A steroid receptor coactivator small molecule “stimulator” attenuates post-stroke ischemic brain injury

Lisa K. McClendon, Roberto L. Garcia, Tyler Lazaro, Ariadna Robledo, Viren Vasandani, Zean Aaron Evan Luna, Abhijit S. Rao, Aditya Srivatsan, David M. Lonard, Clifford C. Dacso, Peter Kan, Bert W. O’Malley

Research output: Contribution to journalArticlepeer-review

Abstract

Introduction: Pathologic remodeling of the brain following ischemic stroke results in neuronal loss, increased inflammation, oxidative stress, astrogliosis, and a progressive decrease in brain function. We recently demonstrated that stimulation of steroid receptor coactivator 3 with the small-molecule stimulator MCB-613 improves cardiac function in a mouse model of myocardial ischemia. Since steroid receptor coactivators are ubiquitously expressed in the brain, we reasoned that an MCB-613 derivative (MCB-10-1), could protect the brain following ischemic injury. To test this, we administered MCB-10-1 to rats following middle cerebral artery occlusion and reperfusion. Methods: Neurologic impairment and tissue damage responses were evaluated on day 1 and day 4 following injury in rats treated with control or 10-1. Results: We show that 10-1 attenuates injury post-stroke. 10-1 decreases infarct size and mitigates neurologic impairment. When given within 30 min post middle cerebral artery occlusion and reperfusion, 10-1 induces lasting protection from tissue damage in the ischemic penumbra concomitant with: (1) promotion of reparative microglia; (2) an increase in astrocyte NRF2 and GLT-1 expression; (3) early microglia activation; and (4) attenuation of astrogliosis. Discussion: Steroid receptor coactivator stimulation with MCB-10-1 is a potential therapeutic strategy for reducing inflammation and oxidative damage that cause neurologic impairment following an acute ischemic stroke.

Original languageEnglish (US)
Article number1055295
JournalFrontiers in Molecular Neuroscience
Volume15
DOIs
StatePublished - Dec 1 2022

Keywords

  • astrocytes
  • cerebral ischemia
  • inflammation
  • neuroprotection
  • oxidative stress
  • steroid receptor coactivator stimulation
  • transcriptional regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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