Propane-2-sulfonic acid octadec-9-enyl-amide,a novel PPARα/γ dual agonist,protects against ischaemiainduced brain damage in mice by inhibiting inflammatory responses

OBJECTIVE Propane-2-sulfonic acid octadec-9-enyl-amide(N15),an analogue of oleoylethanolamide(OEA),is a novel PPARα/γdual agonist.Our previous studies verified the positive effects of OEA on the acute and delayed stages of cerebral ischaemia.However,it is not clear whether N15 is effective against ischaemic cerebral injury.In the present study,male Kunming mice were subjected to middle cerebral artery occlusion(MCAO).METHODS To evaluate its preventive effects,N15(50,100 or 200 mg·kg-1,ip)was administered for3 d before ischaemia.To evaluate its therapeutic effects,N15(200 mg·kg-1,ip)was administered 1 h before reperfusion or 0,1,2 or 4 h after reperfusion.Neurological deficit scores,infarct volume and the degree of brain oedema were determined at 24 h after reperfusion.Blood brain barrier(BBB)disruption was evaluated by Evans blue(EB)leakage at 6 h after reperfusion.The activation/inflammatory responses of microglia were detected using immunohistochemistry and Western blotting.RESULTS N15 pretreatment improved neurological dysfunction,reduced infarct volume and alleviated brain oedema in a dose-dependent manner;the most effective dose was 200 mg·kg-1.The therapeutic time window was within 2 h after reperfusion.Moreover,N15was more potent in the treatment of cerebral ischaemia injury than OEA.N15 treatment preserved the BBB integrity and suppressed the activation of microglia.N15 inhibited inflammatory cytokine expression not only in MCAO mice but also in lipopolysaccharide(LPS)-stimulated BV-2microglial cells.Moreover,N15 decreased the phosphorylation levels of NF-κBp65,STAT3,and ERK1/2 both in vivo and in vitro.CONCLUSION Our findings demonstrated that N15 exerts neuroprotective effects and was more potent than OEA.Additionally,the neuroprotective effects of N15 on cerebral ischaemia may be attributed to its anti-inflammatory properties,at least in part,by enhancing PPARα/γdual signalling and inhibiting the activation of the NF-κB,STAT3,and ERK1/2 signalling pathways.These findings suggest that N15 may be a potential therapeutic choice for the prevention and treatment of ischaemic stroke.