The role of 6R-tetrahydrobiopterin in the nervous system

In addition to its cofactor activities for aromatic L-amino acid hydroxylas es and nitric oxide synthase (NOS), 6R-tetrahydrobiopterin (6R-BH4) shows d iverse actions on neurons. Dopamine release from the rat striatum or PC12 c ells was stimulated by 6R-BH4, The action of 6R-BH4 was independent of its cofactor activities and stereospecific. Ca2+ channels in rat brain and PC12 cells were activated by 6R-BH4 via cAMP-protein kinase A pathway. Membrane potential of PC12 cells was deplorized by 6R-BH4. Thus, it is assumed that 6R-BH4 acts on its specific action site (possibly outside of the cell memb rane) to stimulate dopamine release by activating Ca2+ channels, Apoptosis induced by depletion of serum and nerve growth factor in PC12 cells was pre vented by 6R-BH4. The cell surviving effect of 6R-BH4 was also mediated by activation of Ca2+ channels and cAMP-protein kinase A pathway. However, sin ce 6R-BH4 did not activate mitogen activated protein kinase, it did not sup port neuronal differentiation, Nitric oxide (NO)-induced cell death was pre vented by 6R-BH4 in PC12 cells. NOS activity was not changed by exogenous 6 R-BH4, but NO metabolites in culture medium were decreased by 6R-BH4. When endogenous 6R-BH4 was reduced by inhibition of biosynthesis, cell death was induced in PC12 cells. Superoxide is observed to be generated during autox idation of 6R-BH4. Superoxide producing system mimicked the cell protective action of 6R-BH4 against NO toxicity. Thus, it is considered that 6R-BH4 p rotects PC12 cells against NO toxicity by generating superoxide during its autoxidation. These results raised the possibility that 6R-BH4 is a self-pr otective factor against NO toxicity in NO producing neurons, Our findings i ndicate that 6R-BH4 regulates neuronal activities in the brain and that 6R- BH4 can be a promising drug for neurodegenerative disorders such as Parkins on's disease and Alzheimer's disease. (C) 2000 Elsevier Science Ltd, All ri ghts reserved.