Reduced 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-initiated oxidative DNA damage and neurodegeneration in prostaglandin H synthase-1 knockout mice.
The neurodegenerative potential of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and underlying mechanisms are under debate. Here, we show that MDMA is a substrate for CNS prostaglandin H synthase (PHS)-catalyzed bioactivation to a free radical intermediate that causes reactive oxygen species (ROS) formation and neurodegenerative oxidative DNA damage. In vitro PHS-1-catalyzed bioactivation of MDMA stereoselectively produced free radical intermediate formation and oxidative DNA damage that was blocked by the PHS inhibitor eicosatetraynoic acid. In vivo, MDMA stereoselectively caused gender-independent DNA oxidation and dopaminergic nerve terminal degeneration in several brain regions, dependent on regional PHS-1 levels. Conversely, MDMA-initiated striatal DNA oxidation, nerve terminal degeneration, and motor coordination deficits were reduced in PHS-1 +/- and -/- knockout mice in a gene dose-dependent fashion. These results confirm the neurodegenerative potential of MDMA and provide the first direct evidence for a novel molecular mechanism involving PHS-catalyzed formation of a neurotoxic MDMA free radical intermediate.
Faculty of Pharmacy and ‡Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
Winnie
W
Jeng
Peter G
PG
Wells
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000235:genetics* / Q000502:physiology*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D005838:Genotype; D006213:Hallucinogens / Q000737:chemistry / Q000633:toxicity*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000737:chemistry / Q000633:toxicity*; D016202:N-Methylaspartate / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000648:ultrastructure; D011597:Psychomotor Performance / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013237:Stereoisomerism
D005609:Free Radicals; D006213:Hallucinogens; D017382:Reactive Oxygen Species; D016202:N-Methylaspartate; D000080242:8-Hydroxy-2'-Deoxyguanosine; D051545:Cyclooxygenase 1; D003849:Deoxyguanosine; D018817:N-Methyl-3,4-methylenedioxyamphetamine