Tetrahydrobiopterin scavenges superoxide in dopaminergic neurons

Increased oxidative stresses are implicated in the pathogenesis of Parkinson's disease, and dopaminergic neurons may be intrinsically susceptible to oxidative damage. However, the selective presence of tetrahydrobiopterin (BH4) makes dopaminergic neurons more resistant to oxidative stress caused by glutathione depletion. To further investigate the mechanisms of BH4 protection, we examined the effects of BH4 on superoxide levels in individual living mesencephalic neurons. Dopaminergic neurons have intrinsically lower levels of superoxide than nondopaminergic neurons. In addition, inhibiting BH4 synthesis increased superoxide in dopaminergic neurons, while BH4 supplementation decreased superoxide in nondopaminergic cells. BH4 is also a cofactor in catecholamine and NO production. In order to exclude the possibility that the antioxidant effects of BH4 are mediated by dopamine and NO, we used fibroblasts in which neither catecholamine nor NO production occurs. In fibroblasts, BH4 decreased baseline reactive oxygen species, and attenuated reactive oxygen species increase by rotenone and antimycin A. Physiologic concentrations of BH4 directly scavenged superoxide generated by potassium superoxide in vitro. We hypothesize that BH4 protects dopaminergic neurons from ordinary oxidative stresses generated by dopamine and its metabolites and that environmental insults or genetic defects may disrupt this intrinsic capacity of dopaminergic neurons and contribute to their degeneration in Parkinson's disease.