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

Propane-2-sulfonic acid octadec-9-enyl-amide (N15), an analogue of oleoylethanolamide (OEA), is a novel PPAR alpha/gamma dual agonist. Our previous studies verified the positive effects of OEA on the acute and delayed stages of cerebral ischemia. However, it is not clear whether N15 is effective against ischemic cerebral injury. In the present study, male Kunming mice were subjected to middle cerebral artery occlusion (MCAO). To evaluate its preventive effects, N15 (50, 100 or 200 mg/kg, ip) was administered for 3 days before ischemia. To evaluate its therapeutic effects, N15 (200 mg/kg, 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) and FITC-dextran leakages at 6 h after reperfusion. The activation/inflammatory responses of microglia/macrophages were detected using immunohistochemistry and western blot. 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. The therapeutic time window was within 2 h after reperfusion. N15 treatment preserved the BBB integrity and suppressed the activation of microglia/macrophages. N15 inhibited inflammatory cytokine expression not only in MCAO mice but also in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Additionally, N15 markedly decreased the phosphorylation levels of NF-kappa Bp65, STAT3, and ERK1/2 both in vivo and in vitro. Furthermore, the PPARc antagonist MK886 or PPAR7 antagonist T0070907 respectively partly abolished the anti-inflammatory effects of N15 in vitro. Our findings demonstrated that N15 can exert neuroprotective effects against cerebral ischemic insult. Moreover, the neuroprotective effects of N15 on cerebral ischemia may be attributed to its anti-inflammatory properties, at least in part, by enhancing PPAR alpha/gamma dual signaling and inhibiting the activation of the NF-kappa B, STAT3, and ERK1/2 signaling pathways. These findings suggest that N15 may be a potential therapeutic choice for the prevention and treatment of ischemic stroke. (C) 2017 Published by Elsevier Inc.