Age‐Dependent Striatal Excitotoxic Lesions Produced by the Endogenous Mitochondrial Inhibitor Malonate

Abstract

Abstract: Intrastriatal injection of malonate, a reversible inhibitor of succinate dehydrogenase (SDH), produced age‐dependent striatal lesions, which were significantly greater in 4‐and 12‐month‐old animals than in 1‐month‐old animals. Both histologic and neurochemical studies showed that the lesions were significantly attenuated by administration of the noncompetitive NMDA receptor antagonist MK‐801. Water‐suppressed chemical shift magnetic resonance imaging showed that malonate produces increased striatal lactate concentrations and striatal lesions on T 2‐weighted scans that were attenuated by MK‐801. Neurochemical characterization of the lesions showed significant decreases in markers of medium‐sized spiny neurons (GABA and substance P), whereas a marker of medium‐sized aspiny neurons (somato‐statin) was not different from control values, consistent with an NMDA receptor‐mediated mechanism. The effects of intrastriatal injections of malonate on ATP concentrations were compared with those of the irreversible SDH inhibitor 3‐nitropropionic acid (3‐NP). The ATP depletions following an equimolar injection of malonate were less marked and more transient than those of 3‐NP. These results show that the competitive SDH inhibitor malonate produces more transient and milder bioenergetic defects than 3‐NP, which are associated with selective activation of NMDA receptors. The results strengthen the possibility that a subtle impairment of energy metabolism may play a role in the pathogenesis of Huntington's disease.