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108 HYPOXANTHINE ACCUMULATION AND DOPAMINE DEPLETION IN LESCH-NYHAN DISEASE: ANIMAL MODELS AND HUMAN STUDIES

In LND, Hx is elevated, especially in brain and CSF.Since Hx accumulation may promote lipid peroxidation and since similar mechanisms may subserve 6-OHDA neurotoxicity, we considered a simple relationship between Hx accumulation and DA depletion in patients with LND. Cannulas packed with solid Hx were implanted in caudate nucleus of rats; turning behavior was stimulated by injection of apomorphine. Treated animals show pronounced time and dose-dependent ipsilateral turning, which peaks 14-18 days after cannula implantation. Turning is blacked or reduced by haloperidol, a general DA antagonists and by SCH 23390, a selective D1 antagonist. Uric acid, purines, nucleosides, catecholamines and metabolites and 5HIAA were monitored by HPLC of brain regions. Depletion of DA was inversely related to purine concentration at peak times of behavioral effect. NE was not reduced in limbic or corticol forebrain. DA receptors were increased 1.3-1.7x in treated caudate. Allopurinol did not block the development of DA depletion. In fact, cannulas packed with allopurinol elicited similar behaviors.In a preliminary clinical trial, we tested the ability of encapsulated and immobilized xanthine oxidase to reduce circulating purines. A single HPRT-null patient (age 18 monghs) stopped allopurinol therapy 3 days before admission to the study. Over a 10 day period of microcapsule administration, his UA/Creat ratio returned to 1.9 and his plasma Hx level fell from 190 uM to 100 uM.Support: Medical Research Council of Canada to RMP & TMSC