The neuroprotective agent ebselen modifies NMDA receptor function via the redox modulatory site

Ebselen is a seleno-organic compound currently in clinical trials for the t reatment of ischemic stroke and subarachnoid hemorrhage. Its putative mode of action as a neuroprotectant is via cyclical reduction and oxidation reac tions, in a manner akin to glutathione peroxidase. For this reason, we have investigated the effects of ebselen on the redox-sensitive NMDA receptor. We have found that ebselen readily reversed dithiothreitol (DTT) potentiati on of NMDA-mediated currents in cultured neurons and in Chinese hamster ova ry (CHO) cells expressing wild-type NMDA NR1/NR2B receptors. In contrast, e bselen was unable to modulate NMDA-induced currents in neurons previously e xposed to the thiol oxidant 5,5 ' -dithio-bis(2-nitrobenzoic acid) (DTNB), or in CHO cells expressing a mutant receptor lacking the NR1 redox modulato ry site, suggesting that ebselen oxidizes the NMDA receptor via this site. In addition, ebselen was substantially less effective in modifying NMDA res ponses in neurons exposed to alkylating agent N-ethylmaleimide (NEM) follow ing DTT treatment. Ebselen also reversed DTT block of carbachol-mediated cu rrents in Cos-7 cells expressing the alpha (2)beta delta epsilon subunits o f the acetylcholine receptor, an additional redox-sensitive ion channel. Eb selen was observed to significantly increase cell viability following a 30- min NMDA exposure in cultured neurons. In contrast, other more typical anti oxidant compounds did not afford neuroprotection in a similar paradigm. We conclude that ebselen may be neuroprotective in part due to its actions as a modulator of the NMDA receptor redox modulatory site.