期刊
NEUROPHARMACOLOGY
卷 102, 期 -, 页码 174-185出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2015.11.011
关键词
Synaptamide; Neurogenesis; cAMP; Adenylyl cyclase; Docosahexaenoic acid (DHA, 22:6n-3); G-protein
资金
- National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health
Previous studies demonstrated that prenatal exposure to ethanol interferes with embryonic and fetal development, and causes abnormal neurodevelopment. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid highly enriched in the brain, was shown to be essential for proper brain development and function. Recently, we found that N-docosahexenoyethanolamine (synaptamide), an endogenous metabolite of DHA, is a potent PICA-dependent neurogenic factor for neural stem cell (NSC) differentiation. In this study, we demonstrate that ethanol at pharmacologically relevant concentrations downregulates cAMP signaling in NSC and impairs neurogenic differentiation. In contrast, synaptamide reverses ethanol-impaired NSC neurogenic differentiation through counter-acting on the cAMP production system. NSC exposure to ethanol (25-50 mM) for 4 days dose-dependently decreased the number of Tuj-1 positive neurons and PICA/CREB phosphorylation with a concomitant reduction of cellular cAMP. Ethanol-induced cAMP reduction was accompanied by the inhibition of G-protein activation and expression of adenylyl cyclase (AC) 7 and AC8, as well as PDE4 upregulation. In contrast to ethanol, synaptamide increased cAMP production, GTP gamma S binding, and expression of AC7 and AC8 iso-forms in a cAMP-dependent manner, offsetting the ethanol-induced impairment in neurogenic differentiation. These results indicate that synaptamide can reduce ethanol-induced impairment of neuronal differentiation by counter-affecting shared targets in G-protein coupled receptor (GPCR)/cAMP signaling. The synaptamide-mediated mechanism observed in this study may offer a possible avenue for ameliorating the adverse impact of fetal alcohol exposure on neurodevelopment. Published by Elsevier Ltd.
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