The neuroprotective agent ebselen modifies NMDA receptor function via the redox modulatory site
Article first published online: 20 DEC 2001
Journal of Neurochemistry
Volume 78, Issue 6, pages 1307–1314, September 2001
How to Cite
Herin, G. A., Du, S. and Aizenman, E. (2001), The neuroprotective agent ebselen modifies NMDA receptor function via the redox modulatory site. Journal of Neurochemistry, 78: 1307–1314. doi: 10.1046/j.1471-4159.2001.00517.x
- Issue published online: 20 DEC 2001
- Article first published online: 20 DEC 2001
- Received March 12, 2001; first revision received May 10, 2001; second revision received June 25, 2001; accepted June 28, 2001.
- cerebral cortex;
- NMDA receptor;
- redox modulation;
- tissue culture
Ebselen is a seleno-organic compound currently in clinical trials for the treatment of ischemic stroke and subarachnoid hemorrhage. Its putative mode of action as a neuroprotectant is via cyclical reduction and oxidation reactions, 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) potentiation of NMDA-mediated currents in cultured neurons and in Chinese hamster ovary (CHO) cells expressing wild-type NMDA NR1/NR2B receptors. In contrast, ebselen was unable to modulate NMDA-induced currents in neurons previously exposed to the thiol oxidant 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB), or in CHO cells expressing a mutant receptor lacking the NR1 redox modulatory site, suggesting that ebselen oxidizes the NMDA receptor via this site. In addition, ebselen was substantially less effective in modifying NMDA responses in neurons exposed to alkylating agent N-ethylmaleimide (NEM) following DTT treatment. Ebselen also reversed DTT block of carbachol-mediated currents in Cos-7 cells expressing the α2βδε subunits of the acetylcholine receptor, an additional redox-sensitive ion channel. Ebselen was observed to significantly increase cell viability following a 30-min NMDA exposure in cultured neurons. In contrast, other more typical antioxidant 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.