title: Myeloid mineralocorticoid receptor during experimental ischemic stroke: effects of model and sex.
abstract: BACKGROUND
  Mineralocorticoid receptor (MR) antagonists have protective effects in the brain during experimental ischemic stroke, and we have previously demonstrated a key role for myeloid MR during stroke pathogenesis. In this study, we explore both model- and sex-specific actions of myeloid MR during ischemic stroke.
  
  
  RESULTS
  The MR antagonist eplerenone significantly reduced the infarct size in male (control, 99.5 mm(3); eplerenone, 74.2 mm(3); n=8 to 12 per group) but not female (control, 84.0 mm(3); eplerenone, 83.7 mm(3); n=6 to 7 per group) mice after transient (90-minute) middle cerebral artery occlusion. In contrast to MR antagonism, genetic ablation of myeloid MR in female mice significantly reduced infarct size (myeloid MR knockout, 9.4 mm(3) [5.4 to 36.6]; control, 66.0 mm(3) [50.0 to 81.4]; n=6 per group) after transient middle cerebral artery occlusion. This was accompanied by reductions in inflammatory gene expression and improvement in neurological function. In contrast to ischemia-reperfusion, myeloid MR-knockout mice were not protected from permanent middle cerebral artery occlusion. The infarct size and inflammatory response after permanent occlusion showed no evidence of protection by myeloid MR knockout in photothrombotic and intraluminal filament models of permanent occlusion.
  
  
  CONCLUSIONS
  These studies demonstrate that MR antagonism is protective in male but not female mice during transient middle cerebral artery occlusion, whereas genetic ablation of myeloid MR is protective in both male and female mice. They also highlight important mechanistic differences in the role of myeloid cells in different models of stroke and confirm that specific myeloid phenotypes play key roles in stroke protection.
authors: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors: Ryan A
authors: RA
authors: Frieler
authors: Jessica J
authors: JJ
authors: Ray
authors: He
authors: H
authors: Meng
authors: Sai P
authors: SP
authors: Ramnarayanan
authors: Michael G
authors: MG
authors: Usher
authors: Enming J
authors: EJ
authors: Su
authors: Stefan
authors: S
authors: Berger
authors: David J
authors: DJ
authors: Pinsky
authors: Daniel A
authors: DA
authors: Lawrence
authors: Michael M
authors: MM
authors: Wang
authors: Richard M
authors: RM
authors: Mortensen
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D000077545:Eplerenone; D005260:Female; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D020521:Stroke / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000077545:Eplerenone
keywords: brain ischemia; reperfusion; stroke