CHARACTERIZATION OF THE EXCITOTOXIC POTENTIAL OF THE REVERSIBLE SUCCINATE-DEHYDROGENASE INHIBITOR MALONATE

Although the mechanism of neuronal death in neurodegenerative diseases remains unknown, it has been hypothesized that relatively minor metab olic defects may predispose neurons to N-methyl-D-aspartate (NMDA) rec eptor-mediated excitotoxic damage in these disorders. To further inves tigate this possibility, we have characterized the excitotoxic potenti al of the reversible succinate dehydrogenase (SDH) inhibitor malonate. After its intrastriatal stereotaxic injection into male Sprague-Dawle y rats, malonate produced a dose-dependent lesion when assessed 3 days after surgery using cytochrome oxidase histochemistry. This lesion wa s attenuated by coadministration of excess succinate, indicating that it was caused by specific inhibition of SDH. The lesion was also preve nted by administration of the noncompetitive NMDA antagonist MK-801. M K-801 did not induce hypothermia, and hypothermia itself was not neuro protective, suggesting that the neuroprotective effect of MK-801 was d ue to blockade of the NMDA receptor ion channel and not to any nonspec ific effect. The competitive NMDA antagonist LY274614 and the glycine site antagonist 7-chlorokynurenate also profoundly attenuated malonate neurotoxicity, further indicating an NMDA receptor-mediated event. Fi nally, the pha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) a ntagonist NBQX dihydroxy-6-nitro-7-sulfamoylbenzo(f)-quinoxaline) was ineffective at preventing malonate toxicity at a dose that effectively reduced S-AMPA toxicity, indicating that non-NMDA receptors are invol ved minimally, if at all, in the production of the malonate lesion. We conclude that inhibition of SDH by malonate results in NMDA receptor- mediated excitotoxic neuronal death. If this mechanism of ''secondary' ' or ''weak'' excitotoxicity plays a role in neurodegenerative disease , NMDA antagonists and other ''antiexcitotoxic'' strategies may have t herapeutic potential for these diseases.