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.