INHIBITION OF SUCCINATE-DEHYDROGENASE BY MALONIC-ACID PRODUCES AN EXCITOTOXIC LESION IN RAT STRIATUM

Excitotoxicity and defects in neuronal energy metabolism have both bee n implicated in the pathogenesis of neurodegenerative disease. These t wo mechanisms may be linked through the NMDA receptor, activation of w hich is dependent on neuronal membrane potential. Because the ability to maintain membrane potential is dependent on neuronal energy metabol ism, bioenergetic defects may affect NMDA receptor-mediated excitotoxi city. We now report that reversible inhibition of succinate dehydrogen ase (SDH), an enzyme central to both the tricarboxylic acid cycle and the electron transport chain, produces an ''excitotoxic'' lesion in ra t striatum that can be blocked by the NMDA antagonist MK-801. Male Spr ague-Dawley rats received intrastriatal stereotaxic injections of the SDH inhibitor malonic acid (1 or 2 mumol) in combination with intraper itoneal injections of vehicle or MK-801 (5 mg/kg) 30 min before and 21 0 min after malonic acid. Animals were killed 72 h after surgery, and brains were processed for histology, cytochrome oxidase activity, and [H-3]MK-801 and [H-3]AMPA autoradiography. The higher dose of malonic acid (2 mumol) produced large lesions that were markedly attenuated by treatment with MK-801 (28.1 +/- 3.6 vs. 4.7 +/- 2.6 MM3; p < 0.001). [H-3]MK-801 and [H-3]AMPA binding were reduced in the lesions by 60 an d 63%, respectively. One micromole of malonic acid produced smaller le sions that were almost completely blocked by MK-801 treatment (9.6 +/- 1.3 vs. 0.06 +/- 0.04 MM3; p < 0.0001). The toxic effects of malonic acid were due specifically to inhibition of SDH inasmuch as coinjectio n of a threefold excess of succinate with the malonic acid blocked the striatal lesions (p < 0.002). We conclude that inhibition of SDH can lead to NMDA receptor-mediated excitotoxic neuronal death. These resul ts have implications for the pathogenesis of and therapy for neurodege nerative diseases.