Exacerbation of NMDA, AMPA, and l-Glutamate Excitotoxicity by the Succinate Dehydrogenase Inhibitor Malonate
Article first published online: 23 NOV 2002
Journal of Neurochemistry
Volume 64, Issue 5, pages 2332–2338, May 1995
How to Cite
Greene, J. G. and Greenamyre, J. T. (1995), Exacerbation of NMDA, AMPA, and l-Glutamate Excitotoxicity by the Succinate Dehydrogenase Inhibitor Malonate. Journal of Neurochemistry, 64: 2332–2338. doi: 10.1046/j.1471-4159.1995.64052332.x
- Issue published online: 23 NOV 2002
- Article first published online: 23 NOV 2002
- Received August 25, 1994; revised manuscript received October 25, 1994; accepted November 7, 1994.
- Neurodegenerative disease;
- Succinate dehydrogenase
Abstract: We report that a subtoxic dose of the succinate dehydrogenase (SDH) inhibitor malonate greatly enhances the neurotoxicity of three different excitatory amino acid agonists: N-methyl-d-aspartate (NMDA), S-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (S-AMPA), and l-glutamate. In male Sprague-Dawley rats, intrastriatal stereotaxic injection of malonate alone (0.6 µmol), NMDA alone (15 nmol), S-AMPA alone (1 nmol), or glutamate alone (0.6 µmol) produced negligible toxicity as assessed by measurement of lesion volume. Coinjection of subtoxic malonate with NMDA produced a large lesion (15.2 ± 1.4 mm3), as did coinjection of malonate with S-AMPA (11.0 ± 1.0 mm3) or glutamate (12.8 ± 0.7 mm3). Administration of the noncompetitive NMDA antagonist MK-801 (5 mg/kg i.p.) completely blocked the toxicity of malonate plus NMDA (0.5 ± 0.3 mm3). This dose of MK-801 had little effect on the lesion produced by malonate plus S-AMPA (9.0 ± 0.7 mm3), but it attenuated the toxicity of malonate plus glutamate by ∼40% (7.5 ± 0.9 mm3). Coinjection of the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)-quinoxaline (NBQX; 2 nmol) had no effect on malonate plus NMDA or malonate plus glutamate toxicity (12.3 ± 1.8 and 14.0 ± 0.9 mm3, respectively) but greatly attenuated malonate plus S-AMPA toxicity (1.5 ± 0.9 mm3). Combination of the two antagonists conferred no additional neuroprotection in any paradigm. These results indicate that metabolic inhibition exacerbates both NMDA receptor- and non-NMDA receptor-mediated excitotoxicity. They also suggest that the NMDA receptor may play a major role in situations of metabolic compromise in vivo, where glutamate is the endogenous agonist. Furthermore, glutamate toxicity under conditions of metabolic compromise may not be mediated entirely by ionotropic glutamate receptors.