title: Inhibitors of type IV phosphodiesterases reduce the toxicity of MPTP in substantia nigra neurons in vivo.
abstract: The neuropathology of Parkinson's disease is characterized by the degeneration of dopaminergic neurons in the substantia nigra. We have recently shown that the activation of protein kinase A improves the survival 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 improve 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, phosphodiesterase type IV inhibitors reduced the MPTP-induced dopamine depletion in the striatum of C57BL/6 mice. Furthermore, the loss of tyrosine hydroxylase-immunopositive neurons in the substantia nigra of these animals was diminished. After Nissl staining, a similar reduction of the MPTP-induced loss of neurons was observed in the substantia nigra. The protective effect of protein kinase A activation did not appear to be due to the blocking of MPP+ uptake into dopaminergic neurons. This was not decreased after treatment with forskolin or 8-(4-chlorophenylthio)-cAMP. Thus, protein kinase A regulates the survival and differentiation of dopaminergic substantia nigra neurons in vivo, implicating a therapeutic potential for substances which regulate cAMP turnover in these neurons.
authors.affiliation: Preclinical Research, Sandoz Pharma Ltd., Basel, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Hulley
authors.forename: J
authors.initials: J
authors.lastname: Hartikka
authors.forename: S
authors.initials: S
authors.lastname: Abdel'Al
authors.forename: P
authors.initials: P
authors.lastname: Engels
authors.forename: H R
authors.initials: HR
authors.lastname: Buerki
authors.forename: K H
authors.initials: KH
authors.lastname: Wiederhold
authors.forename: T
authors.initials: T
authors.lastname: Müller
authors.forename: P
authors.initials: P
authors.lastname: Kelly
authors.forename: D
authors.initials: D
authors.lastname: Lowe
authors.forename: H
authors.initials: H
authors.lastname: Lübbert
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects; D010300:Parkinson Disease / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects* / Q000494:pharmacology*; D051381:Rats; D013378:Substantia Nigra / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D010727:Phosphoric Diester Hydrolases; D004298:Dopamine