Pituitary adenylate cyclase-activating polypeptide protects rat cerebellar granule neurons against ethanol-induced apoptotic cell death.
Alcohol exposure during development can cause brain malformations and neurobehavioral abnormalities. In view of the teratogenicity of ethanol, identification of molecules that could counteract the neurotoxic effects of alcohol deserves high priority. Here, we report that pituitary adenylate cyclase-activating polypeptide (PACAP) can prevent the deleterious effect of ethanol on neuronal precursors. Exposure of cultured cerebellar granule cells to ethanol inhibited neurite outgrowth and provoked apoptotic cell death. Incubation of granule cells with PACAP prevented ethanol-induced apoptosis, and this effect was not mimicked by vasoactive intestinal polypeptide, suggesting that PAC1 receptors are involved in the neurotrophic activity of PACAP. Ethanol exposure induced a strong increase of caspase-2, -3, -6, -8, and -9 activities, DNA fragmentation, and mitochondrial permeability. Cotreatment of granule cells with PACAP provoked a significant inhibition of all of the apoptotic markers investigated although the neurotrophic activity of PACAP could only be ascribed to inhibition of caspase-3 and -6 activities. These data demonstrate that PACAP is a potent protective agent against ethanol-induced neuronal cell death. The fact that PACAP prevented ethanol toxicity even when added 2 h after alcohol exposure, suggests that selective PACAP agonists could have potential therapeutic value for the treatment of fetal alcohol syndrome.
Vaudry
David
D
European Institute for Peptide Research (Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23), Laboratory of Cellular and Molecular Neuroendocrinology, University of Rouen, 76821 Mont-Saint-Aignan, France.
Rousselle
Cécile
C
Basille
Magali
M
Falluel-Morel
Anthony
A
Pamantung
Tommy F
TF
Fontaine
Marc
M
Fournier
Alain
A
Vaudry
Hubert
H
Gonzalez
Bruno J
BJ
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000096:biosynthesis / Q000378:metabolism; D016923:Cell Death; D002454:Cell Differentiation; D002470:Cell Survival; D002531:Cerebellum / Q000378:metabolism*; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051381:Rats; D017208:Rats, Wistar; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone / Q000378:metabolism; D013997:Time Factors
C495403:Adcyap1 protein, rat; C495505:Adcyap1r1 protein, rat; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone; D000431:Ethanol; D020169:Caspases