Estrogen receptor beta signaling alters cellular inflammasomes activity after global cerebral ischemia in reproductively senescence female rats

Periodic treatments with estrogen receptor subtype-beta (ER-beta) agonist reduce post-ischemic hippocampal injury in ovariectomized rats. However, the underlying mechanism of how ER-beta agonists protect the brain remains unknown. Global cerebral ischemia activates the innate immune response, and a key component of the innate immune response is the inflammasome. This study tests the hypothesis that ER-beta regulates inflammasome activation in the hippocampus, thus reducing ischemic hippocampal damage in reproductively senescent female rats that received periodic ER-beta agonist treatments. First, we determined the effect of hippocampal ER-beta silencing on the expression of the inflammasome proteins caspase 1, apoptosis-associated speck-like protein containing a CARD (ASC), and interleukin (IL)-1 beta. Silencing of ER-beta attenuated 17 beta-estradiol mediated decrease in caspase 1, ASC, and IL-1 beta. Next, we tested the hypothesis that periodic ER-beta agonist treatment reduces inflammasome activation and ischemic damage in reproductively senescent female rats. Periodic ER-beta agonist treatments significantly decreased inflammasome activation and increased post-ischemic live neuronal counts by 32% (p < 0.05) as compared to the vehicle-treated, reproductively senescent rats. Current findings demonstrated that ER-beta activation regulates inflammasome activation and protects the brain from global ischemic damage in reproductively senescent female rats. Further investigation on the role of a periodic ER-beta agonist regimen to reduce the innate immune response in the brain could help reduce the incidence and the impact of global cerebral ischemia in post-menopausal women.