Novel role for the NMDA receptor redox modulatory site in the pathophysiology of seizures

Redox-active compounds modulate NMDA receptors (NMDARs) such that reduction of NMDAR redox sites increases, and oxidation decreases, NMDAR-mediated ac tivity. Because NMDARs contribute to the pathophysiology of seizures, redox -active compounds also may modulate seizure activity. We report that the ox idant 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB) and the redox cofactor py rroloquinoline quinone (PQQ) suppressed low Mg2+-induced hippocampal epilep tiform activity in vitro. Additionally, in slices exposed to 4-7 mu M bicuc ulline, DTNB and PQQ reversed the potentiation of evoked epileptiform respo nses by the reductants dithiothreitol and Tris(2-carboxyethyl) phosphine (T CEP). NMDA-evoked whole-cell currents in CA1 neurons in slices were increas ed by TCEP and subsequently decreased by DTNB or PQQ at the same concentrat ions that modulated epileptiform activity. However, DTNB and PQQ had little effect on baseline NMDA-evoked currents in control medium, and PQQ did not alter NMDAR-dependent long-term potentiation. In contrast, in slices retur ned to control medium after low Mg2+-induced ictal activity, DTNB significa ntly inhibited NMDAR-mediated currents, indicating endogenous reduction of NMDAR redox sites under this epileptogenic condition. These data suggested that PQQ and DTNB suppressed spontaneous ictal activity by reversing pathol ogical NMDAR redox potentiation without inhibiting physiological NMDAR func tion. In vivo, PQQ decreased the duration of chemoconvulsant-induced seizur es in rat pups with no effect on baseline behavior. Our results reveal endo genous potentiation of NMDAR function via mass reduction of redox sites as a novel mechanism that may enhance epileptogenesis and facilitate the trans ition to status epilepticus. The results further suggest that redox-active compounds may have therapeutic use by reversing NMDAR-mediated pathophysiol ogy without blocking physiological NMDAR function.