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

J Neurochem. 2016 Feb;136(3):492-6. doi: 10.1111/jnc.13404. Epub 2015 Nov 13.


Periodic treatments with estrogen receptor subtype-β (ER-β) agonist reduce post-ischemic hippocampal injury in ovariectomized rats. However, the underlying mechanism of how ER-β 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-β regulates inflammasome activation in the hippocampus, thus reducing ischemic hippocampal damage in reproductively senescent female rats that received periodic ER-β agonist treatments. First, we determined the effect of hippocampal ER-β silencing on the expression of the inflammasome proteins caspase 1, apoptosis-associated speck-like protein containing a CARD (ASC), and interleukin (IL)-1β. Silencing of ER-β attenuated 17β-estradiol mediated decrease in caspase 1, ASC, and IL-1β. Next, we tested the hypothesis that periodic ER-β agonist treatment reduces inflammasome activation and ischemic damage in reproductively senescent female rats. Periodic ER-β 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-β 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-β 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. We propose that estrogen receptor subtype-β (ER-β) activation regulates inflammasome activation and protects the brain from global ischemic damage in reproductively senescent female rats.

Keywords: NOD-like receptor; caspase-1; cerebral ischemia; interleukin 1beta; neuroprotection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Brain Ischemia / complications*
  • Brain Ischemia / drug therapy
  • Brain Ischemia / pathology
  • CARD Signaling Adaptor Proteins
  • Caspase 1 / metabolism
  • Cytokines / metabolism
  • Disease Models, Animal
  • Estrogen Receptor beta / metabolism*
  • Female
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Hippocampus / pathology
  • Immunity, Innate / drug effects
  • Inflammasomes / metabolism*
  • NAD / pharmacology
  • Neurons / drug effects
  • Neurons / metabolism
  • Oligodeoxyribonucleotides, Antisense / pharmacology
  • Ovariectomy
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*


  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Cytokines
  • Estrogen Receptor beta
  • Inflammasomes
  • Oligodeoxyribonucleotides, Antisense
  • Pycard protein, rat
  • NAD
  • Caspase 1