The role of 6R-tetrahydrobiopterin in the nervous system

In addition to its cofactor activities for aromatic L-amino acid hydroxylases and nitric oxide synthase (NOS), 6R-tetrahydrobiopterin (6R-BH(4)) shows diverse actions on neurons. Dopamine release from the rat striatum or PC12 cells was stimulated by 6R-BH(4). The action of 6R-BH(4) was independent of its cofactor activities and stereospecific. Ca(2+) channels in rat brain and PC12 cells were activated by 6R-BH(4) via cAMP-protein kinase A pathway. Membrane potential of PC12 cells was deplorized by 6R-BH(4). Thus, it is assumed that 6R-BH(4) acts on its specific action site (possibly outside of the cell membrane) to stimulate dopamine release by activating Ca(2+) channels. Apoptosis induced by depletion of serum and nerve growth factor in PC12 cells was prevented by 6R-BH(4). The cell surviving effect of 6R-BH(4) was also mediated by activation of Ca(2+) channels and cAMP-protein kinase A pathway. However, since 6R-BH(4) did not activate mitogen activated protein kinase, it did not support neuronal differentiation. Nitric oxide (NO)-induced cell death was prevented by 6R-BH(4) in PC12 cells. NOS activity was not changed by exogenous 6R-BH(4), but NO metabolites in culture medium were decreased by 6R-BH(4). When endogenous 6R-BH(4) was reduced by inhibition of biosynthesis, cell death was induced in PC12 cells. Superoxide is observed to be generated during autoxidation of 6R-BH(4). Superoxide producing system mimicked the cell protective action of 6R-BH(4) against NO toxicity. Thus, it is considered that 6R-BH(4) protects PC12 cells against NO toxicity by generating superoxide during its autoxidation. These results raised the possibility that 6R-BH(4) is a self-protective factor against NO toxicity in NO producing neurons. Our findings indicate that 6R-BH(4) regulates neuronal activities in the brain and that 6R-BH(4) can be a promising drug for neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease.