INHIBITORS OF TYPE-IV PHOSPHODIESTERASES REDUCE THE TOXICITY OF MPTP IN SUBSTANTIA-NIGRA NEURONS IN-VIVO

The neuropathology of Parkinson's disease is characterized by the dege neration of dopaminergic neurons in the substantia nigra, We have rece ntly shown that the activation of protein kinase A improves the surviv al of dopaminergic neurons in culture and, furthermore, protects them from the dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP (+)) in vitro, We have now analysed the potential of phosphodiesterase inhibitors to increase cAMP levels in dopaminergic neurons, to improv e their survival in culture and to protect them from the toxicity of 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in vivo. Increasing intracellular cAMP with phosphodiesterase type IV-specific inhibitors enhanced the survival of dopaminergic neurons in culture. Inhibitors of other phosphodiesterase types were not active. In vivo, phosphodies terase type IV inhibitors reduced the MPTP-induced dopamine depletion in the striatum of C57BL/6 mice. Furthermore, the loss of tyrosine hyd roxylase-immunopositive neurons in the substantia nigra of these anima ls was diminished. After Nissl staining, a similar reduction of the MP TP-induced loss of neurons was observed in the substantia nigra. The p rotective effect of protein kinase A activation did not appear to be d ue to the blocking of MPP(+) uptake into dopaminergic neurons. This wa s not decreased after treatment with forskolin or 8-(4-chlorophenylthi o)-cAMP. Thus, protein kinase A regulates the survival and differentia tion of dopaminergic substantia nigra neurons in vivo, implicating a t herapeutic potential for substances which regulate cAMP turnover in th ese neurons.