EXACERBATION OF NMDA, AMPA, AND L-GLUTAMATE EXCITOTOXICITY BY THE SUCCINATE-DEHYDROGENASE INHIBITOR MALONATE

We report that a subtoxic dose of the succinate dehydrogenase (SDH) in hibitor malonate greatly enhances the neurotoxicity of three different excitatory amino acid agonists: N-methyl-D-aspartate (NMDA), lpha-ami no-3-hydroxy-5-methyl-4-isoxazolepropionic acid (S-AMPA), and L-glutam ate. In male Sprague-Dawley rats, intrastriatal stereotaxic injection of malonate alone (0.6 mu mol), NMDA alone (15 nmol), S-AMPA alone (1 nmol), or glutamate alone (0.6 mu mol) produced negligible toxicity as assessed by measurement of lesion volume. Coinjection of subtoxic mal onate with NMDA produced a large lesion (15.2 +/- 1.4 mm(3)), as did c oinjection of malonate with S-AMPA (11.0 +/- 1.0 mm(3)) or glutamate ( 12.8 +/- 0.7 mm(3)). Administration of the noncompetitive NMDA antagon ist MK-801 (5 mg/kg i.p.) completely blocked the toxicity of malonate plus NMDA (0.5 +/- 0.3 mm(3)). This dose of MK-801 had little effect o n the lesion produced by malonate plus S-AMPA (9.0 +/- 0.7 mm(3)), but it attenuated the toxicity of malonate plus glutamate by similar to 4 0% (7.5 +/- 0.9 mm(3)). Coinjection of the AMPA antagonist 2,3-dihydro xy-6-nitro-7-sulfamoylbenzo (f)-quinoxaline (NBQX; 2 nmol) had no effe ct on malonate plus NMDA or malonate plus glutamate toxicity (12.3 +/- 1.8 and 14.0 +/- 0.9 mm(3), respectively) but greatly attenuated malo nate plus S-AMPA toxicity (1.5 +/- 0.9 mm(3)). Combination of the two antagonists conferred no additional neuroprotection in any paradigm. T hese results indicate that metabolic inhibition exacerbates both NMDA receptor- and non-NMDA receptor-mediated excitotoxicity. They also sug gest that the NMDA receptor may play a major role in situations of met abolic compromise in vivo, where glutamate is the endogenous agonist. Furthermore, glutamate toxicity under conditions of metabolic compromi se may not be mediated entirely by ionotropic glutamate receptors.