Oleoylethanolamide exerts neuroprotection following ischemic stroke through microglial PPARα signal.

Ischemic stroke remains a major cause of morbidity and mortality worldwide, often leading to long-term neurological deficits. The pathophysiology of ischemic stroke involves complex processes, including neuroinflammation, oxidative stress, and blood-brain barrier disruption. Our previous studies have demonstrated the potential of oleoylethanolamide (OEA) as therapeutic drug for ischemic stroke. However, the precise mechanisms underlying the effects of OEA remain poorly understood. Here, we investigated the potential molecular mechanism of OEA in neuroprotection against ischemic stroke in a mice model of middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reperfusion (OGD/R)-induced BV2 and bEnd.3 cells. We found that the ablation of microglia by the PLX3397 dramatically diminishes the therapeutic effects of OEA in ischemic stroke. Additionally, OEA significantly reduced the infiltration of macrophages/monocytes, polymorphonuclear neutrophils, T cells, and B cells in the ischemic brain hemisphere. Meanwhile, OEA remarkably protected the integrity of the blood-brain barrier through increasing the ZO-1 and Occludin expression in vivo and in vitro. Furthermore, the microglia conditional knockout PPARα mice (cKO mice) displayed greater infarct volumes following OEA treatment in comparison to PPARαflox/flox mice (control mice), highlighting the critical role of microglial PPARα signal in the therapeutic effects of OEA. Therefore, we found that OEA exerts its therapeutic effects against ischemic stroke through microglia PPARα signal. Our findings provide new evidence for the therapeutic potential of OEA in ischemic stroke, further indicating that OEA may become a novel candidate for ischemic stroke therapy.