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The Journal of Neuroscience, March 15, 2000, 20(6):2409-2417
Novel Role for the NMDA Receptor Redox Modulatory Site in the Pathophysiology of Seizures
Russell M. Sanchez1, Carl Wang1, Ginger Gardner2, Lianna Orlando3, David L. Tauck4, Paul A. Rosenberg1, 3, Elias Aizenman5, and Frances E. Jensen1, 3 1 Department of Neurology, Children's Hospital and Harvard Medical School, Boston, Massachusetts, 2 Department of Obstetrics and Gynecology, Johns Hopkins Medical School, Baltimore, Maryland, 3 Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, 4 Department of Biology, Santa Clara University, Santa Clara, California, and 5 Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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 Mg2+-induced hippocampal epileptiform activity in vitro. Additionally, in slices exposed to 4-7 µM 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 Mg2+-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.
Key words: NMDA receptor; redox; epilepsy; hippocampus; patch clamp; PQQ
Copyright © 2000 Society for Neuroscience 0270-6474/00/2062409-09$05.00/0
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