Synaptamide, endocannabinoid-like derivative of docosahexaenoic acid with cannabinoid-independent function

Abstract

Docosahexaenoylethanolamide, the structural analog of the endogenous cannabinoid receptor ligand anandamide, is synthesized from docosahexaenoic acid (DHA) in the brain. Although docosahexaenoylethanolamide binds weakly to cannabinoid receptors, it stimulates neurite growth, synaptogenesis and glutamatergic synaptic activity in developing hippocampal neurons at concentrations of 10-100 nM. We have previously proposed the term synaptamide for docosahexaenoylethanolamide to emphasize its potent synaptogenic activity and structural similarity to anandamide. Synaptamide is subjected to hydrolysis by fatty acid amide hydrolase, and can be oxygenated to bioactive metabolites. The brain synaptamide content is dependent on the dietary DHA intake, suggesting an endogenous mechanism whereby diets containing adequate amounts of omega-3 fatty acids improve synaptogenesis in addition to well-recognized anti-inflammatory effects.

Published by Elsevier Ltd.

Figures

Fig. 1

Metabolism and function of synaptamide and anandamide. It is likely that synaptamide and anandamide share common pathways, although biosynthetic mechanisms for synaptamide production have not been characterized. Both are subjected to FAAH-mediated hydrolysis. While it is well-established that anandamide effects are mediated through CB1 and CB2 receptors, synaptamide functions in a cannabiniod-independent manner, promoting neuritogenesis and synaptogenesis. Further conversion to oxygenated metabolites is possible for anandamide and synaptamide.

Fig. 2

Cannabinoid-independent function of synaptamide. Neither agonists nor antagonists of CB1 and CB2 influence the neurite outgrowth and synaptogenesis in developing hippocampal neurons. Neurite growth is visualized by MAP2 (green) with DAPI staining for nuclei on both 3 and 7 days in vitro (DIV). Synaptogenesis is represented by synapsin-positive puncta (red) on day 7 cultures. HU210, CB1 agonist; JHW015, CB2 agonist; SR141716A, CB1 antagonist; SR144528, CB2 antagonist. (H.S. Moon and H.Y. Kim, unpublished data). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)