PACAP Protects the Adolescent and Adult Mice Brain from Ethanol Toxicity and Modulates Distinct Sets of Genes Regulating Similar Networks.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid neuropeptide which has been shown to exert various neuroprotective actions in vitro and in vivo; however, the ability of endogenous PACAP to prevent cell death in vivo remains to be elucidated. To explore the capacity of endogenous PACAP to prevent ethanol toxicity, adolescent and adult PACAP knockout (KO) mice were injected with ethanol in a binge drinking-like manner. Biochemical analyses revealed that ethanol administration induced an increase in the production of reactive oxygen species and the activity of caspase-3 in PACAP KO mice in an age-independent manner. In order to characterize the mechanisms underlying the sensitivity of PACAP KO mice, a whole-genome microarray analysis was performed to compare gene regulations induced by ethanol in adolescent and adult wild-type and PACAP KO mice. Gene expression substantially differed between adolescent and adult wild-type mice, suggesting distinct effects of ethanol according to the state of brain maturation. Interestingly, in adolescent and adult PACAP KO mice, the set of genes regulated were also markedly different but seemed to inhibit some similar regulatory network processes associated in particular with DNA repair and cell cycle. These data imply that ethanol induces serious DNA damages and cell cycle alteration in PACAP KO mice. This hypothesis, based on the transcriptomic data, could be confirmed by functional studies which showed that cell proliferation decreased in adolescent and adult PACAP KO mice treated with ethanol but recovered after a 30-day withdrawal period. These data, obtained with PACAP KO animals, demonstrate that endogenous PACAP protects the brain of adolescent and adult mice from alcohol toxicity and modulates distinct sets of genes according to the maturation status of the brain.
INSERM U982, Neuropeptides, Neuronal Death and Cell Plasticity Team, Mont-Saint-Aignan, France.|International Associated Laboratory Samuel de Champlain, Mont-Saint-Aignan, France.
Hélène
H
Lacaille
INSERM U982, Neuropeptides, Neuronal Death and Cell Plasticity Team, Mont-Saint-Aignan, France.|International Associated Laboratory Samuel de Champlain, Mont-Saint-Aignan, France.
Dominique
D
Duterte-Boucher
INSERM U982, Neuropeptides, Neuronal Death and Cell Plasticity Team, Mont-Saint-Aignan, France.|International Associated Laboratory Samuel de Champlain, Mont-Saint-Aignan, France.|PRIMACEN, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Mont-Saint-Aignan, France.
Hubert
H
Vaudry
Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Rouen, France.
Yasmine
Y
Zerdoumi
Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Rouen, France.
Jean-Michel
JM
Flaman
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.|Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Hitoshi
H
Hashimoto
INSERM U982, Neuropeptides, Neuronal Death and Cell Plasticity Team, Mont-Saint-Aignan, France. david.vaudry@univ-rouen.fr.|International Associated Laboratory Samuel de Champlain, Mont-Saint-Aignan, France. david.vaudry@univ-rouen.fr.|PRIMACEN, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Mont-Saint-Aignan, France. david.vaudry@univ-rouen.fr.
David
D
Vaudry
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D000431:Ethanol / Q000633:toxicity*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000172:deficiency* / Q000235:genetics
C495402:Adcyap1 protein, mouse; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D000431:Ethanol
Adolescent; Adult; Alcohol; Brain; PACAP