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

Abstract

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 H -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 a 2 bd1 subunits of the acetylcholine receptor, an additional redox-sensitive ion channel. Ebselen was observed to signi®cantly 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.

Diphenyl Diselenide-Induced Seizures in Rat Pups: Possible Interaction with Glutamatergic System

“…In fact, diphenyl diselenide reduced about 37% the appearance of seizure episodes induced by glutamate. Although we did not focus on mechanisms by which diphenyl diselenide was capable of protecting seizures induced by glutamate, our results are in accordance with previous data reported by us [2] and others [36]. In fact, diphenyl diselenide produced pharmacological effect in several models of pain through mechanisms that involve an interaction with redox modulatory sites of glutamate receptors [2].…”

Accumulated hippocampal formaldehyde induces age-dependent memory decline

“…3). An analogous study has shown that ethanol inhibits LTP formation by blocking the NMDA receptor, possibly because the cysteine residues of NR2B are sensitive to ethanol (Herin et al 2001), and leads to amnesia (Brioni et al 1989;Dildy and Leslie 1989;Tokuda et al 2007;Wirkner et al 1999). Some studies have shown that formaldehyde can spontaneously modify the cysteine residues of proteins (Metz et al 2006;Toews et al 2008).…”

SNO-ing at the Nociceptive Synapse?

“…5 and 6), resulting in a change of the channel gating properties. Site-directed mutagenesis identified Cys399 as the critical cysteine ( Table 1) targeted by endogenous nitrogen species and various redox modulators, including reducing and oxidizing agents (Tang and Aizenman, 1993;Kim et al, 1999;Sanchez et al, 2000;Herin et al, 2001). They all modify the NMDA receptor at this specific cysteine (Lipton et al, 1993;Choi et al, 2000) and thereby modify glutamateevoked calcium fluxes through the channel.…”