The Influence of Orally Administered N-Docosahexanoylethanolamine (Synaptamide) on Cognitive Function in Mice

Abstract

Abstract Objectives Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is essential for normal brain development and cognitive function, and also consumed as a dietary supplement in worldwide. Recently, N-Docosahexanoylethanolamine (synaptamide) has been reported as an endocannabinoid-like metabolite endogenously synthesized from DHA, which produces neuritogenic and synaptogenic effects in vitro studies. These suggest synaptamide plays crucial roles in brain function and can be a novel dietary intervention to prevent cognitive dysfunction. The purpose of this study was to investigate how orally administered synaptamide act on cognitive function in mice. Methods: Exp1. Male ICR mice were oral ingested synaptamide (100 or 500 mg/kg body weight (BW) and measured synaptamide concentration in blood flow. Exp2. Male ICR mice at 4 weeks of age, and male C57BL/6 J mice at 54 weeks of age were orally administered vehicle (corn oil), or synaptamide (100 or 500 mg/kg BW) for 4 weeks. After that, we performed the Y-maze test and Object Recognition test (ORT) to evaluate cognitive function. Only ICR mice were intraperitoneally injected scopolamine just before 30 minutes performing Y-maze test or ORT. Hippocampal gene expression was analyzed by qPCR, and hippocampal phosphoprotein profiles were analyzed using the Phospho Explorer Antibody Array. Results Synaptamide level in plasma was increased by oral administration of synaptamide. Behavioral performance in the Y-maze test were comparable irrespective of administration. On the other hand, in the ORT, synaptamide-administered mice spent significantly more time exploring the novel object compared to familiar object in a dose dependent manner, while control mice did not discriminate between the objects. Furthermore, in hippocampus from aged mice administered synaptamide, expression of PSS2 gene was increased and several phosphoprotein profiles modification involved in inflammatory signal such as Nf-κB were observed. Conclusions We found that oral administration of synaptamide ameliorates cognitive function in scopolamine-administered mice and aged mice, and increases PSS2 gene expression which is involved in memory formation, in hippocampus of aged mice. Our results suggest that supplementation with synaptamide could improve hippocampal-dependent memory formation. Funding Sources Kyowa Hakko Bio Co., Ltd.