Abstract TP167: Suppression of High-mobility Group Protein Box-1 Signaling by Eicosapentaenoic Acid Ameliorates Brain Ischemic Damage in Oophorectomized Rats

Background and Purpose— Cerebral ischemia triggers the acute inflammation that has been associated with an increase in brain damage. In male rats exposed to ischemic insult, high-mobility group protein box-1 (HMGB1) activates inflammatory pathways via its receptor for advanced glycation products (RAGE) and its toll-like receptors (TLRs). We examined the role of these molecules in female rats with experimental ischemic brain damage. We further investigated the efficacy of eicosapentaenoic acid (EPA) against cerebral ischemia and its effect on HMGB1 signaling. Methods— Before 90-min middle cerebral artery occlusion-reperfusion, 5-week-old female Sprague-Dawley rats were subjected to bilateral oophorectomy (OVX + ) and pretreated with 500mg/kg/day EPA for 4 weeks. The relationship between the efficacy of EPA and the regulation of HMGB1 signaling were investigated using peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone, PPARγ inhibitor GW9662, and vehicle-control. Results— In parallel with the expansion of the cortical infarct size, HMGB1 signaling after cerebral ischemia was increased in OVX + rats. The mRNA level of TLR9 and RAGE but not TLR2 and TLR4 was moderately increased by cerebral ischemia and significantly higher in OVX + - than OVX - rats. The HMGB1 signal in the OVX + rats pretreated with EPA was inhibited in a PPARγ-dependent and independent manner. These effects were associated with a reduction in the infarct size. Conclusions— We first demonstrate that cortical infarct facilitated by OVX is associated with augmented HMGB1 signaling and that the augmented HMGB1 signaling was suppressed by EPA. To assess whether EPA treatment is a promising strategy further clinical studies are required in postmenopausal women.