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A steroid receptor coactivator small molecule "stimulator" attenuates post-stroke ischemic brain injury.

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.

SUBMITTER: McClendon LK

PROVIDER: S-EPMC9751323 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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A steroid receptor coactivator small molecule "stimulator" attenuates post-stroke ischemic brain injury.

McClendon Lisa K LK Garcia Roberto L RL Lazaro Tyler T Robledo Ariadna A Vasandani Viren V Luna Zean Aaron Evan ZAE Rao Abhijit S AS Srivatsan Aditya A Lonard David M DM Dacso Clifford C CC Kan Peter P O'Malley Bert W BW

Frontiers in molecular neuroscience 20221201

<b>Introduction:</b> 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 ...[more]

PMID: 36533127

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Project description:The complication of type 2 diabetes (T2D) exacerbates brain infarction in acute ischemic stroke (AIS). Because butyrate-producing bacteria are decreased in T2D and butyrate has been reported to be associated with attenuated brain injury in AIS, we hypothesize that administering butyrate could ameliorate T2D-associated exacerbation of brain infarction in AIS. Therefore, we first validated that Chinese AIS patients with T2D comorbidity have significantly lower levels of fecal butyrate-producing bacteria and butyrate than AIS patients without T2D. Then, we performed a 4-week intervention in T2D mice receiving either sodium butyrate (SB) or sodium chloride (NaCl) and found that SB improved the diabetic phenotype, altered the gut microbiota, and ameliorated brain injury after stroke. Fecal samples were collected from T2D mice after SB or NaCl treatment and were transplanted into antibiotic-treated C57BL/6 mice. After 2 weeks of transplantation, the gut microbiota profile and butyrate level of recipient mice were tested, and then the recipient mice were subjected to ischemic stroke. Stroke mice that received gut microbiota from SB-treated mice had a smaller cerebral infarct volume than mice that received gut microbiota from NaCl-treated mice. This protection was also associated with improvements in gut barrier function, reduced serum levels of lipopolysaccharide (LPS), LPS binding protein (LBP), and proinflammatory cytokines, and improvements in the blood-brain barrier. IMPORTANCE Ischemic stroke is a major global health burden, and T2D is a well-known comorbidity that aggravates brain injury after ischemic stroke. However, the underlying mechanism by which T2D exacerbates stroke injury has not been completely elucidated. A large amount of evidence suggests that the gut microbiota composition affects stroke outcomes. Our results showed that the gut microbiota of T2D aggravated brain injury after ischemic stroke and could be modified by SB to afford neuroprotection against stroke injury. These findings suggest that supplementation with SB is a potential therapeutic strategy for T2D patients with ischemic stroke.

Project description:Background Myocardial injury post-stroke is a common sequela of acute stroke. Triglyceride-glucose index (TyG index), a valuable surrogate indicator of insulin resistance, has been suggested to be closely related to cardiovascular outcomes. However, it is unknown whether the TyG index is independently associated with a higher risk of myocardial injury post-stroke. We therefore investigated the longitudinal association between TyG index and risk of myocardial injury post-stroke in older patients with first-ever ischemic stroke and no prior cardiovascular comorbidities. Methods We included older patients with first-ever ischemic stroke and no prior cardiovascular comorbidities between January 2021 to December 2021. The individuals were stratified into low and high TyG index groups according to the optimal cutoff value with TyG index. We performed logistic regression analysis, propensity score matching (PSM) analysis, restricted cubic spline analysis, and subgroup analyses to explore the longitudinal association between TyG index and risk of myocardial injury post-stroke. Results We included 386 individuals with a median age of 69.8 years (interquartile range: 66.6, 75.3). The optimal TyG index cut-off for predicting myocardial injury post-stroke was 8.9 (sensitivity 67.8%; specificity 75.5%; area under curve 0.701). Multivariate logistic regression analysis revealed that the risk of genesis of myocardial injury post-stroke increased with elevated TyG index (odds ratio [OR], 2.333; 95% confidence interval [CI], 1.201–4.585; P = 0.013). Furthermore, all covariates were well balanced between the two groups. The longitudinal association between TyG index and myocardial injury post-stroke remained significantly robust (OR: 2.196; 95% CI: 1.416–3.478; P < 0.001) after PSM adjustment. Conclusion Individuals with an elevated TyG index were more susceptible to having an increased risk of myocardial injury post-stroke. TyG index thus might be served as a complementary approach for optimized-for-risk stratification in older patients with first-ever ischemic stroke and no prior cardiovascular comorbidities. Supplementary Information The online version contains supplementary material available at 10.1186/s12877-023-04041-7.

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A steroid receptor coactivator small molecule "stimulator" attenuates post-stroke ischemic brain injury.

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A steroid receptor coactivator small molecule "stimulator" attenuates post-stroke ischemic brain injury.

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