Estrogen receptor beta signaling alters cellular inflammasomes activity after global cerebral ischemia in reproductively senescence female rats.
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.
Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, USA.
Juan Pablo
JP
de Rivero Vaccari
Cerebral Vascular Disease Research Laboratories, Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, USA.
Hersila H
HH
Patel
Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, USA.
Frank J
FJ
Brand
Cerebral Vascular Disease Research Laboratories, Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, USA.
Miguel A
MA
Perez-Pinzon
Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, USA.|Bruce W. Carter Department of Veterans Affairs Medical Center, University of Miami, Miami, Florida, USA.
Helen M
HM
Bramlett
Cerebral Vascular Disease Research Laboratories, Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, USA.
Ami P
AP
Raval
D000375:Aging; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007113:Immunity, Innate / Q000187:drug effects; D058847:Inflammasomes / Q000378:metabolism*; D009243:NAD / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D016207:Cytokines; D047629:Estrogen Receptor beta; D058847:Inflammasomes; D020319:Oligodeoxyribonucleotides, Antisense; C498535:Pycard protein, rat; D009243:NAD; D020170:Caspase 1
NOD-like receptor; caspase-1; cerebral ischemia; interleukin 1beta; neuroprotection