d-MDMA during vitamin E deficiency: effects on dopaminergic neurotoxicity and hepatotoxicity.
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 hx4, 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.
Johnson
Elizabeth Anne
EA
Chronic Stress Laboratory, Toxicology and Molecular Biology Branch, National Institute for Occupational Safety and Health/Centers for Disease Control, Mailstop 3014, 1095 Willowdale Road, 26505, Morgantown, WV, USA. edj@cdc.gov
Shvedova
Anna A
AA
Kisin
Elena
E
O'Callaghan
James P
JP
Kommineni
Choudari
C
Miller
Diane B
DB
D018759:Adrenergic Uptake Inhibitors / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001833:Body Temperature Regulation / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005526:Food, Formulated; D016166:Free Radical Scavengers / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D009336:Necrosis; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D014810:Vitamin E / Q000378:metabolism; D014811:Vitamin E Deficiency / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
D018759:Adrenergic Uptake Inhibitors; D000975:Antioxidants; D016166:Free Radical Scavengers; D005609:Free Radicals; D009498:Neurotoxins; D014810:Vitamin E; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine