title: PACAP protects cerebellar granule neurons against oxidative stress-induced apoptosis.
abstract: Oxidative stress, resulting from accumulation of reactive oxygen species, plays a critical role in neuronal cell death associated with neurodegenerative diseases and stroke. In the present study, we have investigated the potential neuroprotective effect of pituitary adenylate cyclase-activating polypeptide (PACAP) on oxidative stress-induced apoptosis. Incubation of cerebellar granule cells with PACAP inhibited hydrogen peroxide-evoked cell death in a concentration-dependent manner. The effect of PACAP on granule cell survival was not mimicked by vasoactive intestinal polypeptide and was blocked by the antagonist PACAP6-38. The protective action of PACAP upon hydrogen peroxide-induced neuronal cell death was abolished by the MAP-kinase kinase (MEK) inhibitor U0126 and mimicked by the caspase-3 inhibitor Z-DEVD-FMK. PACAP markedly inhibited hydrogen peroxide-evoked caspase-3 activation and DNA fragmentation. Taken together, these data indicate that PACAP, acting through PACAP receptor type 1, exerts a potent protective effect against neuronal degeneration induced by hydrogen peroxide. The anti-apoptotic effect of PACAP is mediated through the MAP-kinase pathway and can be accounted for by inhibition of caspase-3 activation resulting from oxidative stress.
authors.affiliation: European Institute for Peptide Research (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology, INSERM U413, UA CNRS, University of Rouen, 76821 Mont-Saint-Aignan, France.
authors.forename: D
authors.initials: D
authors.lastname: Vaudry
authors.forename: T F
authors.initials: TF
authors.lastname: Pamantung
authors.forename: M
authors.initials: M
authors.lastname: Basille
authors.forename: C
authors.initials: C
authors.lastname: Rousselle
authors.forename: A
authors.initials: A
authors.lastname: Fournier
authors.forename: H
authors.initials: H
authors.lastname: Vaudry
authors.forename: J C
authors.initials: JC
authors.lastname: Beauvillain
authors.forename: B J
authors.initials: BJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D003994:Bucladesine / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009479:Neuropeptides / Q000494:pharmacology* / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: C495403:Adcyap1 protein, rat; D004791:Enzyme Inhibitors; D009479:Neuropeptides; D018696:Neuroprotective Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D003994:Bucladesine; D006861:Hydrogen Peroxide; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases