Neuroprotective effect of Estrogen Receptor α against neuroinflammation induced by hypoxia/ischemia via SIRT1-dependent AMPK pathway

Abstract Background: Stroke-related damage in rats is protected against by estrogen which also has an anti-cerebral ischemia role mostly conducted via its association with estrogen receptor (ER) α .However,processes governing ER α-mediated neuroprotection are poorly comprehended. This study sought to establish whether ERα’s control of neuroinflammation caused by NLRP3 inflammasome activation emanating from SIRT1-AMPK signaling allowed ERα’s improvement of hypoxia/ischemic damage. Methods: The intraperitoneal administration of estrogen was performed to ovariectomized (bilaterally) (OVA) SD rats prior to middle cerebral artery occlusion (MCAO). The strong rise in NLRP3 inflammasome activation including caspase-1, ASC, IL-1β and IL-18 occurred following OVA and were specifically decreased following estrogen treatment. Moreover, the expression of Silent Information Regulator 1 (SIRT1) and ERα were reversed. The association between ERα-led inhibition of the NLRP3 inflammasome in conditions of hydrogen peroxide (H 2 O 2 ) and SIRT1-AMPK signaling were also examined. Results: Findings confirmed the prevention of NLRP3 inflammasome activation instigated by H 2 O 2 and the in vitro production of IL-1β, IL-18 together with the enhancement of this impact by SIRT1. Additionally, ERα's neuroprotective impact was prevented by inhibiting of AMPK. The synergistic impact of SIRT1 on ERα increased AMPK activation; however, SIRT1 knockout eliminated this. Conclusions: The findings indicate that inhibition of the NLRP3 inflammasome by ERα results in neuroprotection against hypoxia/ischemic injury and that ERα’s neuroprotection can be highly improved by the SIRT1-dependent AMPK pathway.