title: Novel role for the NMDA receptor redox modulatory site in the pathophysiology of seizures.
abstract: Redox-active compounds modulate NMDA receptors (NMDARs) such that reduction of NMDAR redox sites increases, and oxidation decreases, NMDAR-mediated activity. Because NMDARs contribute to the pathophysiology of seizures, redox-active compounds also may modulate seizure activity. We report that the oxidant 5, 5'-dithio-bis(2-nitrobenzoic acid) (DTNB) and the redox cofactor pyrroloquinoline quinone (PQQ) suppressed low Mg(2+)-induced hippocampal epileptiform activity in vitro. Additionally, in slices exposed to 4-7 microM bicuculline, DTNB and PQQ reversed the potentiation of evoked epileptiform responses by the reductants dithiothreitol and Tris(2-carboxyethyl)phosphine (TCEP). NMDA-evoked whole-cell currents in CA1 neurons in slices were increased by TCEP and subsequently decreased by DTNB or PQQ at the same concentrations 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 returned to control medium after low Mg(2+)-induced ictal activity, DTNB significantly 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 pathological NMDAR redox potentiation without inhibiting physiological NMDAR function. In vivo, PQQ decreased the duration of chemoconvulsant-induced seizures in rat pups with no effect on baseline behavior. Our results reveal endogenous potentiation of NMDAR function via mass reduction of redox sites as a novel mechanism that may enhance epileptogenesis and facilitate the transition to status epilepticus. The results further suggest that redox-active compounds may have therapeutic use by reversing NMDAR-mediated pathophysiology without blocking physiological NMDAR function.
authors.affiliation: Department of Neurology, Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Sanchez
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.forename: G
authors.initials: G
authors.lastname: Gardner
authors.forename: L
authors.initials: L
authors.lastname: Orlando
authors.forename: D L
authors.initials: DL
authors.lastname: Tauck
authors.forename: P A
authors.initials: PA
authors.lastname: Rosenberg
authors.forename: E
authors.initials: E
authors.lastname: Aizenman
authors.forename: F E
authors.initials: FE
authors.lastname: Jensen
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001640:Bicuculline; D002630:Chemotactic Factors / Q000494:pharmacology; D003292:Convulsants; D004228:Dithionitrobenzoic Acid / Q000494:pharmacology; D004827:Epilepsy / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism / Q000503:physiopathology*; D007202:Indicators and Reagents / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D010084:Oxidation-Reduction; D045542:PQQ Cofactor; D018408:Patch-Clamp Techniques; D010433:Pentylenetetrazole; D010720:Phosphines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D013439:Sulfhydryl Reagents / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D001640:Bicuculline; D002630:Chemotactic Factors; D003292:Convulsants; D004228:Dithionitrobenzoic Acid; D007202:Indicators and Reagents; D045542:PQQ Cofactor; D010433:Pentylenetetrazole; D010720:Phosphines; D015363:Quinolones; D011809:Quinones; D016194:Receptors, N-Methyl-D-Aspartate; D013439:Sulfhydryl Reagents; C080938:tris(2-carboxyethyl)phosphine