d-MDMA during vitamin E deficiency: Effects on dopaminergic neurotoxicity and hepatotoxicity

Chronic Stress Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health/Centers for Disease Control, Mailstop 3014, 1095 Willowdale Road, Morgantown, WV 26505, USA
Brain Research (Impact Factor: 2.84). 05/2002; 933(2):150-163. DOI: 10.1016/S0006-8993(02)02313-2
Source: PubMed


The mechanism of 3,4-methylenedioxymethamphetamine (d-MDMA)-induced neurotoxicity may involve formation of toxic radical species. Endogenous defenses against toxic radical species include tissue stores of vitamin E, and thiols. We examined whether vitamin E deficiency could alter d-MDMA-induced neurotoxicity by administration of the drug to animals with diet induced vitamin E deficiency. Brain vitamin E levels in deficient mice were reduced 75% compared to sufficient animals. Animals received d-MDMA 5 or 10 mg/kg or saline (delivered every 2 h×4, s.c.). Diet slightly altered d-MDMA-induced temperature modulation. In brain, MDMA treatment reduced vitamin E, total antioxidant reserve and protein thiols 72 h after the first dose. In liver, MDMA treatment reduced glutathione and total antioxidant reserve at the same time point. The vitamin E-deficient group, treated with the low dose of d-MDMA, exhibited neurotoxic responses, including reduced striatal dopamine (47%) and elevated GFAP protein (3-fold): while the sufficient diet group was not altered. The higher d-MDMA dose caused neurotoxic responses in both diet groups. Liver toxicity was determined by histopathologic examination. d-MDMA caused hepatic necrosis that was more severe in vitamin E deficient than sufficient mice. These data indicate that (1) d-MDMA administration reduces antioxidant measures at a time coincident with d-MDMA-induced neuronal damage and (2) vitamin E deficiency increases susceptibility to d-MDMA-induced neurotoxicity and hepatic necrosis.

Download full-text


Available from: Diane Miller
  • Source
    • "Vitamin E deficiency increased susceptibility to 3,4-methylenedioxymethamphetamine (d- MDMA)-induced neurotoxicity and hepatic necrosis. d-MDMA reduced vitamin E in mouse brain, and vitamin E-deficient animals treated with a sub-neurotoxic dose of d-MDMA exhibited neurotoxic responses, including reduced striatal dopamine (47%) and elevated glial fibrillary acidic protein (Johnson et al., 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The neurotoxic actions of chemical agents on humans and animals are usually studied with little consideration of the subject's nutritional status. States of protein-calorie, vitamin and/or mineral undernutrition are associated with a range of neurodevelopmental, neurological and psychiatric disorders, commonly with involvement of both the central and the peripheral nervous system. Undernutrition can modify risk for certain chemical-induced neurologic diseases, and in some cases undernutrition may be a prerequisite for neurotoxicity to surface. In addition, neurologic disease associated with undernutrition or neurotoxicity may show similarities in clinical and neuropathological expression, especially in the peripheral nervous system. The combined effects of undernutrition and chemical neurotoxicity are most relevant to people with low incomes who experience chronic hunger, parasitism and infectious disease, monotonous diets of plants with neurotoxic potential (notably cassava), environmental pollution from rapid industrial development, chronic alcohol abuse, or prolonged treatment with certain therapeutic drugs. Undernutrition alone or in combination with chemical exposure is also important in high-income societies in the setting of drug and alcohol abuse, old age, food faddism, post-bariatric surgery, and drug treatment for certain medical conditions, including cancer and tuberculosis. The nutritional demands of pregnancy and lactation increase the risk of fetal and infant undernutrition and chemical interactions therewith.
    Full-text · Article · Feb 2012 · NeuroToxicology
  • Source
    • "MAO's location in the outer membrane of the mitochondria (Zhuang et al., 1988, 1992) facilitates oxidative damage of mitochondrial macromolecules through diffusion of peroxides into the mitochondrial matrix. Additionally, it has been shown that exposure to MDMA reduces concentrations of neuronal antioxidant elements, such as ascorbic acid (Shankaran et al., 2001), glutathione (Capela et al., 2007a), and vitamin E (Johnson et al., 2002), and increases the concentration of ROS, evidencing the neuroprotective role of antioxidants against MDMA neurotoxicity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: 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-l-carnitine (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 (4x10 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 formation, 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.
    Full-text · Article · Nov 2008 · Neuroscience
  • Source
    • "A . R . Green et al . / European Journal of Pharmacology 500 ( 2004 ) 3 – 13 6 20 mg / kg ( Carvalho et al . , 2002 ) . In contrast , MDMA produces dose - dependent hypothermia in BALB / c mice which was very long lasting ( Johnson et al . , 2002a ) . Swiss - Webster mice have a biphasic response to repeated doses of MDMA , hypothermia being the predominant effect follow - ing repeated doses of 10 mg / kg while hyperthermia followed by hypothermia being seen after repeat doses of 30 mg / kg ( O ' Shea et al . , 2001 ) . We observed only dose - dependent hyperthermia when NIH / S"
    [Show abstract] [Hide abstract]
    ABSTRACT: The predominant severe acute adverse effect following ingestion of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) by recreational users is hyperthermia which can induce other associated clinical problems and occasionally death. There is no pharmacologically specific treatment. MDMA also induces dose-dependent hyperthermia in experimental animals. This review examines the consequences of MDMA administration on body temperature in humans and rodents. In rats hyperthermia results primarily from dopamine release and is influenced by dose, ambient temperature and other housing conditions. The response is increased in rats with a prior MDMA-induced neurotoxic lesion of 5-hydroxytryptamine (5-HT) nerve endings. Increased MDMA-induced locomotor activity appears to play no role in the hyperthermic response. However, the size of the acute hyperthermic response plays a major role in determining the severity of the subsequent neurotoxicity. These results suggest that any MDMA-induced hyperthermic response will be enhanced in hot, crowded dance club conditions and that ingesting the drug in such conditions increases the possibility of subsequent cerebral neurotoxic effect.
    Full-text · Article · Nov 2004 · European Journal of Pharmacology
Show more