Carbamoylation of Brain Glutamate Receptors by a Disulfiram Metabolite

Abstract

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). Unfortunately, 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). Unlike classical antagonists, 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). At present S-nitrosylation of glutamate receptors by an NO ϩ donor (e.g. nitroglycerin) is the only mechanism for partially blocking receptor response in vivo that would achieve this effect by interaction with the redox modulatory sites (5, 6).Disulfiram has been used in the treatment of alcoholism for almost 50 years (7,8). 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 now report that DETC-MeSO also 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. MATERIALS AND METHODS Animals-MaleSwiss Webster mice (20 -30 g) or male SpragueDawley rats (250 -300 g) were used in the study. All experiments that employed animals were conducted in strict compliance with the National Institutes of Health guidelines on animal use and institutional regulations concerning animal experimentation. Animals were exposed to hyperbaric oxygen in a specially designed pressure chamber as described previously (11, 12). The time to first clonic-tonic seizure after bringing animals to a final pressure of 5 atmospheres of 100% oxygen or after intraperitoneal injection of convulsants was noted by criteria outlined previously (11, 12). Unless otherwise specified, the ability of DETC-MeSO to prevent seizures was tested by intraperitoneal injection of 5.2 mg/kg DETC-MeSO 1-2 h prior to bringing the animal to a final pressure of 5 atmospheres of 100% oxygen or intraperitoneal injection of N-methyl-D-aspartate (NMDA) (125 mg/kg) or L-methionine sulfoximine (MetSOX) (250 mg/kg). Evaluation of the statistics for whole animal experiments or for changes in brain glutamate binding after administration of DETC-MeSO was conducted by use of the program GraphPAD InStat from GraphPAD Software (San Diego, CA).Binding Studies-Synap...

Activation of Extrasynaptic, But Not Synaptic, NMDA Receptors Modifies Amyloid Precursor Protein Expression Pattern and Increases Amyloid-β Production

“…Several studies have described a rapid modification of cerebral gene expression (at both mRNA and protein levels) in mice subjected to intraperitoneal NMDA injection (Nagendra et al, 1997;Chung et al, 2000;Taniura et al, 2007). To validate our in vitro findings, we evaluated the expression of KPI-APP in cortex of NMDA-treated mice by a single intraperitoneal injection.…”

Role of Glutamatergic and GABAergic Systems in Alcoholism

“…However, recently we have shown that the active metabolite of disulfiram, DETC-MeSO, not only inhibits acetaldehyde dehydrogenase but also partially blocks glutamate receptors [155]. Furthermore, DETCMeSO is quite effective in preventing seizures induced by NMDA or hyperbaric conditions [155]. Additionally disulfiram has been shown to markedly enhance the anticraving activity of acamprosate [14], suggesting that DETC-MeSO may also have anti-craving activity.…”

Biomedical Vignette

“…S-methyl N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO), the active metabolite of disulfiram, has recently been shown to exert an antagonistic effect on brain glutamate receptors [21]. It is also possible that the clinical efficacy of disulfiram in the treatment of alcoholism is due, at least in part, to its effect on glutamate receptors.…”