Journal of Neuroscience, Vol 12, 2362-2369, Copyright © 1992 by Society for Neuroscience
Interaction of the putative essential nutrient pyrroloquinoline quinone with the N-methyl-D-aspartate receptor redox modulatory site
E Aizenman, KA Hartnett, C Zhong, PM Gallop and PA Rosenberg
Department of Physiology, University of Pittsburgh School of Medicine, Pennsylvania 15261.
The putative essential nutrient pyrroloquinoline quinone (PQQ) can
efficiently mediate reduction and oxidation reactions in a variety of
systems. Therefore, we investigated whether this compound could alter the
function of the NMDA receptor via a recently described redox modulatory
site. In rat cortical neurons in vitro, 50 microM PQQ could reverse the
enhancement of 30 microM NMDA-induced whole-cell ionic currents produced by
the reducing agent dithiothreitol (DTT; 2-4 mM). PQQ also depressed native
responses in a DTT-reversible fashion. In addition, 50-200 microM PQQ
produced a significant degree of neuroprotection in an acute model of
NMDA-mediated neurotoxicity in astrocyte-rich cultures of rat cerebral
cortex. Under certain conditions, PQQ can lead to the formation of
oxygen-derived free radicals, and we have previously observed that these
reactive species can oxidize the NMDA receptor. Nevertheless, the enzymatic
free radical scavengers superoxide dismutase and catalase (10 micrograms/ml
each) did not abolish the actions of PQQ. This observation held true even
in astrocyte-poor cortical cultures, where neuronal processes are directly
exposed to the extracellular milieu. Therefore, under in vitro conditions
in which PQQ is presented without an exogenous electron donor, it appears
as if the entire neuroprotective effect of PQQ is attributable to a direct
oxidation of the NMDA receptor redox site. These results suggest the
possibility of a novel role for PQQ, PQQ-like substances, and
quinone-containing proteins in the brain, and may represent a novel
therapeutic approach for the amelioration of NMDA receptor-mediated
neurotoxic injury.
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