- 作者: Nagendra S. Ningaraj Weiqing Chen John V. Schloss Morris D. Faiman Jang-Yen Wu
- 作者服務機構: Departments of Pharmacology and Toxicology, Molecular Biosciences and Medicinal Chemistry. University of Kansas, Lawrence, Kans., USA
- 中文摘要: --
- 英文摘要: Glutamatergic neurotransmission, particularly of theNMDA receptor type, has been implicated in the excito-toxic response to several external and internal stimuli. Inthe present investigation,we report that S-methyl-N,N-diethylthiocarbamate sulfoxide (DETC-MeSO) selective-ly and specifically blocks the NMDA receptor subtype ofthe glutamate receptors, and attenuates glutamate-in-duced neurotoxicity in rat-cultured primary neurons.Other major ionotropic glutamate receptor subtypes,a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acidand kainate, were insensitive to DETC-MeSO both invitro and in vivo. Disulfiram, the parent compound ofDETC-MeSO, also inhibits glutamate receptors partiallyin vivo; however, it fails to inhibit glutamate receptors inmice pretreated with N-butyl imidazole, a cytochromeP450 enzyme inhibitor, implicating the need for bioacti-vation of disulfiram to be an effective antagonist. Weshowed that glutamate-induced increase in Ca wasattenuated in rat-cultured primary neurons followingpretreatment with DETC-MeSO. The Ca influx into pri-mary neurons, studied by confocal microscopy of the flu-orescent Ca dye fura-2, demonstrated a complete at-tenuation of NMDA-induced Ca influx. Similarly, DETC-MeSO attenuated NMDA-induced Ca uptake. Gluta-mate-induced Ca uptake and Ca influx, however,were partially blocked by DETC-MeSO, and this is consis-tent with both in vitro and in vivo studies in which DETC-MeSO partially blocked mouse brain glutamate recep-tors. In addition, DETC-MeSO pretreatment effectivelyprevented seizures in mice induced either by NMDA,ammonium acetate, or ethanol-induced kindling sei-zures, all of which are believed to be mediated by NMDAreceptors. These data demonstrate that DETC-MeSOproduces the neuroprotectiveeffectthrough antagonismof NMDA receptors in vivo.
- 中文關鍵字: --
- 英文關鍵字: S-methyl-N, N-diethylthiocarbamate sulfoxide. Disulfiram. N-methyl-D-aspartate receptor. Alcoholism. Neurotoxicity. Anticraving agent