6-hydroxydopamine injections into the nigrostriatal pathway attenuate striatal malonate and 9-nitropropionic acid lesions

The mitochondrial inhibitors malonate and 3-nitropropionic (3NP) acid are p otent neurotoxins in vivo. Administration of these compounds results in neu ronal loss similar to that seen in Huntington's disease. Although the mecha nism of cell death produced by these compounds likely involves activation o f N-methyl-D-aspartate receptors, it remains unclear why the striatum demon strates regional susceptibility to the toxicity of these and other mitochon drial poisons. We hypothesized that dopamine, a weak neurotoxin that occurs in high concentrations in the striatum, may contribute to the neuronal dam age caused by mitochondrial inhibition. We investigated whether depletion o f striatal dopamine using the catecholaminergic toxin B-hydroxydopamine wou ld attenuate lesions induced by mitochondrial inhibition. We found that dop amine depletion reduced significantly the extent of histological damage in the striatum elicited by both intraparenchymal injections of 0.8 mu mol mal onate and 20 mg/kg systemic administration of 3NP. These data suggest that dopamine or one of its metabolites may contribute to mitochondrial toxin-in duced cell death. (C) 1998 Academic Press.