N-docosahexaenoylethanolamine reduces neuroinflammation and cognitive impairment after mild traumatic brain injury in rats

Arina I Ponomarenko,Ruslan M Sultanov,Evgeny A Pislyagin,Igor V Manzhulo,Anna A Tyrtyshnaia,Inessa V Dyuizen

doi:10.1038/s41598-020-80818-9

Abstract

At present, there is a growing interest in the study of the neurotropic activity of polyunsaturated fatty acids ethanolamides (N-acylethanolamines). N-docosahexaenoylethanolamine (DHEA, synaptamide) is an endogenous metabolite and structural analogue of anandamide, a widely studied endocannabinoid derived from arachidonic acid. The results of this study demonstrate that DHEA, when administered subcutaneously (10 mg/kg/day, 7 days), promotes cognitive recovery in rats subjected to mild traumatic brain injury (mTBI). In the cerebral cortex of experimental animals, we analyzed the dynamics of Iba-1-positive microglia activity changes and the expression of pro-inflammatory markers (IL1β, IL6, CD86). We used immortalized mouse microglial cells (SIM-A9) to assess the effects of DHEA on LPS-induced cytokines/ROS/NO/nitrite, as well as on CD206 (anti-inflammatory microglia) and the antioxidant enzyme superoxide dismutase (SOD) production. In vivo and in vitro experiments showed that DHEA: (1) improves indicators of anxiety and long-term memory; (2) inhibits the pro-inflammatory microglial cells activity; (3) decrease the level of pro-inflammatory cytokines/ROS/NO/nitrites; (4) increase CD206 and SOD production. In general, the results of this study indicate that DHEA has a complex effect on the neuroinflammation processes, which indicates its high therapeutic potential.

Highlights

At present, there is a growing interest in the study of the neurotropic activity of polyunsaturated fatty acids ethanolamides (N-acylethanolamines)
There were no significant differences in the distribution of points on the Neurological Severity Scale (NSS) scale in the acute period between animals of all experimental groups
The results of the present study indicate that the use of DHEA leads to the development of several metabolic and cellular events that contribute to the cognitive functions recovery in animals with mild traumatic brain injury (mTBI)

Summary

Introduction

There is a growing interest in the study of the neurotropic activity of polyunsaturated fatty acids ethanolamides (N-acylethanolamines). The animal model studies of mTBI are performed by the formation of a closed head injury using a free-falling weight Such a mechanism for the TBIs formation to the greatest extent imitates the TBIs obtained in real conditions[6]. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian In this regard, the effect on microglia using pharmacological agents seems to be the most promising therapeutic option in the treatment of the mTBI consequences. DHEA attenuates the lipopolysaccharide-induced neuroinflammatory response and reduces the deleterious effects of ethanol on neurogenic neural stem cell (NSC) differentiation These actions are mediated by the specific target receptor for synaptamide GPR110 (ADGRF1), a G-protein coupled receptor. The observed effects are similar to the previously established DHA biological activity, the activity of synaptamide is at least 10–100 times h igher[17,18]

Methods

Results

Conclusion