Protection of midbrain dopaminergic neurons by the end-product of purine metabolism uric acid: potentiation by low-level depolarization

High plasma levels of the end product of purine metabolism uric acid (UA) predict a reduced risk of developing Parkinson's disease suggesting that UA may operate as a protective factor for midbrain dopaminergic neurons. Consistent with this view, UA exerted partial but long-term protection in a culture model in which these neurons die spontaneously. The rescued neurons were functional as they accumulated dopamine, efficiently. The use of the fluorescent probe dihydrorhodamine-123 revealed that UA operated by an antioxidant mechanism. The iron chelating agent desferrioxamine, the H₂O₂ scavenger enzyme catalase and the inhibitor of lipid peroxidation Trolox mimicked the effects of UA, suggesting that UA neutralized reactive oxygen species produced via a Fenton-type chemical reaction. UA was, however, not significantly accumulated into neurons, which indicates that the antioxidant effect occurred probably extracellularly. Structure – activity relationships among purine derivatives revealed that the antioxidant properties of UA resulted from the presence of a 8-one substituent in its chemical structure. Of interest, the stimulation of L-type Ca²⁺ channels by high K⁺-induced depolarization and the ensuing activation of extracellular signal-regulated kinases 1/2 strongly improved the neuroprotective effect of UA whereas the depolarizing signal alone had no effect. In summary, our data indicate that UA may interfere directly with the disease's pathomechanism.