h-89 and Parkinson-Disease

In vivo and in vitro studies have suggested a neuroprotective role for Pituitary adenylate cyclase activating polypeptide (PACAP) against neuronal insults. Here, we showed that PACAP27 protects against neurotoxicity induced by rotenone, a mitochondrial complex I inhibitor that has been implicated in the pathogenesis of Parkinson's disease (PD). The neuroprotective effect of PACAP27 was dose-dependent and blocked by its specific receptor antagonist, PACAP6-27. The effects of PACAP27 on rotenone-induced cell death were mimicked by dibutyryl-cAMP (db-cAMP), forskolin and prevented by the PKA inhibitor H89, the ERK inhibitor PD98059 and the p38 inhibitor SB203580. PACAP27 administration blocked rotenone-induced increases in the level of caspase-3-like activity, whereas could not restore mitochondrial activity damaged by rotenone. Thus, our results demonstrate that PACAP27 has a neuroprotective role against rotenone-induced neurotoxicity in neuronal differentiated PC12 cells and the neuroprotective effects of PACAP are associated with activation of MAP kinase pathways by PKA and with inhibition of caspase-3 activity; the signaling mechanism appears to be mediated through mitochondrial-independent pathways.

Topics: Animals; Bucladesine; Caspase 3; Caspases; Cell Differentiation; Cell Survival; Colforsin; Dose-Response Relationship, Drug; Enzyme Inhibitors; Flavonoids; Intracellular Membranes; Isoquinolines; MAP Kinase Signaling System; Membrane Potentials; Mitochondria; Nerve Growth Factors; Neurons; Neuropeptides; Neurosecretory Systems; Neurotransmitter Agents; p38 Mitogen-Activated Protein Kinases; Parkinson Disease; PC12 Cells; Pituitary Adenylate Cyclase-Activating Polypeptide; Protein Kinase Inhibitors; Rats; Rotenone; Signal Transduction; Sulfonamides