ELEVATED HYDROXYL RADICAL GENERATION IN-VIVO IN AN ANIMAL-MODEL OF AMYOTROPHIC-LATERAL-SCLEROSIS

Mutations in the enzyme copper/zinc superoxide dismutase-1 (SOD1) are associated with familiar amyotrophic lateral sclerosis (FALS). The mea ns by which the mutations cause FALS appears to be due to an adverse p roperty of the mutant SOD1 protein that may involve increased generati on of free radicals. We used in vivo microdialysis to measure the conv ersion of 4-hydroxybenzoic acid to 3,4-dihydroxybenzoic acid (3,4-DHBA ) as a measure of ''hydroxyl radical-like'' production in transgenic a myotrophic lateral sclerosis (ALS) mice with the G93A mutation as well as littermate controls. The conversion of 4-hydroxybenzoic acid to 3, 4-DHBA was significantly increased in the striatum of transgenic ALS m ice at baseline but not in mice overexpressing wild-type human SOD1. F ollowing administration of 3-nitropropionic acid 3,4-DHBA generation w as significantly increased as compared with baseline, and the increase in the transgenic ALS mice was significantly greater than those in co ntrols, whereas the increase in mice overexpressing wildtype human SOD 1 was significantly attenuated. The present results provide in vivo ev idence that expression of mutations in SOD1 can lead to increased gene ration of ''hydroxyl radical-like'' activity, which further implicates oxidative damage in the pathogenesis of ALS.