Abstract
S-Methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO), a metabolite of the drug disulfiram, is a selective carbamoylating agent for sulfhydryl groups. Treatment of glutamate receptors isolated from mouse brain with DETC-MeSO blocks glutamate binding. In vivo, carbamoylated glutathione, administered directly to mice or formed by reaction of DETC-MeSO with glutathione in the blood, also blocks brain glutamate receptors. Carbamoyl groups appear to be delivered to brain glutamate receptors or to liver aldehyde dehydrogenase in vivo by a novel glutathione-mediated mechanism. Seizures caused by the glutamate analogs N-methyl-D-aspartate and methionine sulfoximine, or by hyperbaric oxygen, are prevented by DETC-MeSO, indicating that carbamoylation of glutamate receptors gives an antagonist effect. These observations offer an explanation for some of the previously reported neurological effects of disulfiram, such as its ability to prevent O2-induced seizures. Furthermore, some of the physiology of the disulfiram-ethanol reaction, that could not be accounted for based on the known inhibition of aldehyde dehydrogenase alone, may be explained by disulfiram's effect on glutamate receptors.
Highlights
Considerable effort has been devoted to discovery of glutamate antagonists [1, 2] in recent years, due to increasing evidence linking glutamate excitotoxicity to various neurological disorders [3]
It has recently been demonstrated that disulfiram exerts its anti-alcohol effect in vivo only after bioactivation to the active metabolite S-methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO)1 [9] that is a potent and selective carbamoylating agent for sulfhydryl groups [10]
We report that DETC-MeSO partially blocks glutamate binding to synaptic membrane preparations isolated from the brains of mice, and in addition, DETC-MeSO prevents seizures induced in mice by glutamate analogs or by exposure to hyperbaric oxygen
Summary
Considerable effort has been devoted to discovery of glutamate antagonists [1, 2] in recent years, due to increasing evidence linking glutamate excitotoxicity to various neurological disorders [3]. While known antagonists can provide neuroprotection, excessive action of these classical blocking agents can obtain undesirable side effects [1, 2]. To minimize these undesirable side effects, modification of the redox modulatory sulfhydryl groups of the glutamate receptor has been suggested as a possibly superior therapeutic strategy [4]. That can give complete inhibition by interaction at the glutamate receptor (e.g. CGS 19755) or directly at receptor-linked, calcium ion channels (e.g. phencyclidine or MK-801) [2], inhibition via the redox modulatory sites are expected to give only partial inhibition of function and thereby limit unwanted side effects associated with excessive antagonism [4]. We report that DETC-MeSO partially blocks glutamate binding to synaptic membrane preparations isolated from the brains of mice, and in addition, DETC-MeSO prevents seizures induced in mice by glutamate analogs or by exposure to hyperbaric oxygen
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