Cyclic AMP promotes the survival of dopaminergic neurons in vitro and protects 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 messenger system nor affect the survival of dopaminergic neurons but stimulated dopamine uptake per neuron. Phorbol esters, which stimulate protein kinase C, had no effect on dopamine uptake. Dibutyryl-cAMP caused an increase in dopamine uptake, which was blocked with (Rp)-cAMPS, a specific 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 bFGF nor activation dependent astrocyte factor (ADAF), was able to prevent the degeneration of dopaminergic neurons induced by MPP+. These results suggest that increased intracellular cAMP protects dopaminergic neurons in situations of stress and therefore reveal novel possibilities for the treatment of Parkinson's disease.
Hulley
P
P
Preclinical Research, Sandoz Pharma Ltd, Basel, Switzerland.
Hartikka
J
J
Lübbert
H
H
D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors*; D000818:Animals; D001685:Biological Factors / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010703:Phorbol Esters / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D001685:Biological Factors; D018696:Neuroprotective Agents; D010703:Phorbol Esters; D016222:Fibroblast Growth Factor 2; D007334:Insulin-Like Growth Factor I; D000242:Cyclic AMP; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine