PACAP protects neuronal differentiated PC12 cells against the neurotoxicity induced by a mitochondrial complex I inhibitor, rotenone.
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.
Wang
Gang
G
Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Second Medical University, Shanghai, China.
Qi
Chen
C
Fan
Guo-Hua
GH
Zhou
Hai-Yan
HY
Chen
Sheng-Di
SD
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival; D005576:Colforsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009414:Nerve Growth Factors / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D009479:Neuropeptides / Q000378:metabolism / Q000502:physiology*; D009490:Neurosecretory Systems / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism / Q000502:physiology*; D016716:PC12 Cells; D010300:Parkinson Disease / Q000378:metabolism; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C495403:Adcyap1 protein, rat; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007546:Isoquinolines; D009414:Nerve Growth Factors; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D012402:Rotenone; D005576:Colforsin; D003994:Bucladesine; D048051:p38 Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one