Dieldrin-induced oxidative stress and neurochemical changes contribute to apoptopic cell death in dopaminergic cells.

We examined the acute toxicity of dieldrin, a possible environmental risk factor of Parkinson's disease, in a dopaminergic cell model, PC12 cells, to determine early cellular events underlying the pesticide-induced degenerative processes. EC(50) for 1 h dieldrin exposure was 143 microM for PC12 cells, whereas EC(50) for non-dopaminergic cells was 292-351 microM, indicating that dieldrin is more toxic to dopaminergic cells. Dieldrin also induced rapid, dose-dependent releases of dopamine and its metabolite, DOPAC, resulting in depletion of intracellular dopamine. Additionally, dieldrin exposure caused depolarization of mitochondrial membrane potential in a dose-dependent manner. Flow cytometric analysis showed generation of reactive oxygen species (ROS) within 5 min of dieldrin treatment, and significant increases in lipid peroxidation were also detected following 1 h exposure. ROS generation was remarkably inhibited in the presence of SOD. Dieldrin-induced apoptosis was significantly attenuated by both SOD and MnTBAP (SOD mimetic), suggesting that dieldrin-induced superoxide radicals serve as important signals in initiation of apoptosis. Furthermore, pretreatment with deprenyl (MAO-inhibitor) or alpha-methyl-L-p-tyrosine (TH-inhibitor) also suppressed dieldrin-induced ROS generation and DNA fragmentation. Taken together, these results suggest that rapid release of dopamine and generation of ROS are early cellular events that may account for dieldrin-induced apoptotic cell death in dopaminergic cells.     

Comparison of base-excision repair capacity in proliferating and differentiated PC 12 cells following acute challenge with dieldrin.

Dieldrin, an organochlorine pesticide and known neurotoxicant, is ubiquitously distributed in the environment. Dieldrin depletes brain monoamines in some animal species and is toxic for dopaminergic neurons in vitro. Dieldrin interferes with mitochondrial electron transport and increases generation of superoxide anion. Reactive oxygen species have been shown to produce oxidative lesions to DNA bases, i.e., 8-hydroxy-2'-deoxyguanosine (8-oxodGuo). Accumulation of 8-oxodGuo has been shown to be promutagenic in proliferating cells, and can lead to degeneration in fully differentiated cells. The objective of this study was to determine the effects of dieldrin exposure on the activity of the enzyme responsible for removing 8-oxodGuo, OGG1, from undifferentiated (untreated with NGF) and differentiated (NGF-treated) PC 12 cells. Proliferating PC 12 cells exhibited a mild upregulation of glycosylase activity, reaching a maximum by 1 h and returning to baseline by 6 h. Differentiated (+) NGF cells showed a time-dependent decline in activity reaching a nadir at 3 h with a return towards baseline by 6 h. Levels of the damaged base, 8-oxodGuo, in the differentiated PC12 cells appeared to be regulated by the activity of OGG1. In contrast, levels of the damaged base in actively proliferating cells were independent of the OGG1 activity. This difference between actively dividing and differentiated cells in the regulation of base-excision repair and DNA damage accumulation explains, in part, the vulnerability of postmitotic neurons to oxidative stresses and neurotoxins.     

Effect of centrophenoxine against rotenone-induced oxidative stress in an animal model of Parkinson's disease

Oxidative stress has been implicated in the etiology of Parkinson's disease (PD). The important biochemical features of PD, being profound deficit in dopamine (DA) content, reduced glutathione (GSH), and enhanced lipid peroxidation (LPO) in dopaminergic (DA-ergic) neurons resulting in oxidative stress, mitochondrial dysfunction and apoptosis. Rotenone-induced neurotoxicity is a well acknowledged preclinical model for studying PD in rodents as it produces selective DA-ergic neuronal degeneration. In our previous study, we have shown that chronic administration of rotenone to rats is able to produce motor dysfunction, which increases progressively with rotenone treatment and centrophenoxine (CPH) co-treatment is able to attenuate these motor defects. The present study was carried out to evaluate the antioxidant potential of CPH against rotenone-induced oxidative stress. Chronic administration of rotenone to SD rats resulted in marked oxidative damage in the midbrain region compared to other regions of the brain and CPH co-treatment successfully attenuated most of these changes. CPH significantly attenuated rotenone-induced depletion in DA, GSH and increase in LPO levels. In addition, the drug prevented the increase in nitric oxide (NO) and citrulline levels and also enhanced the activity of catalase and superoxide dismutase (SOD). Histological analysis carried out using hematoxylin and eosin staining has indicated severe damage to mid brain in comparison to cortex and cerebellum and this damage is attenuated by CPH co-treatment. Our results strongly indicate the possible therapeutic potential of centrophenoxine as an antioxidant in Parkinson's disease and other movement disorders where oxidative stress is a key player in the disease process.     

Oxidative stress in zinc-induced dopaminergic neurodegeneration: implications of superoxide dismutase and heme oxygenase-1

The study was undertaken to investigate the effect of zinc (Zn) on glutathione S-transferase (GST) and superoxide dismutases (SOD) activities and on the expressions of cytosolic Cu, Zn-SOD (SOD1), mitochondrial Mn-SOD (SOD2), γ-glutamyl cysteine synthetase (γ-GCS) and heme oxygenase-1 (HO-1) in the nigrostriatal tissue of rats. Additionally, Zn-induced alterations in the neurobehavioral parameters, lipid peroxidation (LPO), striatal dopamine and its metabolites and tyrosine hydroxylase (TH) protein expression were measured to assess their correlations with the oxidative stress. Zn exposure reduced the locomotor activity, rotarod performance, striatal dopamine and its metabolites and TH protein expression. LPO, total SOD, SOD1 and SOD2 activities were increased while GST and catalase were reduced in a dose and time dependent manner. Expressions of SOD1 and HO-1 were increased while no change was observed in SOD2 and γ-GCS expressions. The results obtained suggest that Zn-induced augmentation of total SOD, SOD1, SOD2 and HO-1 was associated with increased oxidative stress and neurodegenerative indexes indicating the involvement of both cytosolic and mitochondrial machinery in Zn-induced oxidative stress leading to dopaminergic neurodegeneration.     

Oxidative stress in zinc-induced dopaminergic neurodegeneration: Implications of superoxide dismutase and heme oxygenase-1

Abstract

The study was undertaken to investigate the effect of zinc (Zn) on glutathione S-transferase (GST) and superoxide dismutases (SOD) activities and on the expressions of cytosolic Cu, Zn-SOD (SOD1), mitochondrial Mn-SOD (SOD2), γ-glutamyl cysteine synthetase (γ-GCS) and heme oxygenase-1 (HO-1) in the nigrostriatal tissue of rats. Additionally, Zn-induced alterations in the neurobehavioral parameters, lipid peroxidation (LPO), striatal dopamine and its metabolites and tyrosine hydroxylase (TH) protein expression were measured to assess their correlations with the oxidative stress. Zn exposure reduced the locomotor activity, rotarod performance, striatal dopamine and its metabolites and TH protein expression. LPO, total SOD, SOD1 and SOD2 activities were increased while GST and catalase were reduced in a dose and time dependent manner. Expressions of SOD1 and HO-1 were increased while no change was observed in SOD2 and γ-GCS expressions. The results obtained suggest that Zn-induced augmentation of total SOD, SOD1, SOD2 and HO-1 was associated with increased oxidative stress and neurodegenerative indexes indicating the involvement of both cytosolic and mitochondrial machinery in Zn-induced oxidative stress leading to dopaminergic neurodegeneration.     

Parallel increases in lipid and protein oxidative markers in several mouse brain regions after methamphetamine treatment

The neurotoxic actions of methamphetamine (METH) may be mediated in part by reactive oxygen species (ROS). Methamphetamine administration leads to increases in ROS formation and lipid peroxidation in rodent brain; however, the extent to which proteins may be modified or whether affected brain regions exhibit similar elevations of lipid and protein oxidative markers have not been investigated. In this study we measured concentrations of TBARs, protein carbonyls and monoamines in various mouse brain regions at 4 h and 24 h after the last of four injections of METH (10 mg/kg/injection q 2 h). Substantial increases in TBARs and protein carbonyls were observed in the striatum and hippocampus but not the frontal cortex nor the cerebellum of METH-treated mice. Furthermore, lipid and protein oxidative markers were highly correlated within each brain region. In the hippocampus and striatum elevations in oxidative markers were significantly greater at 24 h than at 4 h. Monoamine levels were maximally reduced within 4 h (striatal dopamine [DA] by 95% and serotonin [5-HT] in striatum, cortex and hippocampus by 60-90%). These decrements persisted for 7 days after METH, indicating effects reflective of nerve terminal damage. Interestingly, NE was only transiently depleted in the brain regions investigated (hippocampus and cortex), suggesting a pharmacological and non-toxic action of METH on the noradrenergic nerve terminals. This study provides the first evidence for concurrent formation of lipid and protein markers of oxidative stress in several brain regions of mice that are severely affected by large neurotoxic doses of METH. Moreover, the differential time course for monoamine depletion and the elevations in oxidative markers indicate that the source of oxidative stress is not derived directly from DA or 5HT oxidation.     

Rat MYH,a glycosylase for repair of oxidatively damaged DNA,has brain-specific isoforms that localize to neuronal mitochondria

Mitochondrial genomes are exposed to a heavy load of reactive oxygen species (ROS) that damage DNA. Since in neurons, mitochondrial DNA integrity must be maintained over the entire mammalian life span, neuronal mitochondria most likely repair oxidatively damaged DNA. We show that the Escherichia coli MutY DNA glycosylase homolog (MYH) in rat (rMYH) involved in repair of oxidative damage is abundantly expressed in the rat brain, with isoforms that are exclusive to brain tissue. Confocal microscopy and western analyses reveal localization of rMYH in neuronal mitochondria. To assess involvement of MYH in the neuronal response to oxidative DNA damage, we used a rat model of respiratory hypoxia, in which acutely reduced blood oxygenation leads to generation of superoxide, and formation and subsequent removal of 8-hydroxy-2'-deoxyguanosine (8OHdG). Removal of 8OHdG is accompanied by a spatial increase in rMYH immunoreactivity in the brain and an increase in levels of one of the three mitochondrial MYH isoforms, suggesting that inducible and non-inducible MYH isoforms exist in the brain. The mitochondrial localization of oxidative DNA damage repair enzymes in neurons may represent a specialized neuronal mechanism that safeguards mitochondrial genomes in the face of routine and accidental exposures to heavy loads of injurious ROS.     

Dose dependent effects of ghrelin on pentylenetetrazole-induced oxidative stress in a rat seizure model

It has been suggested that free oxygen radicals play a role in the genesis of epilepsy and in post-seizure neuronal death. The aim of this study was to investigate the dose dependent effect of ghrelin on pentylenetetrazole (PTZ)-induced oxidative stress in a rat seizure model. For this purpose, the ghrelin groups were treated with intraperitoneal injections of ghrelin at doses of 20, 40, 60 and 80 microg/kg before the PTZ injection. Superoxide dismutase (SOD) and catalase (CAT) activities, and reduced glutathione (GSH) and thiobarbituric acid-reactive substance (TBARS) levels were measured in erythrocytes, liver and brain tissue. TBARS, the indicator of lipid peroxidation, was significantly increased in erythrocytes, liver and brain tissue, while antioxidant enzyme activities and glutathione levels were significantly decreased in PTZ injected rats. Ghrelin pretreatment prevented lipid peroxidation and the reduction in antioxidant enzyme activities and GSH levels against PTZ-induced oxidative stress in a dose dependent manner. The present data indicates that PTZ at a convulsive dose induces an oxidative stress response by depleting the antioxidant defense systems and increasing lipid peroxidation in the erythrocytes, liver and brain of rats. Ghrelin pretreatment diminished oxidative stress and prevented the decrease in antioxidant enzyme activities, and thus may reduce neuronal death in the brain during seizures. However, further studies are needed in order to confirm our hypothesis.     

Mitochondrial susceptibility in a model of paraquat neurotoxicity

Abstract

Paraquat is a highly toxic herbicide capable of generating oxidative stress and producing brain damage after chronic exposure. The aim of this research was to investigate the contribution of mitochondria to the molecular mechanism of apoptosis in an in vivo experimental model of paraquat neurotoxicity. Sprague-Dawley adult female rats received paraquat (10 mg/kg i.p.) or saline once a week during a month. Paraquat treatment increased cortical and striatal superoxide anion levels by 45% and 18%, respectively. As a consequence, mitochondrial aconitase activity was significantly inhibited in cerebral cortex and striatum. Paraquat treatment increased cortical and striatal lipid peroxidation levels by 16% and 28%, respectively, as compared with control mitochondria Also, cortical and striatal cardiolipin levels were decreased by 13% and 49%, respectively. Increased Bax and Bak association to mitochondrial membranes was observed after paraquat treatment in cerebral cortex and striatum. Also, paraquat induced cytochrome c and AIF release from mitochondria.

These findings support the conclusion that a weekly dose of paraquat during four weeks induces oxidative damage that activates mitochondrial pathways associated with molecular mechanisms of cell death. The release of apoptogenic proteins from mitochondria to cytosol after paraquat treatment would be the consequence of an alteration in mitochondrial membrane permeability due to the presence of high superoxide anion levels. Also, our results suggest that under chronic exposure, striatal mitochondria were more sensitive to paraquat oxidative damage than cortical mitochondria. Even in the presence of a high oxidative stress in striatum, equal levels of apoptosis were attained in both brain areas.     

Thyroid hormone-induced oxidative damage on lipids, glutathione and DNA in the mouse heart

Oxygen radicals of mitochondrial origin are involved in oxidative damage. In order to analyze the possible relationship between metabolic rate, oxidative stress and oxidative damage, OF1 female mice were rendered hyper- and hypothyroid by chronic administration of 0.0012% L-thyroxine (T₄) and 0.05% 6-n-propyl-2-thiouracil (PTU), respectively, in their drinking water for 5 weeks.

Hyperthyroidism significantly increased the sensitivity to lipid peroxidation in the heart, although the endogenous levels of lipid peroxidation were not altered. Thyroid hormone-induced oxidative stress also resulted in higher levels of GSSG and GSSG/GSH ratio. Oxidative damage to mitochondrial DNA was greater than that to genomic DNA. Hyperthyroidism decreased oxidative damage to genomic DNA. Hypothyroidism did not modify oxidative damage in the lipid fraction but significantly decreased GSSG and GSSG/GSH ratio and oxidative damage to mitochondrial DNA.

These results indicate that thyroid hormones modulate oxidative damage to lipids and DNA, and cellular redox potential in the mouse heart. A higher oxidative stress in the hyperthyroid group is presumably neutralized in the case of nuclear DNA by an increase in repair activity, thus protecting this key molecule. Treatment with PTU, a thyroid hormone inhibitor, reduced oxidative damage in the different cell compartments.     

帕金森病黑质多巴胺神经元易损伤性的内在因素

帕金森病（Parkinson’s disease,PD）主要症状是由中脑黑质致密部（substantia nigra compact,SNc）的多巴胺（dopamine,DA）神经元死亡引起。帕金森病发病过程中,路易小体病理（Lewy pathology,LP）和线粒体功能障碍最为突出,但SNc 多巴胺神经元为什么特别易遭受这两种病理损害尚不清楚。研究表明,与脑内其他神经元相比,SNc 多巴胺神经元具有特殊的解剖形态、生理和生化表型。SNc 多巴胺神经元具有高分支无髓鞘轴突和众多的突触终端,突触末梢物质和能量代谢的高要求需要大量的线粒体,巨大突触终端增加了突触蛋白质的表达、转运和降解的负担。SNc 多巴胺神经元具有独特的自主起搏电活动和缓慢钙振荡特性,Cav1-3钙通道活动及后续的级联反应增加了SNc 多巴胺神经元线粒体负担,增加了基础氧化应激、线粒体损伤和自噬,降低了处理错误折叠蛋白质的能力。SNc 多巴胺神经元特有的神经递质--多巴胺易被氧化成为反应性醌,具有潜在毒性,可破坏葡糖脑苷脂酶导致其活性降低,引起线粒体氧化应激和溶酶体功能障碍。总之,SNc 多巴胺神经元具有的这些内在因素综合起来,可能导致了其对线粒体功能障碍和路易小体病理损伤的易感性,并且SNc 多巴胺神经元所处的神经网络障碍也促使了帕金森病的进展。认识到这些特征会对研究帕金森病相关病理学机制和阻止疾病进展创造新的机会。     

帕金森病黑质多巴胺神经元易损伤性的内在因素

帕金森病（Parkinson’s disease,PD）主要症状是由中脑黑质致密部（substantia nigra compact,SNc）的多巴胺（dopamine,DA）神经元死亡引起。帕金森病发病过程中,路易小体病理（Lewy pathology,LP）和线粒体功能障碍最为突出,但SNc 多巴胺神经元为什么特别易遭受这两种病理损害尚不清楚。研究表明,与脑内其他神经元相比,SNc 多巴胺神经元具有特殊的解剖形态、生理和生化表型。SNc 多巴胺神经元具有高分支无髓鞘轴突和众多的突触终端,突触末梢物质和能量代谢的高要求需要大量的线粒体,巨大突触终端增加了突触蛋白质的表达、转运和降解的负担。SNc 多巴胺神经元具有独特的自主起搏电活动和缓慢钙振荡特性,Cav1-3钙通道活动及后续的级联反应增加了SNc 多巴胺神经元线粒体负担,增加了基础氧化应激、线粒体损伤和自噬,降低了处理错误折叠蛋白质的能力。SNc 多巴胺神经元特有的神经递质——多巴胺易被氧化成为反应性醌,具有潜在毒性,可破坏葡糖脑苷脂酶导致其活性降低,引起线粒体氧化应激和溶酶体功能障碍。总之,SNc 多巴胺神经元具有的这些内在因素综合起来,可能导致了其对线粒体功能障碍和路易小体病理损伤的易感性,并且SNc 多巴胺神经元所处的神经网络障碍也促使了帕金森病的进展。认识到这些特征会对研究帕金森病相关病理学机制和阻止疾病进展创造新的机会。     

Flaxseed Oil as a Neuroprotective Agent on Lead Acetate-Induced Monoamineric Alterations and Neurotoxicity in Rats

Lead remains a considerable occupational and public health problem, which is known to cause a number of adverse effects in both man and animals. Here, the neuroprotective effect of flaxseed oil (1,000 mg/kg) on lead acetate (20 mg/kg) induced alternation in monoamines and brain oxidative stress was examined in rats. The levels of lead, dopamine (DA), norepinephrine (NE), serotonin (5-HT), lipid peroxidation, nitrite/nitrate (NO), and glutathione (GSH) were determined; also, the activity of acetylcholinesterase (AChE) and Na(+)-K(+)-ATPase were estimated on different brain regions of adult male albino rats. The level of lead was markedly elevated in different brain regions of rats. This leads to enhancement of lipid peroxidation and NO production in brain with concomitant reduction in AChE activity and GSH level. In addition, the levels of DA, NE, and 5-HT were decreased in the brain. These findings were associated with BAX over expression. Treatment of rats with flaxseed oil induced a marked improvement in most of the studied parameters as well as the immunohistochemistry features. These data indicated that dietary flaxseed oil provide protection against lead-induced oxidative stress and neurotoxic effects.     

Effect of overexpression of wild-type and mutant Cu/Zn-superoxide dismutases on oxidative damage and antioxidant defences: relevance to Down's syndrome and familial amyotrophic lateral sclerosis

Patients with Down's syndrome (DS) show elevated levels of copper, zinc-containing superoxide dismutase (SOD1) and appear to have increased lipid peroxidation and oxidative damage to DNA as well as elevated glutathione peroxidase activity. Increasing SOD1 levels by gene transfection in NT-2 and SK-N-MC cell lines also led to a rise in glutathione peroxidase activity, but this was nevertheless accompanied by decreased proliferation rates, increased lipid peroxidation and protein carbonyls, and a trend to a rise in 8-hydroxyguanine and protein-bound 3-nitrotyrosine. Transfection of these cell lines with DNA encoding two mutant SOD1 enzymes (G37R and G85R) associated with familial amyotrophic lateral sclerosis (FALS), produced similar, but more severe changes, i.e. even lower growth rates, higher lipid peroxidation, 3-nitrotyrosine and protein carbonyl levels, decreased GSH levels, raised GSSG levels and higher glutathione peroxidase activities. Since G85R has little SOD activity, these changes cannot be related to increased O(2)(-) scavenging. In no case was SOD2 (mitochondrial Mn-SOD) level altered. Our cellular systems reproduce many of the biochemical changes observed in patients with DS or ALS, and in transgenic mice overexpressing mutant SOD1. They also show the potentially deleterious effects of SOD1 overexpression on cellular proliferation, which may be relevant to abnormal development in DS.     

Induction of mixed function oxidases on oral administration of dieldrin

The administration of dieldrin (30 mg/kg body weight) caused an increase in the liver weight of rats. The metabolism of aflatoxins B₁ and G₁ by the microsomes obtained from the liver of dieldrin-treated animals was enhanced significantly as compared to the controls showing that dieldrin increased the activity of mixed function hydroxylases. Dieldrin caused an increase in the activity of liver microsomal NADPH oxidase and a decrease in the lipid peroxidation. Dieldrin brought about an increase in the phosphatidylcholine content of rat liver.     

Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer's disease

Increasing evidence supports a role for oxidative DNA damage in aging and several neurodegenerative diseases including Alzheimer's disease (AD). Attack of DNA by reactive oxygen species (ROS), particularly hydroxyl radicals, can lead to strand breaks, DNA–DNA and DNA–protein cross-linking, and formation of at least 20 modified bases adducts. In addition, α,β-unsaturated aldehydic by-products of lipid peroxidation including 4-hydroxynonenal and acrolein can interact with DNA bases leading to the formation of bulky exocyclic adducts. Modification of DNA bases by direct interaction with ROS or aldehydes can lead to mutations and altered protein synthesis. Several studies of DNA base adducts in late-stage AD (LAD) brain show elevations of 8-hydroxyguanine (8-OHG), 8-hydroxyadenine (8-OHA), 5-hydroxycytosine (5-OHC), and 5-hydroxyuracil, a chemical degradation product of cytosine, in both nuclear and mitochondrial DNA (mtDNA) isolated from vulnerable regions of LAD brain compared to age-matched normal control subjects. Previous studies also show elevations of acrolein/guanine adducts in the hippocampus of LAD subjects compared to age-matched controls. In addition, studies of base excision repair show a decline in repair of 8-OHG in vulnerable regions of LAD brain. Our recent studies show elevated 8-OHG, 8-OHA, and 5,6-diamino-5-formamidopyrimidine in both nuclear and mtDNA isolated from vulnerable brain regions in amnestic mild cognitive impairment, the earliest clinical manifestation of AD, suggesting that oxidative DNA damage is an early event in AD and is not merely a secondary phenomenon.     

Liposome-entrapped superoxide dismutase reduces ischemia/reperfusion ‘oxidative stress’ in gerbil brain

Bilateral common carotid artery occlusion (15 min.) followed by two hours of recirculation reduced mitochondrial superoxide dismutase (SOD) and glutathione reductase (GR) activities, and increased susceptibility of mitochondrial membranes to in vitro lipid peroxidation in brain regions (i.e., cortex, striatum and hippocampus) of Mongolian gerbil. Intraperitoneal bolus injection (2 mg/kg b.w.) of liposome-entrapped CuZn superoxide dismutase (l-SOD) increased the endogenous SOD activity in normal brain tissue and, when given at the end of ischemia, counteracted both the ischemic reduction of endogenous SOD and the increased peroxidation of mitochondrial membranes. 1-SOD treatment was ineffective in reducing brain swelling, suggesting that superoxide radicals are not a main participant in the process of (post)ischemic brain edema formation.     

Systemic administration of d-amphetamine induces long-lasting oxidative stress in the rat striatum

The long-term effect of d-amphetamine (AMPH) on the induction of oxidative stress was examined in vivo in the rat brain. In this study, 2,3-dihydroxybenzoic acid (2,3-DHBA) and malonaldehyde (MDA) were used as the index of the hydroxyl radical and lipid peroxidation, respectively. The levels of 2,3-DHBA, MDA and dopamine (DA) in striatal homogenates were examined 7 days following injection of a single large dose of AMPH (7.5 mg/kg, i.p.) in rats pretreated with desipramine (10 mg/kg, i.p.), an agent that inhibits the metabolism of AMPH. Our results showed that 2,3-DHBA and MDA levels were significantly increased by AMPH, whereas DA and its metabolites, DOPAC and HVA were depleted in the striatum. Pretreatment with the glutamate NMDA receptor subtype antagonist MK-801 (1 mg/kg, i.p.) attenuated the increases of 2,3-DHBA and MDA, and provided partial protection against the long-lasting loss of DA produced by AMPH. Overall, the results demonstrate that AMPH could induce sustained production of free radical and oxidative damage, and lead to DA terminal degeneration in the striatum of the rat.     

N-acetylcysteine exposure on lead-induced lipid peroxidative damage and oxidative defense system in brain regions of rats

Lead (Pb) is known to disrupt the pro-oxidant/antioxidant balance of tissues, which leads to biochemical and physiological dysfunction. Oxidative stress is considered a possible molecular mechanism involved in Pb neurotoxicity. Considering the vulnerability of the brain to oxidative stress under Pb neurotoxicity, this study investigated the effects of exposure of the thiol antioxidant N-acetylcysteine (NAC) on lead-induced oxidative damage and lipid peroxidation in brain regions of the rat. Wister strain rats were exposed to lead in the form of lead acetate (20 mg/kg body wt/d) for a period of 2 wk and the effects of NAC on lead-induced neurotoxicity in rat brain regions were assessed by postadministration of NAC (160 mg/kg body wt/d) for a period of 3 wk. The lipid peroxidation byproduct, malondialdehyde (MDA) increased following lead exposure in both of the regions, and the antioxidant capacities of the cell in terms of the activity of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) was diminished. Following NAC treatment, lead-induced lipid peroxidation decreased and antioxidant enzyme activities improved, with CAT showing enhancement in the cerebral region only and SOD showing enhancements in the cerebellar region. Our result suggests that thiol-antioxidant supplementation following Pb exposure might enhance the reductive status of brain regions by arresting the lipid peroxidative damage in brain regions.     

Chronically and acutely exercised rats: biomarkers of oxidative stress and endogenous antioxidants.

The responses to oxidative stress induced by chronic exercise (8-wk treadmill running) or acute exercise (treadmill running to exhaustion) were investigated in the brain, liver, heart, kidney, and muscles of rats. Various biomarkers of oxidative stress were measured, namely, lipid peroxidation [malondialdehyde (MDA)], protein oxidation (protein carbonyl levels and glutamine synthetase activity), oxidative DNA damage (8-hydroxy-2'-deoxyguanosine), and endogenous antioxidants (ascorbic acid, alpha-tocopherol, glutathione, ubiquinone, ubiquinol, and cysteine). The predominant changes are in MDA, ascorbic acid, glutathione, cysteine, and cystine. The mitochondrial fraction of brain and liver showed oxidative changes as assayed by MDA similar to those of the tissue homogenate. Our results show that the responses of the brain to oxidative stress by acute or chronic exercise are quite different from those in the liver, heart, fast muscle, and slow muscle; oxidative stress by acute or chronic exercise elicits different responses depending on the organ tissue type and its endogenous antioxidant levels.