INCREASED VULNERABILITY TO 3-NITROPROPIONIC ACID IN AN ANIMAL-MODEL OF HUNTINGTONS-DISEASE

There is substantial evidence for both metabolic dysfunction and oxida tive damage in Huntington's disease(HD). In the present study, we used in vivo microdialysis to measure the conversion of 4-hydroxybenzoic a cid to 3,4-dihydroxybenzoic acid (3,4-DHBA) as a measure of hydroxyl r adical production in a transgenic mouse model of HD, as well as in lit termate controls. The conversion of 4-hydroxybenzoic acid to 3,4-DHBA was unchanged in the striatum of transgenic HD mice at baseline. Follo wing administration of the mitochondrial toxin 3-nitropropionic acid ( 3-NP), there were significant increases in 3,4-DHBA generation in both control and transgenic HD mice, and the increases in the transgenic H D mice were significantly greater than those in controls. Furthermore, administration of 3-NP produced significantly larger striatal lesions in transgenic HD mice than in littermate controls. The present result s show increased sensitivity to the mitochondrial toxin 3-NP in transg enic HD mice, which suggests metabolic dysfunction in this mouse model of HD.