| Abstrakt: |
Glutamatergic neurotransmission, particularly of the NMDA receptor type, has been implicated in the excitotoxic response to several external and internal stimuli. In the present investigation, we report that S-methyl-N,N-diethylthiocarbamate sulfoxide (DETC-MeSO) selectively and specifically blocks the NMDA receptor subtype of the glutamate receptors, and attenuates glutamate-induced neurotoxicity in rat-cultured primary neurons. Other major ionotropic glutamate receptor subtypes, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate, were insensitive to DETC-MeSO both in vitro and in vivo. Disulfiram, the parent compound of DETC-MeSO, also inhibits glutamate receptors partially in vivo; however, it fails to inhibit glutamate receptors in mice pretreated with N-butyl imidazole, a cytochrome P450 enzyme inhibitor, implicating the need for bioactivation of disulfiram to be an effective antagonist. We showed that glutamate-induced increase in [sup 45] Ca[sup 2+] was attenuated in rat-cultured primary neurons following pretreatment with DETC-MeSO. The Ca[sup 2+] influx into primary neurons, studied by confocal microscopy of the fluorescent Ca[sup 2+ ] dye fura-2, demonstrated a complete attenuation of NMDA-induced Ca[sup 2+] influx. Similarly, DETC-MeSO attenuated NMDA-induced [sup 45] Ca[sup 2+ ] uptake. Glutamate-induced [sup 45] Ca[sup 2+ ] uptake and[sup ] Ca[sup 2+] influx, however, were partially blocked by DETC-MeSO, and this is consistent with both in vitro and in vivo studies in which DETC-MeSO partially blocked mouse brain glutamate receptors. In addition, DETC-MeSO pretreatment effectively prevented seizures in mice induced either by NMDA, ammonium acetate, or ethanol-induced kindling seizures, all of which are believed to be mediated by NMDA receptors. These data demonstrate that DETC-MeSO produces the neuroprotective effect through antagonism of NMDA receptors in vivo.Copyright © 2001 National Science Council, ROC and S. Karger AG, Basel [ABSTRACT FROM AUTHOR] |
