N-Stearidonoylethanolamine Restores CA1 Synaptic Integrity and Reduces Astrocytic Reactivity After Mild Traumatic Brain Injury.

Abstract

Mild traumatic brain injury (mTBI) disrupts hippocampal network function through coordinated alterations in glial reactivity, synaptic integrity, and adult neurogenesis. Effective therapeutic approaches targeting these interconnected processes remain limited. Lipid-derived molecules capable of modulating these mTBI-induced disturbances are emerging as promising neuroprotective candidates. Here, we investigated the effects of N-stearidonylethanolamine (SDEA), an ω-3 ethanolamide, in a mouse model of mTBI. SDEA treatment attenuated astrocytic reactivity, restored Arc expression, and improved dendritic spine density and morphology in the CA1 hippocampal area. In the dentate gyrus, mTBI reduced Ki-67-indexed proliferation while leaving DCX-positive immature neurons unchanged, and SDEA partially rescued proliferative activity. These effects were accompanied by improvements in anxiety-like behavior and working-memory performance. Together, these findings demonstrate that SDEA modulates several key components of the glia-synapse-neurogenesis axis and supports functional recovery of hippocampal circuits following mTBI. These results suggest that ω-3 ethanolamides may represent promising candidates for multi-target therapeutic strategies in mTBI.