S-methyl-N,N-diethylthiocarbamate sulfoxide elicits neuroprotective effect against N-methyl-D-aspartate receptor-mediated neurotoxicity.
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, alpha-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 (45)Ca2+ was attenuated in rat-cultured primary neurons following pretreatment with DETC-MeSO. The Ca2+ influx into primary neurons, studied by confocal microscopy of the fluorescent Ca2+ dye fura-2, demonstrated a complete attenuation of NMDA-induced Ca2+ influx. Similarly, DETC-MeSO attenuated NMDA-induced (45)Ca2+ uptake. Glutamate-induced (45)Ca2+ uptake and Ca2+ 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.
Ningaraj
N S
NS
Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045-2106, USA.
Chen
W
W
Schloss
J V
JV
Faiman
M D
MD
Wu
J Y
JY
D020270:Alcohol Withdrawal Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D000818:Animals; D001921:Brain / Q000166:cytology / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002493:Central Nervous System Diseases / Q000139:chemically induced; D004195:Disease Models, Animal; D004050:Ditiocarb / Q000031:analogs & derivatives / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D018698:Glutamic Acid / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017470:Receptors, Glutamate / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013570:Synaptic Membranes / Q000737:chemistry
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C073220:S-methyl N,N-diethylthiolcarbamate sulfoxide; D018698:Glutamic Acid; D004050:Ditiocarb; D002118:Calcium