Characterization of the excitotoxic potential of the reversible succinate dehydrogenase inhibitor malonate.


Greene, J G; Greenamyre, J T

Publication Year 1995
Journal Journal of Neurochemistry
Pages 430-436
Volume 64
Issue 1
PMID 7528265.0
DOI 10.1046/j.1471-4159.1995.64010430.x

Although the mechanism of neuronal death in neurodegenerative diseases remains unknown, it has been hypothesized that relatively minor metabolic defects may predispose neurons to N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxic damage in these disorders. To further investigate this possibility, we have characterized the excitotoxic potential of the reversible succinate dehydrogenase (SDH) inhibitor malonate. After its intrastriatal stereotaxic injection into male Sprague-Dawley rats, malonate produced a dose-dependent lesion when assessed 3 days after surgery using cytochrome oxidase histochemistry. This lesion was attenuated by coadministration of excess succinate, indicating that it was caused by specific inhibition of SDH. The lesion was also prevented by administration of the noncompetitive NMDA antagonist MK-801. MK-801 did not induce hypothermia, and hypothermia itself was not neuroprotective, suggesting that the neuroprotective effect of MK-801 was due to blockade of the NMDA receptor ion channel and not to any nonspecific 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. Finally, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonist NBQX (2,3-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 involved 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 therapeutic potential for these diseases.