title: Activity-dependent neurotrophic factor-derived peptide prevents alcohol-induced apoptosis, in part, through Bcl2 and c-Jun N-terminal kinase signaling pathways in fetal brain of C57BL/6 mouse.
abstract: Fetal alcohol exposure is known to induce alteration in fetal brain development. In this study, we focused on neuroprotection against the effects of alcohol exposure using ADNF-9, a peptide derived from activity-dependent neurotrophic factor. We used a mouse model of fetal alcohol exposure to identify the intracellular mechanisms underlying the neuroprotective effects of ADNF-9. On embryonic day 7 (E7), weight-matched pregnant females were assigned to the following groups: (1) ethanol liquid diet (ALC) of 25% (4.49%, v/v) ethanol-derived calories; (2) pair-fed control (PF); (3) ALC combined with administration (i.p.) of ADNF-9 (ALC/ADNF-9); and (4) pair-fed combined with administration (i.p.) of ADNF-9 (PF/ADNF-9). On E13, fetal brains were collected, weighed, and apoptosis was determined using TdT-mediated dUTP nick-end labeling (TUNEL) assay. Bcl2 protein and phospho-c-Jun N-terminal kinase (JNK) levels were determined using Western blot and enzyme immunometric assay, respectively. ADNF-9 administration significantly prevented alcohol-induced reductions in fetal brain weight. In addition, ADNF-9 prevented an alcohol-induced increase in cell death in the primordium of the cerebral cortex and ganglionic eminence. Western blot analysis of the mitochondrial protein fractions revealed that ADNF-9 administration prevented an alcohol-induced reduction in the Bcl2 level. Moreover, an analysis of the proteins in the upstream signaling pathway revealed that ADNF-9 downregulated the phosphorylation of JNK. These data indicate that the mitochondrial Bcl2 pathway and JNK upstream signaling pathway are the intracellular targets of ADNF-9. The neuroprotective mechanism of action of ADNF-9 provides a direction for potential therapeutics against alcohol-induced neural damage involving mitochondrial dysfunction.
authors.affiliation: Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, 3000 Arlington Ave. Toledo, OH 43614, USA. youssef.sari@utoledo.edu
authors.forename: Y
authors.initials: Y
authors.lastname: Sari
authors.forename: J M
authors.initials: JM
authors.lastname: Weedman
authors.forename: S
authors.initials: S
authors.lastname: Ge
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D002492:Central Nervous System Depressants / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D002540:Cerebral Cortex / Q000196:embryology / Q000473:pathology; D000431:Ethanol / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000378:metabolism / Q000517:prevention & control; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009479:Neuropeptides / Q000494:pharmacology*; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D002492:Central Nervous System Depressants; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D018696:Neuroprotective Agents; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; C410622:activity-dependent neurotrophic factor; D000431:Ethanol; D048031:JNK Mitogen-Activated Protein Kinases