Possible Mechanism For Synaptamide Induced Neuritogenesis

Docosahexaenoic acid (DHA, 22:6), an omega-3 long chain fatty acid (LCFA), constitutes the primary structural LCFA of the brain. It is esterified as phosphatidylserine (PS) and phosphatidylethanolamine (PE) phospholipids localized primarily in the inner leaflet of cell membranes. DHA prevents apoptosis, promotes neuronal differentiation and activates neuronal gene expression by functioning as a ligand at the retinoid X receptor, thereby playing an important role in neuronal survival and maturation. Recent evidence claims that the metabolite of DHA, synaptamide (N-docosahexaenoylethanolamine (PMID: 21810478); the N-acylethanolamine of DHA) is responsible for the effect of DHA on neuronal maturation. We are investigating the possible mechanism behind this proclamation by evaluating the metabolic fate of synaptamide both in vitro and in vivo. Based on previous work done in our lab on LCFA ethanolamides, we hypothesized that the ethanolamides might generally be useful to deliver LCFA's to the brain, in other words, to act as pro-drugs. Preliminary studies in vitro show that the neurite elongation occurred with synaptamide supplementation but not with DHA supplementation suggesting that synaptamide may enter the brain more efficiently than DHA and releases DHA upon hydrolysis; which in turn can mediate neuronal maturation. To test this hypothesis, we synthesized the radiolabelled synaptamide, ([C-14] synaptamide) to carry out in vivo studies to determine brain uptake and preferential phospholipid composition. Results from this study will provide insight into the metabolism and a possible mechanism of action of synaptamide.