Protective Effects of N-Acetyl-L-cystein on 3,4-Methylene Dioxymethamphetamie-Induced Neurotoxicity in Cerebellum of Male Rats (original) (raw)
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Metabolic Brain Disease, 2013
Introduction: 3-4, methylenedioxymethamphetamine (MDMA) causes apoptosis in nervous system and several studies suggest that oxidative stress contributes to MDMA-induced neurotoxicity. The aim of this study is to examine the effects of N-acetyl-L-Cystein (NAC) as an antioxidant on MDMAinduced apoptosis. Methods: 21 Sprague dawley male rats (200-250mg) were treated with MDMA (2×0,5mg/kg) or MDMA plus NAC (100mg/kg IP for 7 day). After last administration of MDMA, rats were killed, cerebellum was removed and Bax and Bcl-2 expression was assessed by western blotting method. Results: The results of this study showed that MDMA causes up-regulation of Bax and down-regulation of Bcl-2 and NAC administration attenuated MDMAinduced apoptosis. Discussion: The present study suggests that NAC treatment may improve MDMA-induced neurotoxicity.
Biochemical Pharmacology, 2004
''Ecstasy'' (3,4-methylenedioxymethamphetamine, MDMA), is a derivative of amphetamine with hepatotoxic effects that has been shown to induce apoptosis of cultured liver cells. In the present work, we studied the role played by oxidative stress in the apoptotic response caused by MDMA on a cell line of hepatic stellate cells (HSC). MDMA-treatment provoked oxidative stress determined as reactive oxygen species (ROS) accumulation and decrease of intracellular reduced glutathione levels. Pre-treatment with the antioxidant pyrrolidine dithiocarbamate blocked ROS production but did not prevent MDMA-induced apoptosis of HSC. The pro-oxidant menadione induced in HSC ROS production and apoptosis that were prevented by pyrrolidine dithiocarbamate, showing HSC to be susceptible to oxidative stress-induced apoptosis. Addition of exogenous GSH or its precursor NAC potentiated the apoptotic action of MDMA but blocked apoptosis induced by menadione. Pre-treatment of HSC with the cytochrome P450 inhibitor quinine diminished the extent of apoptosis caused by MDMA, suggesting the involvement of a metabolic derivative of MDMA on its apoptotic effect. Nuclear factor NF-kB was activated by MDMA in a oxidative stress independent fashion and played a protective role in the apoptotic response, since inhibition of NF-kB by treatment with parthenolide or by viral infection with a dominant-negative form of NIK (Ad5dnNIK) resulted in an increase of MDMA-induced cell death. In summary, MDMA-induced apoptosis of HSC is accompanied, but not caused by oxidative stress; a metabolic derivative of the drug is responsible for the apoptotic effect of MDMA, which is partially blocked by NF-kB activation.
Attenuation of ecstasy-induced neurotoxicity by N-acetylcysteine
Metabolic Brain Disease, 2014
Exposure to 3, 4-methylenedioxymethamphetamine (MDMA) can lead to spatial memory impairments and hippocampal cell death. Numerous evidence indicates that the antioxidant N-acetylcysteine (NAC) exerts protective effects in the brain. The present study evaluates the effects of NAC on MDMA-induced neurotoxicity. Methods: We intraperitoneally injected 28 adult male Sprague-Dawley rats (200-250 g) with either 0, 10 mg/kg of MDMA, or 10 mg/kg of MDMA plus 100 mg/kg of NAC. Spatial memory was assessed with a Morris Water Maze (MWM). At the end of the study, rats' brains were removed to study the structure and ultrastructure of CA1, and measure Bcl-2 and Bax expressions in the hippocampus. In the MWM, NAC treatment significantly attenuated the MDMA-induced increase in distance traveled (p<0.05) and escape latency (p<0.001). The decreased time spent in the target quadrant in MDMA-treated animals was attenuated by NAC (p<0.01). NAC significantly protected against MDMAinduced apoptosis and the up-and down-regulation of Bax and Bcl-2, respectively. These data have suggested that NAC could protect against behavioral changes and apoptosis in the hippocampus following administration of MDMA. NAC might be useful for the treatment of neurotoxicity in MDMA users.
Brain Research, 2009
Oxidative stress plays an important role in neurodegenerative disorders such as Parkinson's Disease and Alzheimer's Disease. Methamphetamine (METH) is an amphetamine analog that causes degeneration of the dopaminergic system in mammals and subsequent oxidative stress. In our present study, we have used immortalized human brain microvascular endothelial (HBMVEC) cells to test whether N-Acetylcysteineamide (NACA), a novel antioxidant, prevents METH-induced oxidative stress in vitro. Our studies showed that NACA protects against METH-induced oxidative stress in HBMVEC cells. NACA significantly protected the integrity of our blood brain barrier (BBB) model, as shown by permeability and trans-endothelial electrical resistance (TEER) studies. NACA also significantly increased the levels of intracellular glutathione (GSH) and glutathione peroxidase (GPx). Malondialdehyde (MDA) levels increased dramatically after METH exposure, but this increase was almost completely prevented when the cells were treated with NACA. Generation of reactive oxygen species (ROS) also increased after METH exposure, but was reduced to control levels with NACA treatment, as measured by dichlorofluorescin (DCF). These results suggest that NACA protects the BBB integrity in vitro, which could prevent oxidative stress-induced damage; therefore, the effectiveness of this antioxidant should be evaluated for the treatment of neurodegenerative diseases in the future.
Journal of Neural Transmission, 1996
The extent of long-term depletion of serotonin (5-HT) produced by 3,4-methylenedioxymethamphetmaine (MDMA) was assessd in rats treated with the antioxidants sodium ascorbate or L-cysteine. There was a 30-35% reduction in the striatal concentration of 5-HT 7 days following a single injection of MDMA (20mg/kg, sc). MDMA had no significant effect on striatal concentrations of 5-HT in rats that had been treated with ascorbate (250mg/kg_ ip) or cysteine (500mg/kg, ip) 30min prior to and 5hrs following the administration of MDMA. Treatment with ascorbate or cysteine did not alter the accumulation of MDMA in brain as determined by in vivo microdialysis. Moreover, neither ascorbate nor cysteine altered the stimulation of dopamine release elicited by MDMA. These data are supportive of the view that MDMA-induced toxicity of 5-HT neurons may be related to the production of free radicals and subsequent oxidative damage.
Toxicology, 2013
Chloroacetic acid (CA), a toxic chlorinated analog of acetic acid, is widely used in chemical industries as an herbicide, detergent, and disinfectant, and chemical intermediates that are formed during the synthesis of various products. In addition, CA has been found as a by-product of chlorination disinfection of drinking water. However, there is little known about neurotoxic injuries of CA on the mammalian, the toxic effects and molecular mechanisms of CA-induced neuronal cell injury are mostly unknown. In this study, we examined the cytotoxicity of CA on cultured Neuro-2a cells and investigated the possible mechanisms of CA-induced neurotoxicity. Treatment of Neuro-2a cells with CA significantly reduced the number of viable cells (in a dose-dependent manner with a range from 0.1 to 3 mM), increased the generation of ROS, and reduced the intracellular levels of glutathione depletion. CA also increased the number of sub-G1 hypodiploid cells; increased mitochondrial dysfunction (loss of MMP, cytochrome c release, and accompanied by Bcl-2 and Mcl-1 down-regulation and Bax up-regulation), and activated the caspase cascades activations, which displayed features of mitochondria-dependent apoptosis pathway. These CAinduced apoptosis-related signals were markedly prevented by the antioxidant N-acetylcysteine (NAC). Moreover, CA activated the JNK and p38-MAPK pathways, but did not that ERK1/2 pathway, in treated Neuro-2a cells. Pretreatment with NAC and specific p38-MAPK inhibitor (SB203580), but not JNK inhibitor (SP600125) effectively abrogated the phosphorylation of p38-MAPK and attenuated the apoptotic signals (including: decrease in cytotoxicity, caspase-3/-7 activation, the cytosolic cytochrome c release, and the reversed alteration of Bcl-2 and Bax mRNA) in CA-treated Neuro-2a cells. Taken together, these data suggest that oxidative stress-induced p38-MAPK activated pathway-regulated mitochondria-dependent apoptosis plays an important role in CA-caused neuronal cell death.
Biomedical Reports
Recent investigations indicated that morphine has protective effects in different ischemia/reperfusion models and may protect against neuronal cell death, while other evidence showed that morphine induces apoptosis in neurons. Therefore, the current study was conducted to investigate preand post-conditioning effects of morphine on hippocampal cell apoptosis in a rat model of homocysteine (Hcy)-induced oxidative stress. In the present study, 0.5 µmol/µl Hcy was injected into bilateral intrahipocampal in the rat brain and morphine at a therapeutic dose of 10 mg/kg was injected intraperitoneally 5 days before and after Hcy injection in rats. The left and right rat hippocampus were removed for biochemical and histopathological analysis. In addition, hippocampal cell apoptosis was assayed by the TUNEL kit. Our results indicated that malondialdehyde (MDA) and superoxide anion (SOA) levels in the Hcy group were increased significantly compared to the control group (P<0.001). In addition, morphine pre-and post-treatment increased the MDA and SOA levels significantly in rat hippocampus compared with other groups (P<0.001). It was found that Hcy alone induced apoptosis in hippocampus cells and significantly increased the number of TUNEL-positive cells in rat hippocampus compared to the other group (P<0.001). Notably, our results indicated that pre-and post-treatment by morphine increased apoptosis in hippocampus cells compared with the other group (P<0.001). In conclusion, morphine neuroprotection and neurotoxicity needs to be further investigated to determine morphine side-effects in medical applications and to identify new targets for potential therapies.
Neurochemical Research, 2008
Antioxidants have possible therapeutic value in neurodegenerative disorders, although they may have prooxidant effects under certain conditions. Glutathione (GSH) is a key free radical scavenger. N-acetylcysteine (NAC) bolsters GSH and intracellular cysteine and also has effective free radical scavenger properties. The effects of chronic NAC administration (50 mg/kg/day, 500 mg/kg/ day, 1500 mg/kg/day · 21 days) on cellular markers of oxidative status was studied in striatum of healthy male Sprague-Dawley rats as well as in animals with apparent striatal oxidative stress following chronic haloperidol treatment (1.5 mg/kg/day · 3 weeks). In non-haloperidol treated animals, NAC 50 and 500 mg/kg did not affect oxidative status, although NAC 1,500 mg/kg significantly increased striatal superoxide levels, decreased lipid peroxidation and increased consumption of reduced glutathione (GSH). Haloperidol alone evoked a significant increase in superoxide and lipid peroxidation. All NAC doses blocked haloperidol induced increases in superoxide levels, while NAC 500 mg/kg and 1,500 mg/kg prevented haloperidol-associated lipid peroxidation levels and also increased the GSSG/GSH ratio. NAC may protect against conditions of striatal oxidative stress, although possible pro-oxidative actions at high doses in otherwise healthy individuals, e.g. to offset worsening of neurodegenerative illness, should be viewed with caution.
Neuroscience, 2009
3,4-Methylenedioximethamphetamine (MDMA, ecstasy) is a worldwide abused stimulant drug, with persistent neurotoxic effects and high prevalence among adolescents. The massive release of 5-HT from pre-synaptic storage vesicles induced by MDMA followed by monoamine oxidase B (MAO-B) metabolism, significantly increases oxidative stress at the mitochondrial level. L-Carnitine and its ester, acetyl-Lcarnitine (ALC), facilitate the transport of long chain free fatty acids across the mitochondrial membrane enhancing neuronal anti-oxidative defense. Here, we show the potential of ALC against the neurotoxic effects of MDMA exposure. Adolescent male Wistar rats were assigned to four groups: control saline solution, isovolumetric to the MDMA solution, administered i.p.; MDMA (4؋10 mg/kg MDMA, i.p.); ALC/MDMA (100 mg/kg 30 min of ALC prior to MDMA, i.p.) and ALC (100 mg/kg, i.p.). Rats were killed 2 weeks after exposure and brains were analyzed for lipid peroxidation, carbonyl forma-tion, mitochondrial DNA (mtDNA) deletion and altered expression of the DNA-encoded subunits of the mitochondrial complexes I (NADH dehydrogenase, NDII) and IV (cytochrome c oxidase, COXI) from the respiratory chain. Levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were also assessed. The present work is the first to successfully demonstrate that pretreatment with ALC exerts effective neuroprotection against the MDMA-induced neurotoxicity at the mitochondrial level, reducing carbonyl formation, decreasing mtDNA deletion, improving the expression of the respiratory chain components and preventing the decrease of 5-HT levels in several regions of the rat brain. These results indicate potential benefits of ALC application in the prevention and treatment of neurodegenerative disorders.