levels. The chronic mild stress model has been used as an animal model of depression. The consumption of sweet food, locomotor activity, body weight, lipid and protein oxidation levels and superoxide dismutase and catalase activities in the rat hippocampus, prefrontal cortex and cortex were assessed in rats exposed to chronic mild stress. Our findings demonstrated a decrease on sweet food intake, no effect on locomotor activity, lack of body weight gain, increase in protein (prefrontal, hippocampus, striatum and cortex) and lipidic peroxidation (cerebellum and striatum), and an increase in catalase (cerebellum, hippocampus, striatum, cortex) and a decrease in superoxide dismutase activity (prefrontal, hippocampus, striatum and cortex) in stressed rats. In conclusion, our results support the idea that stress produces oxidants and an imbalance between superoxide dismutase and catalase activities that contributes to stress-related diseases, such as depression.     

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.     

Long Lasting Effects of Electroconvulsive Seizures on Brain Oxidative Parameters

This work was performed in order to determine the level of oxidative damage and antioxidant enzymes activities late after acute and chronic electroconvulsive shock (ECS) in rats. We measured oxidative parameters in hippocampus, cortex, and striatum, at 45, 60, 90 and 120 days after a single or multiple ECS. We demonstrated an increase in lipid peroxidation after multiple ECS in the hippocampus and striatum. This was also the case for protein carbonyls in the single or multiple protocols. In this way, we demonstrated an increase in catalase in cortex in contrast to striatum and hippocampus, were there were decreases sometimes in chronic ECS. The superoxide dismutase activities decrease in different times after single and multiple ECS in the hippocampus. Our findings demonstrated that there is a delayed increase after ECS in oxidative damage and decrease in antioxidant enzymes activities in hippocampus and striatum.     

Central Nervous System Involvement in the Animal Model of Myodystrophy

Congenital muscular dystrophies present mutated gene in the LARGE mice model and it is characterized by an abnormal glycosylation of α-dystroglycan (α-DG), strongly implicated as having a causative role in the development of central nervous system abnormalities such as cognitive impairment seen in patients. However, the pathophysiology of the brain involvement remains unclear. Therefore, the objective of this study is to evaluate the oxidative damage and energetic metabolism in the brain tissue as well as cognitive involvement in the LARGE^(myd) mice model of muscular dystrophy. With this aim, we used adult homozygous, heterozygous, and wild-type mice that were divided into two groups: behavior and biochemical analyses. In summary, it was observed that homozygous mice presented impairment to the habituation and avoidance memory tasks; low levels of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex, hippocampus, cortex and cerebellum; increased lipid peroxidation in the prefrontal cortex, hippocampus, striatum, and cerebellum; an increase of protein peroxidation in the prefrontal cortex, hippocampus, striatum, cerebellum, and cortex; a decrease of complex I activity in the prefrontal cortex and cerebellum; a decrease of complex II activity in the prefrontal cortex and cerebellum; a decrease of complex IV activity in the prefrontal cortex and cerebellum; an increase in the cortex; and an increase of creatine kinase activity in the striatum and cerebellum. This study shows the first evidence that abnormal glycosylation of α-DG may be affecting BDNF levels, oxidative particles, and energetic metabolism thus contributing to the memory storage and restoring process.     

Increased Oxidative Parameters and Decreased Cytokine Levels in an Animal Model of Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) is a highly heterogeneous disorder characterized by impairing levels of hyperactivity, impulsivity and inattention. Oxidative and inflammatory parameters have been recognized among its multiple predisposing pathways, and clinical studies indicate that ADHD patients have increased oxidative stress. In this study, we aimed to evaluate oxidative (DCFH oxidation, glutathione levels, glutathione peroxidase, catalase and superoxide dismutase activities) and inflammatory (TNF-α, IL-1β and IL-10) parameters in the most widely accepted animal model of ADHD, the spontaneously hypertensive rats (SHR). Prefrontal cortex, cortex (remaining regions), striatum and hippocampus of adult male SHR and Wistar Kyoto rats were studied. SHR presented increased reactive oxygen species (ROS) production in the cortex, striatum and hippocampus. In SHR, glutathione peroxidase activity was decreased in the prefrontal cortex and hippocampus. TNF-α levels were reduced in the prefrontal cortex, cortex (remaining regions), hippocampus and striatum of SHR. Besides, IL-1β and IL-10 levels were decreased in the cortex of the ADHD model. Results indicate that SHR presented an oxidative profile that is characterized by an increase in ROS production without an effective antioxidant counterbalance. In addition, this strain showed a decrease in cytokine levels, mainly TNF-α, indicating a basal deficit. These results may present a new approach to the cognitive disturbances seen in the SHR.     

Region specific increase in the antioxidant enzymes and lipid peroxidation products in the brain of rats exposed to lead

The objective of this study is to determine the effect of lead (pb) on antioxidant enzymes and lipid peroxidation products in different regions of rat brain. Wistar male rats were treated with lead acetate (500 ppm) through drinking water for a period of 8 weeks. Control animals were maintained on sodium acetate. Treated and control rats were sacrificed at intervals of 1st, 4th and 8th week and the whole brains were dissected on ice into four regions namely the cerebellum, the hippocampus, the frontal cortex and the brain stem. Antioxidant enzymes namely catalase and superoxide dismutase in all the four regions of brain were determined. In addition, lipid peroxidation products were also estimated. The results indicated a gradual increase in the activity of antioxidant enzymes in different regions of the brain and this response was time-dependent. However, the increase was more in the cerebellum and the hippocampus compared to other regions of the brain. The lipid peroxidation products also showed a similar trend suggesting increased effect of lead in these two regions of the brain. The data indicated a region-specific oxidative stress in the brain exposed to lead.     

Age-dependent variations in mitochondrial and cytosolic antioxidant enzymes and lipid peroxidation in different regions of central nervous system of guinea pigs

The age-related changes in the activities of antioxidant enzymes of mitochondrial and cytosolic fractions were measured in different regions of the central nervous system (CNS) in 10 and 32 months old guinea pigs. In old animals, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) were reduced (p < 0.05) in all the regions of CNS studied but catalase (CAT) declined significantly only in the cerebral cortex, hypothalamus and cerebellum. Glutathione reductase (GRd) activity declined in cerebral cortex and hypothalamus in the cytosolic fractions and only in cerebellum in the mitochondrial fraction. It is concluded that age-related decline in the activities of antioxidant enzymes is both region and enzyme specific. The endogenous lipid peroxide was found to be significantly higher (p < 0.05) in the 32 month old animals whereas, lipid peroxidation after incubating the tissue homogenate in air was found to be lower (p < 0.05). The in vitro mitochondrial lipid peroxidation decreased with age. The results indicate that accumulation of lipid peroxides takes place with ageing but the susceptibility of lipid peroxidation decreases in the older animals.     

Effects of melatonin on oxidative stress and spatial memory impairment induced by acute ethanol treatment in rats

Melatonin has recently been suggested as an antioxidant that may protect neurons from oxidative stress. Acute ethanol administration produces both lipid peroxidation as an indicator of oxidative stress in the brain and impairs water-maze performance in spatial learning and memory tasks. The present study investigated the effect of melatonin against ethanol-induced oxidative stress and spatial memory impairment. The Morris water maze was used to evaluate the cognitive functions of rats. Thiobarbituric acid reactive substances (TBARS), which are the indicators of lipid peroxidation, and the activities of antioxidative enzymes (glutathione peroxidase and superoxide dismutase) were measured in the rat hippocampus and prefrontal cortex which form interconnected neural circuits for spatial memory. Acute administration of ethanol significantly increased TBARS levels in the hippocampus. Combined melatonin-ethanol treatment caused a significant increase in glutathione peroxidase activities and a significant decrease of TBARS in the rat hippocampus. In the prefrontal cortex, there was only a significant decrease of TBARS levels in the combined melatonin-ethanol receiving group as compared to the ethanol-treated group. Melatonin did not affect the impairment of spatial memory due to acute ethanol exposure, but melatonin alone had a positive effect on water maze performances. Our study demonstrated that melatonin decreased ethanol-induced lipid peroxidation and increased glutathione peroxidase activity in the rat hippocampus.     

Antioxidant activities of Ptychopetalum olacoides (“muirapuama”) in mice brain

Ptychopetalum olacoides (PO) roots are used by Amazonian peoples to prepare traditional remedies for treating various central nervous system conditions in which free radicals are likely to be implicated. Following the identification of PO ethanol extract (POEE) free-radical scavenging properties in vitro, the aim of this study was to verify the in vivo antioxidant effect of POEE. Aging mice (14 months) were treated (i.p.) with saline, DMSO (20%) or POEE (100mg/kg body wt.), and the hippocampi, cerebral cortex, striata, hypothalamus and cerebellum dissected out 60 min later to measure antioxidant enzyme activities, free-radical production and damage to macromolecules. POEE administration reduced free-radical production in the hypothalamus, lead to significant decrease in lipid peroxidation in the cerebral cortex, striatum and hypothalamus, as well as in the carbonyl content in cerebellum and striatum. In terms of antioxidant enzymes, catalase activity was increased in the cortex, striatum, cerebellum and hippocampus, while glutathione peroxidase activity was increased in the hippocampus. This study suggests that POEE contains compounds able to improve the cellular antioxidant network efficacy in the brain, ultimately reducing the damage caused by oxidative stress.     

Deprenyl and the relationship between its effects on spatial memory, oxidant stress and hippocampal neurons in aged male rats

Oxidative stress may play a major role in the aging process and associated cognitive decline. Therefore, antioxidant treatment may alleviate age-related impairment in spatial memory. Cognitive impairment could also involve the age-related morphological alterations of the hippocampal formation. The aim of this study was to examine the relationship between the effects of deprenyl, an irreversible monoamine-oxidase B inhibitor, on spatial memory by oxidant stress and on the total number of neurons in the hippocampus CA1 region of aged male rats. In this study, 24-month-old male rats were used. Rats were divided into control and experimental groups which received an injection of deprenyl for 21 days. Learning experiments were performed for six days in the Morris water maze. Spatial learning was significantly better in deprenyl-treated rats compared to saline-treated rats. Deprenyl treatment elicited a significant decrease of lipid peroxidation in the prefrontal cortex, striatum and hippocampus regions and a significant increase of glutathione peroxidase activity in the prefrontal cortex and hippocampus. It was observed that deprenyl had no effect on superoxide dismutase activity. The total number of neurons in the hippocampus CA1 region was significantly higher in the deprenyl group than in the control group. In conclusion, we demonstrated that deprenyl increases spatial memory performance in aged male rats and this increase may be related to suppression of lipid peroxidation and alleviation of the age-related decrease of the number of neurons in the hippocampus. The results of such studies may be useful in pharmacological alleviation of the aging process.     

Oxidative stress in the hippocampus after pilocarpine-induced status epilepticus in Wistar rats

The role of oxidative stress in pilocarpine-induced status epilepticus was investigated by measuring lipid peroxidation level, nitrite content, GSH concentration, and superoxide dismutase and catalase activities in the hippocampus of Wistar rats. The control group was subcutaneously injected with 0.9% saline. The experimental group received pilocarpine (400 mg.kg(-1), subcutaneous). Both groups were killed 24 h after treatment. After the induction of status epilepticus, there were significant increases (77% and 51%, respectively) in lipid peroxidation and nitrite concentration, but a 55% decrease in GSH content. Catalase activity was augmented 88%, but superoxide dismutase activity remained unaltered. These results show evidence of neuronal damage in the hippocampus due to a decrease in GSH concentration and an increase in lipid peroxidation and nitrite content. GSH and catalase activity are involved in mechanisms responsible for eliminating oxygen free radicals during the establishment of status epilepticus in the hippocampus. In contrast, no correlations between superoxide dismutase and catalase activities were observed. Our results suggest that GSH and catalase activity play an antioxidant role in the hippocampus during status epilepticus.     

Changes in Antioxidant Defense Enzymes after d-amphetamine Exposure: Implications as an Animal Model of Mania

Studies have demonstrated that oxidative stress is associated with amphetamine-induced neurotoxicity, but little is known about the adaptations of antioxidant enzymes in the brain after amphetamine exposure. We studied the effects of acute and chronic amphetamine administration on superoxide dismutase (SOD) and catalase (CAT) activity, in a rodent model of mania. Male Wistar rats received either a single IP injection of d-amphetamine (1 mg/kg, 2 mg/kg, or 4 mg/kg) or vehicle (acute treatment). In the chronic treatment rats received a daily IP injection of either d-amphetamine (1 mg/kg, 2 mg/kg, or 4 mg/kg) or vehicle for 7 days. Locomotor behavior was assessed using the open field test. SOD and CAT activities were measured in the prefrontal cortex, hippocampus, and striatum. Acute and to a greater extent chronic amphetamine treatment increased locomotor behavior and affected SOD and CAT activities in the prefrontal cortex, hippocampus and striatum. Our findings suggest that amphetamine exposure is associated with an imbalance between SOD and CAT activity in the prefrontal cortex, hippocampus and striatum.     

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.     

The role of antioxidant enzymes in TCDD-induced oxidative stress in various brain regions of rats after subchronic exposure

The induction of oxidative stress by TCDD in various brain regions of rats has been investigated after subchronic exposure. TCDD was administered by gavage to female Sprague-Dawley rats at daily doses of 0, 10, 22, and 46 ng/kg for 13 weeks. The brains were dissected to cerebral cortex (Cc), hippocampus (H), cerebellum (C), and brain stem (Bs); the production of superoxide anion (SA) and lipid peroxides and the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px) were determined in those regions. TCDD caused dose-dependent increases in the production of SA and lipid peroxidation in Cc and H and those were associated with dose-dependent suppressions of SOD. While a TCDD dose of 10 ng/kg/d resulted in significant increases in catalase and GSH-Px activities in Cc and H, doses of 22 and 46 ng/kg/d resulted in dose-dependent suppressions of these two enzymes in the same regions. In the C and Bs, TCDD treatment did not result in significant production of SA and lipid peroxidation but it resulted in dose-dependent increases in the activities of various antioxidant enzymes. These results suggest that Cc and H are vulnerable to TCDD-induced oxidative stress after subchronic exposure, and that C and Bs are protected against that effect.     

Effect of Acute Administration of l-Tyrosine on Oxidative Stress Parameters in Brain of Young Rats

Tyrosinemia type II, also known as Richner–Hanhart syndrome, is an autosomal recessive inborn error of metabolism caused by a deficiency of hepatic cytosolic tyrosine aminotransferase, and is associated with neurologic and development difficulties in numerous patients. Considering that the mechanisms underlying the neurological dysfunction in hypertyrosinemic patients are poorly known and that studies demonstrated that high concentrations of tyrosine provoke oxidative stress in vitro and in vivo in the cerebral cortex of rats, in the present study we investigate the oxidative stress parameters (enzymatic antioxidant defenses, thiobarbituric acid-reactive substances and protein carbonyl content) in cerebellum, hippocampus and striatum of 30-old-day rats after acute administration of l-tyrosine. Our results demonstrated that the acute administration of l-tyrosine increased the thiobarbituric acid reactive species levels in hippocampus and the carbonyl levels in cerebellum, hippocampus and striatum. In addition, acute administration of l-tyrosine significantly decreased superoxide dismutase activity in cerebellum, hippocampus and striatum, while catalase was increased in striatum. In conclusion, the oxidative stress may contribute, along with other mechanisms, to the neurological dysfunction characteristic of hypertyrosinemia and the administration of antioxidants may be considered as a potential adjuvant therapy for tyrosinemia, especially type II.     

Hypobaric hypoxia induces oxidative stress in rat brain

High altitude exposure results in decreased partial pressure of oxygen and an increased formation of reactive oxygen and nitrogen species (RONS), which causes oxidative damage to lipids, proteins and DNA. Exposure to high altitude appears to decrease the activity and effectiveness of antioxidant enzyme system. The antioxidant system is very less in brain tissue and is very much susceptible to hypoxic stress. The aim of the present study was to investigate the time dependent and region specific changes in cortex, hippocampus and striatum on oxidative stress markers on chronic exposure to hypobaric hypoxia. The rats were exposed to simulated high altitude equivalent to 6100 m in animal decompression chamber for 3 and 7 days. Results indicate an increase in oxidative stress as seen by increase in free radical production, nitric oxide level, lipid peroxidation and lactate dehydrogenase levels. The magnitude of increase in oxidative stress was more in 7 days exposure group as compared to 3 days exposure group. The antioxidant defence system such as reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) and reduced/oxidized glutathione (GSH/GSSG) levels were significantly decreased in all the three regions. The observation suggests that the hippocampus is more susceptible to hypoxia than the cortex and striatum. It may be concluded that hypoxia differentially affects the antioxidant status in the cortex, hippocampus and striatum.     

Structure-Related Oxidative Damage in Rat Brain After Acute and Chronic Electroshock

The role of oxidative stress in electroconvulsive therapy-related effects is not well studied. The purpose of this study was to determine oxidative stress parameters in several brain structures after a single electroconvulsive seizure or multiple electroconvulsive seizures. Rats were given either a single electroconvulsive shock or a series of eight electroconvulsive shocks. Brain regions were isolated, and levels of oxidative stress in the brain tissue (cortex, hippocampus, striatum and cerebellum) were measured. We demonstrated a decrease in lipid peroxidation and protein carbonyls in the hippocampus, cerebellum, and striatum several times after a single electroconvulsive shock or multiple electroconvulsive shocks. In contrast, lipid peroxidation increases both after a single electroconvulsive shock or multiple electroconvulsive shocks in cortex. In conclusion, we demonstrate an increase in oxidative damage in cortex, in contrast to a reduction of oxidative damage in hippocampus, striatum, and cerebellum.     

Regional vulnerability to oxidative stress in a model of experimental epilepsy

We evaluated oxidative stress associated with a model of experimental epilepsy. Male Wistar rats were injected i.p. with 150 mg/kg convulsant 3-mercaptopropionic acid and decapitated in two stages: during seizures or in the post-seizure period. Spontaneous chemiluminescence, levels of thiobarbituric acid reactive substances, total antioxidant capacity and antioxidant enzyme activities were measured in cerebellum, hippocampus, cerebral cortex and striatum. In animals killed at seizure, increases of 42% and 90% were observed in spontaneous chemiluminescence of cerebellum and cerebral cortex homogenates, respectively, accompanied by a 25% increase in cerebral cortex levels of thiobarbituric acid reactive substances. In the post-seizure stage, emission completely returned to control levels in cerebral cortex and partly in cerebellum, thus showing oxidative stress reversibility in time. Hippocampus and striatum seemed less vulnerable areas to oxidative damage. A 30% decrease in glutathione peroxidase activity was only observed in cerebral cortex during seizures, while catalase and superoxide dismutase remained unchanged in all four areas during either stage. Likewise, total antioxidant capacity was unaffected in any of the studied areas. It is suggested that oxidative stress in this model of epilepsy arises from an increase in oxidant species rather than from depletion of antioxidant defences.     

Regional Heterogeneity of Cerebral Microvessels and Brain Susceptibility to Oxidative Stress

The hippocampus is one of the earliest and most affected regions in Alzheimer’s disease (AD), followed by the cortex while the cerebellum is largely spared. Importantly, endothelial dysfunction is a common feature of cerebral blood vessels in AD. In this study, we sought to determine if regional heterogeneity of cerebral microvessels might help explain the susceptibility of the hippocampus and cortex as compared to the cerebellum. We isolated microvessels from wild type mice from the cerebellum, cortex, and hippocampus to characterize their vascular phenotype. Superoxide anion was significantly higher in microvessels isolated from the cortex and hippocampus as compared to the cerebellum. Importantly, protein levels of NADPH oxidase (NOX)-2 and NOX-4 were significantly higher in the cortical and hippocampal microvessels as compared to microvessels from the cerebellum. In addition, expression of manganese superoxide dismutase protein was significantly lower in microvessels from the cortex and hippocampus as compared to cerebellum while other antioxidant enzymes were unchanged. There was no difference in eNOS protein expression between the microvessels of the three brain regions; however, bioavailability of tetrahydrobiopterin (BH₄), an essential cofactor for eNOS activity, was significantly reduced in microvessels from the hippocampus and cortex as compared to the cerebellum. Higher levels of superoxide and reduced tetrahydrobiopterin bioavailability may help explain the vulnerability of the hippocampus and cortical microvessels to oxidative stress and development of endothelial dysfunction.