title: N-Docosahexaenoylethanolamine is a potent neurogenic factor for neural stem cell differentiation.
abstract: Docosahexaenoic acid (DHA) has been shown to promote neuronal differentiation of neural stem cells (NSCs) in vivo and in vitro. Previously, we found that N-docosahexaenoylethanolamine (synaptamide), an endogenous DHA metabolite with an endocannabinoid-like structure, promotes neurite growth, synaptogenesis, and synaptic function. In this study, we demonstrate that synaptamide potently induces neuronal differentiation of NSCs. Differentiating NSCs were capable of synthesizing synaptamide from DHA. Treatment of NSCs with synaptamide at low nanomolar concentrations significantly increased the number of MAP2 and Tuj-1-positive neurons with concomitant induction of protein kinase A (PKA)/cAMP response element binding protein (CREB) phosphorylation. Conversely, PKA inhibitors or PKA knockdown abolished the synaptamide-induced neuronal differentiation of NSCs. URB597, a fatty acid amide hydrolase (FAAH) inhibitor, elevated the level of DHA-derived synaptamide and further potentiated the DHA- or synaptamide-induced neuronal differentiation of NSCs. Similarly, NSCs obtained from FAAH KO mice exhibited greater capacity to induce neuronal differentiation in response to DHA or synaptamide compared to the wild type NSCs. Neither synaptamide nor DHA affected NSC differentiation into GFAP-positive glia cells. These results suggest that endogenously produced synaptamide is a potent mediator for neurogenic differentiation of NSCs acting through PKA/CREB activation.
authors.affiliation: Laboratory of Molecular Signaling, DICBR, NIAAA, NIH, Bethesda, Maryland 20892-9410, USA.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Rashid
authors.forename: Masanori
authors.initials: M
authors.lastname: Katakura
authors.forename: Giorgi
authors.initials: G
authors.lastname: Kharebava
authors.forename: Karl
authors.initials: K
authors.lastname: Kevala
authors.forename: Hee-Yong
authors.initials: HY
authors.lastname: Kim
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000378:metabolism* / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D063388:Endocannabinoids; D004983:Ethanolamines / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D017362:Cyclic AMP Response Element-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases; D004281:Docosahexaenoic Acids; D063388:Endocannabinoids; D004983:Ethanolamines; D034741:RNA, Small Interfering; D000099252:Fatty Acid Amide Hydrolases; C561061:N-docosahexaenoylethanolamide