Oxidative Stress In Cerebellum Research Articles

Perinatal exposure to lead: reduction in alterations of brain mitochondrial antioxidant system with calcium supplement.

Lead (Pb) is a potent neurotoxicant that causes several neurochemical and behavioral alterations. Previous studies showed that the gestational and lactational exposure to Pb reduces the cholinergic and aminergic systems, and behavior of rats. The present study was designed to examine the protective effects of calcium supplementation against Pb-induced oxidative stress in cerebellum and hippocampus of brain at postnatal day (PND) 21, PND 28, PND 35, and PND 60. Pregnant rats were exposed to 0.2 % Pb (Pb acetate in drinking water) from gestational day 6 (GD 6) and pups were exposed through maternal milk till weaning (PND 21). We found that the activity of serum ceruloplasmin oxidase (Cp), mitochondrial manganese superoxide dismutase (Mn-SOD), copper zinc superoxide dismutase (Cu/Zn-SOD), glutathione peroxidase (GPx), catalase (CAT), and xanthine oxidase (XO) enzyme activities were decreased, whereas the malondialdehyde (MDA) levels increased in the cerebellum and hippocampus of Pb-exposed rats. These changes were more prominent at PND 35 and greater in hippocampus compared to cerebellum. Among the enzyme activities, Mn-SOD and Cu/Zn-SOD showed maximum decrease compared to GPx, CAT, XO, and Cp. Furthermore, 0.02 % calcium supplementation together with 0.2 % Pb significantly reversed the Pb-induced alterations in the enzyme activities, and MDA levels. In conclusion, these data suggest that early life exposure to Pb induce alterations in the mitochondrial antioxidant system of brain regions which remain for long even after Pb exposure has stopped. Calcium supplementation may potentially be beneficial in treating Pb toxicity in the developing rat brain.

Vitamin E is essential for Purkinje neuron integrity

α-Tocopherol (vitamin E) is an essential dietary antioxidant with important neuroprotective functions. α-Tocopherol deficiency manifests primarily in neurological pathologies, notably cerebellar dysfunctions such as spinocerebellar ataxia. To study the roles of α-tocopherol in the cerebellum, we used the α-tocopherol transfer protein for the murine version (Ttpa(-/)(-)) mice which lack the α-tocopherol transfer protein (TTP) and are a faithful model of vitamin E deficiency and oxidative stress. When fed vitamin E-deficient diet, Ttpa(-/)(-) mice had un-detectable levels of α-tocopherol in plasma and several brain regions. Dietary supplementation with α-tocopherol normalized plasma levels of the vitamin, but only modestly increased its levels in the cerebellum and prefrontal cortex, indicating a critical function of brain TTP. Vitamin E deficiency caused an increase in cerebellar oxidative stress evidenced by increased protein nitrosylation, which was prevented by dietary supplementation with the vitamin. Concomitantly, vitamin E deficiency precipitated cellular atrophy and diminished dendritic branching of Purkinje neurons, the predominant output regulator of the cerebellar cortex. The anatomic decline induced by vitamin E deficiency was paralleled by behavioral deficits in motor coordination and cognitive functions that were normalized upon vitamin E supplementation. These observations underscore the essential role of vitamin E and TTP in maintaining CNS function, and support the notion that α-tocopherol supplementation may comprise an effective intervention in oxidative stress-related neurological disorders.

An in vitro approach to assess the neurotoxicity of valproic acid-induced oxidative stress in cerebellum and cerebral cortex of young rats

Valproic acid (VPA), a branched short-chain fatty acid, is generally used as an antiepileptic drug and a mood stabilizer. VPA is a relatively safe drug, but its use in higher concentrations is associated with idiosyncratic neurotoxicity. Investigations involving cerebral cortex and cerebellum can shed light on whether neurotoxicity induced by branched chain fatty acids like VPA is mediated by oxidative stress. The aim of our investigation was to evaluate the neurotoxic potential of VPA by using preparation of cerebral cortex and cerebellum of young rats as an in vitro model. Oxidative stress indexes such as lipid peroxidation (LPO) and protein carbonyl (PC) formation were evaluated to visualize whether the first line of defence was breached. The levels of oxidative stress markers, LPO and PC were significantly elevated. Non-enzymatic antioxidants' effect was also demonstrated as a significant depletion in reduced glutathione (GSH) and non-protein thiol activity (NP-SH), but there was no significant increase or decrease in the concentrations of total thiol (T-SH) and protein thiol (P-SH). VPA also showed significant reduction in the activities of glutathione metabolizing enzymes such as glutathione-S-transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GPx) and other antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT) in cerebellum and cerebral cortex. A significant elevation was also observed in the activity of xanthine oxidase (XO). Some neurotoxicity biomarkers were investigated in which the activity of acetylcholinesterase (AChE) and sodium-potassium ATPase (Na(+), K(+)-ATPase) was decreased and monoamine oxidase (MAO) was increased. These results indicate that VPA induces oxidative stress by compromising the antioxidant status of the neuronal tissue. Further studies are required to decipher the cellular and molecular mechanisms of branched chain fatty acid-induced neurotoxicity.

Pro-oxidant status based alterations in cerebellar antioxidant response to aluminum insult

Cerebellum is unique in restraining amyloid-induced neurodegenerative changes. Amyloidosis and oxidant imbalance is common in aluminum exposure. Interestingly, aluminum itself does not pose any redox activity still it is associated with oxidant imbalance, and, it can aggravate the situation of already existing oxidant threat. Male rats were exposed to aluminum for 4 weeks along with exposure to 4 different doses of ethanol. After the treatment period, cerebellar level of protein, reduced glutathione (GSH), lipid perioxidation (TBARS) were measured. Activities of catalase, superoxide dismutase (SOD), glutathione reductase (GR) and glutathione perioxidase (GPx) were also estimated from the homogenized cerebellar tissue. In the present regimen of aluminum exposure, the cerebellum has shown significant reduction only in GPx activity. However, when aluminum was coexposed with ethanol, it contributed significantly to increase the cerebellar oxidant imbalance by (a) compromising the GSH restoration system, (b) reducing enzymatic peroxide scavenging system of cerebellum, (c) restricting the capability to cope with oxidative stress, as well as (d) downgrading the resistance to oxidative damage in response to chemical stress. Present study demonstrates that coexposure of aluminum with pro-oxidant favored development of aluminum-induced oxidative stress in cerebellum. These observations enlighten the role of pro-oxidants in the process of oxidative degeneration of cerebellum. With further studies, the present observation can be useful to understand the mechanism of neurodegenerative disorders and ways to ameliorate them.

Protective effect of Bacopa monniera on methyl mercury-induced oxidative stress in cerebellum of rats.

Methyl mercury (MeHg) is a ubiquitous environmental pollutant leading to neurological and developmental deficits in animals and human beings. Bacopa monniera (BM) is a perennial herb and is used as a nerve tonic in Ayurveda, a traditional medicine system in India. The objective of the present study was to investigate whether Bacopa monniera extract (BME) could potentially inhibit MeHg-induced toxicity in the cerebellum of rat brain. Male Wistar rats were administered with MeHg orally at a dose of 5 mg/kg b.w. for 21 days. Experimental rats were given MeHg and also administered with BME (40 mg/kg, orally) for 21 days. After the treatment period, we observed that MeHg exposure significantly inhibited the activities of superoxide dismutase, catalase, glutathione peroxidase, and increased the glutathione reductase activity in cerebellum. It was also found that the level of thiobarbituric acid-reactive substances was increased with the concomitant decrease in the glutathione level in MeHg-induced rats. These alterations were prevented by the administration of BME. Behavioral interference in the MeHg-exposed animals was evident through a marked deficit in the motor performance in the rotarod task, which was completely recovered to control the levels by BME administration. The total mercury content in the cerebellum of MeHg-induced rats was also increased which was measured by atomic absorption spectrometry. The levels of NO(2) (-) and NO(3) (-) in the serum were found to be significantly increased in the MeHg-induced rats, whereas treatment with BME significantly decreased their levels in serum to near normal when compared to MeHg-induced rats. These findings strongly implicate that BM has potential to protect brain from oxidative damage resulting from MeHg-induced neurotoxicity in rat.

Induction of oxidative stress and inhibition of superoxide dismutase expression in rat cerebral cortex and cerebellum by PTU-induced hypothyroidism and its reversal by curcumin

The present study was carried out to elucidate the effectiveness of curcumin in ameliorating the expression of superoxide dismutase (SOD) in cerebral cortex and cerebellum of rat brain under 6-propyl-2-thiouracil (PTU)-induced hypothyroidism. Induction of hypothyroidism in adult rats by PTU resulted in augmentation of lipid peroxidation (LPx), an index of oxidative stress in cerebellum but not in cerebral cortex. Curcumin-supplementation to PTU-treated (hypothyroid) rats showed significant reduction in the level of LPx in both the regions of brain. The decreased translated products (SOD1 and SOD2) and the unchanged activity of SOD in cerebral cortex of PTU-treated rats were increased on supplementation of curcumin to the hypothyroid rats. Declined translated products of SOD1 and SOD2 in cerebellum of PTU-treated rats were alleviated on administration of curcumin to hypothyroid rats. On the other hand, the decreased activity of SOD in cerebellum of PTU-treated rats was further declined on administration of curcumin to the hypothyroid rats. Results of the present investigation indicate that curcumin differentially modulates the expression of superoxide dismutase in rat brain cortex and cerebellum under PTU-induced hypothyroidism.

Improvement of Cerebellum Redox States and Cholinergic Functions Contribute to the Beneficial Effects of Silymarin Against Manganese-Induced Neurotoxicity

Manganese (Mn) is a potent neurotoxin involved in the initiation and progression of various cognitive disorders. Oxidative stress is reported as one of accepted mechanisms of Mn toxicity. The present study was designed to explore the effects of silymarin, a natural antioxidant, in attenuating the toxicity induced by Mn in rat cerebellum. In this investigation, rats were treated orally with MnCl₂ (20 mg/ml) for 30 days, subsets of these animals were treated intraperitoneally daily with silymarin (100 mg/kg) along with respective controls. Mn exposure caused a marked oxidative stress in cerebellum as indicated by a significant decrease in the activities of enzymatic antioxidants like superoxide dismutase, catalase and glutathione peroxidase and in the levels of non-enzymatic antioxidants like reduced glutathione (GSH), total thiols and vitamin C. Conversely an increase was obtained in lipid and protein markers such as thiobarbituric reactive acid substances, lipid hydroperoxide and protein carbonyl products contents. A significant increase in acetylcholinesterase and a decrease in Na⁺/K⁺-ATPase activities were also shown, with a substantial rise in the expression of acetylcholinesterase and inducible nitric oxide synthase (iNOS), and nitric oxide levels. The potential effect of SIL to prevent Mn induced neurotoxicity was also reflected by histopathological observations. Rats exposed to Mn showed a reduced number and morphological alterations of cerebellar Purkinje cells. These phenomenons were completely reversed by SIL co-treatment. We concluded that silymarin may protect against Mn-induced oxidative stress in cerebellum by inhibiting both lipid and protein oxidation and by activating acetylcholinesterase and inducible nitric oxide synthase (iNOS) gene expression.

Maternal Thimerosal Exposure Results in Aberrant Cerebellar Oxidative Stress, Thyroid Hormone Metabolism, and Motor Behavior in Rat Pups; Sex- and Strain-Dependent Effects

Methylmercury (Met-Hg) and ethylmercury (Et-Hg) are powerful toxicants with a range of harmful neurological effects in humans and animals. While Met-Hg is a recognized trigger of oxidative stress and an endocrine disruptor impacting neurodevelopment, the developmental neurotoxicity of Et-Hg, a metabolite of thimerosal (TM), has not been explored. We hypothesized that TM exposure during the perinatal period impairs central nervous system development, and specifically the cerebellum, by the mechanism involving oxidative stress. To test this, spontaneously hypertensive rats (SHR) or Sprague-Dawley (SD) rat dams were exposed to TM (200μg/kg body weight) during pregnancy (G10-G15) and lactation (P5-P10). Male and female neonates were evaluated for auditory and motor function; cerebella were analyzed for oxidative stress and thyroid metabolism. TM exposure resulted in a delayed startle response in SD neonates and decreased motor learning in SHR male (22.6%), in SD male (29.8%), and in SD female (55.0%) neonates. TM exposure also resulted in a significant increase in cerebellar levels of the oxidative stress marker 3-nitrotyrosine in SHR female (35.1%) and SD male (14.0%) neonates. The activity of cerebellar type 2 deiodinase, responsible for local intra-brain conversion of thyroxine to the active hormone, 3',3,5-triiodothyronine (T3), was significantly decreased in TM-exposed SHR male (60.9%) pups. This coincided with an increased (47.0%) expression of a gene negatively regulated by T3, Odf4 suggesting local intracerebellar T3 deficiency. Our data thus demonstrate a negative neurodevelopmental impact of perinatal TM exposure which appears to be both strain- and sex-dependent.

Neurochemical evidence that phytanic acid induces oxidative damage and reduces the antioxidant defenses in cerebellum and cerebral cortex of rats

In the present work we investigated the in vitro effects of phytanic acid (Phyt), that accumulates in Refsum disease and other peroxisomal diseases, on important parameters of oxidative stress in cerebellum and cerebral cortex from young rats. The parameters thiobarbituric acid-reactive substances levels (TBA-RS; lipid peroxidation), carbonyl formation and sulfhydryl oxidation (protein oxidative damage) and the concentrations of the most important nonenzymatic antioxidant defense reduced glutathione (GSH) were determined. It was observed that Phyt significantly increased TBA-RS levels in both cerebral structures. This effect was prevented by the antioxidants alpha-tocopherol and melatonin, suggesting the involvement of free radicals. Phyt also provoked protein oxidative damage in both cerebellum and cerebral cortex, as determined by increased carbonyl content and sulfhydryl oxidation. Furthermore, Phyt significantly diminished the concentrations of GSH, while melatonin and alpha-tocopherol treatment totally blocked this effect. We also verified that Phyt does not behave as a direct acting oxidant, since Phyt did not oxidize commercial solutions of GSH and reduced cytochrome c to Phyt in a free cell medium. Our data indicate that oxidative stress is elicited in vitro by Phyt, a mechanism that may contribute at least in part to the pathophysiology of Refsum disease and other peroxisomal disorders where Phyt is accumulated.

Mice Deficient in Neuropeptide PACAP Demonstrate Increased Sensitivity to In Vitro Kidney Hypoxia

One of the well-known effects of pituitary adenylate cyclase activating polypeptide (PACAP) is its neuroprotective and cytoprotective actions including renoprotective effects. Mice deficient in endogenous PACAP exhibit several behavioral, metabolic, and developmental alterations. Furthermore, PACAP-deficient mice have larger infarct volume in a model of cerebral ischemia, delayed axonal regeneration, and increased cell death in cerebellar oxidative stress. We have previously demonstrated that PACAP-deficient mice have increased susceptibility to in vitro oxidative stress, which can be counteracted by exogenous PACAP treatment. These results demonstrate that endogenous PACAP has a protective role against various stressors. The objective of the present study was to investigate whether endogenous PACAP has a protective effect in the kidney against in vitro hypoxia. Kidney cell cultures were isolated from wild-type and PACAP-deficient mice, and cell viability was assessed after in vitro hypoxia induced using CoCl(2). The sensitivity of cells from PACAP-deficient mice was increased to hypoxia: both after 24 and 48 hours of exposure, cell viability was significantly reduced compared with that in control wild-type mice. These results show that endogenous PACAP protects against noxious stimuli in the kidney and that PACAP may act as a stress sensor in renal cells.

Mice deficient in the neuropeptide PACAP display increased susceptibility to renal oxidative stress and hypoxia in vitro

Event Abstract Back to Event Mice deficient in the neuropeptide PACAP display increased susceptibility to renal oxidative stress and hypoxia in vitro Gabriella Horváth1*, Péter Szakály2, Boglárka Rácz3, Péter Kiss1, Zsuzsanna Helyes4, Andrea Tamás1, Andrea Lubics1, Hitoshi Hashimoto5, Akemichi Baba5, Norihito Shintani5 and Dóra Reglodi1 1 University of Pécs, Department of Anatomy, Medical School, Hungary 2 University of Pécs, Department Of Surgery, Medical School, Hungary 3 University of Pécs, Department Of Biochemistry and Medical Chemistry, Medical School, Hungary 4 University of Pécs, Department Of Pharmacology and Pharmacotherapeutics, Medical School, Hungary 5 Osaka University, Graduate School of Pharmaceutical Sciences, Japan One of the well-known effects of pituitary adenylate cyclase activating polypeptide (PACAP) is its neuro- and cytoprotective actions, including renoprotective effects. PACAP deficient mice display several behavioral, metabolic and developmental alterations. Furthermore, it has been shown that PACAP deficient mice have larger infarct volume in a model of cerebral ischemia, delayed axonal regeneration and increased cell death in cerebellar oxidative stress. These results show that endogenous PACAP plays a protective role against different stressors. The aim of the present study was to investigate whether endogenous PACAP has protective effect in the kidney against oxidative stress and in vitro hypoxia. Kidney cell cultures were isolated from wild type and PACAP deficient mice and cell viability was assessed following oxidative stress induced by 0.5, 1.5 and 3 mM H2O2. In vitro hypoxia was induced by CoCl2. We found that the sensitivity of cells from PACAP deficient mice was greatly increased to oxidative stress: both after 2 or 4hrs of exposure, cell viability was significantly reduced compared to control wild type mice. These results show that endogenous PACAP protects against oxidative stress in the kidney, and that PACAP may act as a stress sensor in renal cells. Support: OTKAF67830,K72592,73044,CNK78480,ETT,PTE AOK Research Grant 2009, Bolyai Scholarship, Richter Foundation, Japan Society for the Promotion of Science. Conference: IBRO International Workshop 2010, Pécs, Hungary, 21 Jan - 23 Jan, 2010. Presentation Type: Poster Presentation Topic: Cellular neuroscience Citation: Horváth G, Szakály P, Rácz B, Kiss P, Helyes Z, Tamás A, Lubics A, Hashimoto H, Baba A, Shintani N and Reglodi D (2010). Mice deficient in the neuropeptide PACAP display increased susceptibility to renal oxidative stress and hypoxia in vitro. Front. Neurosci. Conference Abstract: IBRO International Workshop 2010. doi: 10.3389/conf.fnins.2010.10.00069 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 21 Apr 2010; Published Online: 21 Apr 2010. * Correspondence: Gabriella Horváth, University of Pécs, Department of Anatomy, Medical School, Pécs, Hungary, gabriella.horvath@aok.pte.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Gabriella Horváth Péter Szakály Boglárka Rácz Péter Kiss Zsuzsanna Helyes Andrea Tamás Andrea Lubics Hitoshi Hashimoto Akemichi Baba Norihito Shintani Dóra Reglodi Google Gabriella Horváth Péter Szakály Boglárka Rácz Péter Kiss Zsuzsanna Helyes Andrea Tamás Andrea Lubics Hitoshi Hashimoto Akemichi Baba Norihito Shintani Dóra Reglodi Google Scholar Gabriella Horváth Péter Szakály Boglárka Rácz Péter Kiss Zsuzsanna Helyes Andrea Tamás Andrea Lubics Hitoshi Hashimoto Akemichi Baba Norihito Shintani Dóra Reglodi PubMed Gabriella Horváth Péter Szakály Boglárka Rácz Péter Kiss Zsuzsanna Helyes Andrea Tamás Andrea Lubics Hitoshi Hashimoto Akemichi Baba Norihito Shintani Dóra Reglodi Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Potential role of oxidative stress in mediating the effect of altered gravity on the developing rat cerebellum

We have previously reported that perinatal exposure to hypergravity affects cerebellar structure and motor coordination in rat neonates. In the present study, we explored the hypothesis that exposure to hypergravity results in oxidative stress that may contribute to the decrease in Purkinje cell number and the impairment of motor coordination in hypergravity-exposed rat neonates. To test this hypothesis we compared cerebellar oxidative stress marker 3-nitrotyrosine (3-NT; an index of oxidative protein modification) and 8-hydroxy-2'-deoxyguanosine (8-OH-dG; an index of oxidative DNA damage) between stationary control (SC) and rat neonates exposed to 1.65 G (HG) on a 24-ft centrifuge from gestational day (G) 8 to P21. The levels of 3-NT and 8-OH-dG were determined by specific ELISAs. We also compared the Purkinje cell number (stereorologically) and rotarod performance between the two groups. The levels of 3-NT were increased only in HG females on P6 and on P12 in the cerebellum, and only in HG females on P12 in the extracellabellar tissue. Limited cerebellar data suggests an increase in the levels of 8-OH-dG on P12 only in HG females. In extracerebellar tissue the increase in 8-OH-dG levels was observed in both HG males and HG females except on P6 when it was only observed in HG males. While preliminary, these data suggest that the effect of hypergravity on the developing brain is sex-dependent and may involve oxidative stress. Oxidative stress may, in turn, contribute to the decrease Purkinje cell number and impaired motor behavior observed in hypergravity-exposed rats.

Radiation-induced cognitive dysfunction and cerebellar oxidative stress in mice: Protective effect of α-lipoic acid

Reactive oxygen species are implicated in neurodegeneration and cognitive disorders due to higher vulnerability of neuronal tissues. The cerebellum is recently reported to be involved in cognitive function. Therefore, present study aimed at investigating the role alpha-lipoic acid against radiation-induced oxidative stress and antioxidant status in cerebellum and its correlation with cognitive dysfunction. We observed spontaneous motor activities and spatial memory task of mice using pyroelectric infrared sensor and programmed video tracking system, respectively. Whole body X-irradiation (6 Gy) of mice substantially impaired the reference memory and motor activities of mice. However, acute intraperitoneal treatment of mice with alpha-lipoic acid prior to irradiation significantly attenuated such cognitive dysfunction. Alpha-lipoic acid pretreatment exerted a very high magnitude of protection against radiation-induced augmentation of protein carbonyls and thiobarbituric acid reactive substance (TBARS) in mice cerebellum. Further, radiation-induced deficit of total, nonprotein and protein-bound sulfhydryl (T-SH, NP-SH, PB-SH) contents of cerebellum and plasma ferric reducing power (FRAP) was also inhibited by alpha-lipoic acid pre-treatment. Moreover, alpha-lipoic acid treated mice showed an intact cytoarchitecture of cerebellum, higher counts of intact Purkinje cells and granular cells in comparison to untreated irradiated mice. Results clearly indicate that alpha-lipoic acid is potent neuroprotective antioxidant.

The Activities of Antioxidant Enzymes and the Level of Malondialdehyde in Cerebellum of Rats Subjected to Methotrexate: Protective Effect of Caffeic Acid Phenethyl Ester

Methotrexate (MTX), a folic acid antagonist, is widely used as a cytotoxic chemotherapeutic agent. MTX-associated neurotoxicity is an important clinical problem. The aim of this study was to investigate the role of caffeic acid phenethyl ester (CAPE) on cerebellar oxidative stress induced by MTX in rats. A total of 19 adult male rats were divided into three experimental groups as follows: MTX group (MTX treated), MTX+CAPE group (MTX+CAPE treated), and control group. MTX was administered intraperitoneally (i.p.) with a single dose of 20 mg kg(-1) on the second day of experiment. CAPE was administered i.p. with a dose of 10 micromol kg(-1) day(-1) for 7 days. Malondialdehyde (MDA) levels and activities of superoxide dismutase (SOD) and catalase (CAT) were determined in cerebellar tissue of rats. MTX caused to significant increase in MDA levels (an important marker of lipid peroxidation) in the MTX group compared with the controls (p = 0.006). CAPE significantly reduced the MTX induced lipid peroxidation in the MTX+CAPE group compared to the MTX (p = 0.007). The activities of SOD and CAT were significantly increased in the MTX group when compared with the control group (p = 0.0001, p = 0.004, respectively). The increased activities of these enzymes were significantly reduced by CAPE treatment (p = 0.004, p = 0.034, respectively). As a result, CAPE may protect from oxidative damage caused by MTX treatment in rat cerebellum.

Postnatal Methylmercury Exposure Induces Hyperlocomotor Activity and Cerebellar Oxidative Stress in Mice: Dependence on the Neurodevelopmental Period

During the early postnatal period the central nervous system (CNS) is extremely sensitive to external agents. The present study aims at the investigation of critical phases where methylmercury (MeHg) induces cerebellar toxicity during the suckling period in mice. Animals were treated with daily subcutaneous injections of MeHg (7 mg/kg of body weight) during four different periods (5 days each) at the early postnatal period: postnatal day (PND) 1-5, PND 6-10, PND 11-15, or PND 16-20. A control group was treated with daily subcutaneous injections of a 150 mM NaCl solution (10 ml/kg of body weight). Subjects exposed to MeHg at different postnatal periods were littermate. At PND 35, behavioral tests were performed to evaluate spontaneous locomotor activity in the open field and motor performance in the rotarod task. Biochemical parameters related to oxidative stress (levels of glutathione and thiobarbituric acid reactive substances, as well as glutathione peroxidase and glutathione reductase activity) were evaluated in cerebellum. Hyperlocomotor activity and high levels of cerebellar thiobarbituric acid reactive substances were observed in animals exposed to MeHg during the PND 11-15 or PND 16-20 periods. Cerebellar glutathione reductase activity decreased in MeHg-exposed animals. Cerebellar glutathione peroxidase activity was also decreased after MeHg exposure and the lowest enzymatic activity was found in animals exposed to MeHg during the later days of the suckling period. In addition, low levels of cerebellar glutathione were found in animals exposed to MeHg during the PND 16-20 period. The present results show that the postnatal exposure to MeHg during the second half of the suckling period causes hyperlocomotor activity in mice and point to this phase as a critical developmental stage where mouse cerebellum is a vulnerable target for the neurotoxic and pro-oxidative effects of MeHg.

ETHANOL-INDUCED LIPID PEROXIDATION AND OXIDATIVE STRESS IN EXTRAHEPATIC TISSUES

An ethanol-induced oxidative stress is not restricted to the liver, where ethanol is actively oxidized, but can affect various extrahepatic tissues as shown by experimental data obtained in the rat during acute or chronic ethanol intoxication. Most of these data concern the central nervous system, the heart and the testes. An acute ethanol load has been reported to enhance lipid peroxidation in the cerebellum. This is accompanied by an increase in the cytosolic concentration of low-molecular-weight iron derivatives which may contribute to the generation of aggressive free radicals. The ethanol-induced decrease in the main antioxidant systems (superoxide dismutase, alpha-tocopherol, ascorbate and selenium) is a likely contributor to the cerebellar oxidative stress. Most of these disturbances can be prevented by allopurinol administration. Some experimental data support also the occurrence of pro- and anti-oxidant disturbances in the cerebellum and in other regions of the central nervous system after chronic ethanol administration. Chronic ethanol administration enhances lipid peroxidation in the heart. The increased conversion of xanthine dehydrogenase into xanthine oxidase as well as the activation of peroxisomal acyl CoA-oxidase linked to ethanol administration could contribute to the oxidative stress. Chronic ethanol administration elicits in the testes an enhancement in mitochondrial lipid peroxidation and a decrease in the glutathione level, which appear to be correlated to the gross testicular atrophy observed. Vitamin A supplementation attenuates the changes in lipid peroxidation, glutathione and testicular morphology. Whether the reported disturbances are involved in the pathogenesis of the tissue disorders observed in alcoholic patients remains unanswered.(ABSTRACT TRUNCATED AT 250 WORDS)