CYCLIC-AMP PROMOTES THE SURVIVAL OF DOPAMINERGIC-NEURONS IN-VITRO ANDPROTECTS THEM FROM THE TOXIC EFFECTS OF MPP(+)

We have studied how stimulation of protein kinase C and cAMP-dependent protein kinases affect the development of mesencephalic dopaminergic neurons in vitro. IGF-I and bFGF did not activate either second messen ger system nor affect the survival of dopaminergic neurons but stimula ted dopamine uptake per neuron. Phorbol esters, which stimulate protei n kinase C, had no effect on dopamine uptake. Dibutyryl-cAMP caused an increase in dopamine uptake, which was blocked with (Rp)-cAMPS, a spe cific inhibitor of cAMP-dependent protein kinases. Treating cells with specific phosphodiesterase type IV inhibitors elevated the forskolin- induced increase in dopamine uptake. Furthermore, cAMP, but neither bF GF nor activation dependent astrocyte factor (ADAF), was able to preve nt the degeneration of dopaminergic neurons induced by MPP(+). These r esults suggest that increased intracellular cAMP protects dopaminergic neurons in situations of stress and therefore reveal novel possibilit ies for the treatment of Parkinson's disease.