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Myeloid-specific deletion of the mineralocorticoid receptor reduces infarct volume and alters inflammation during cerebral ischemia.

ABSTRACT: mineralocorticoid receptor (MR) antagonists have protective effects in rodent models of ischemic stroke, but the cell type-specific actions of these drugs are unknown. In the present study, we examined the contribution of myeloid cell MR during focal cerebral ischemia using myeloid-specific MR knockout mice.myeloid-specific MR knockout mice were subjected to transient (90 minutes) middle cerebral artery occlusion followed by 24 hours reperfusion (n=5 to 7 per group). Ischemic cerebral infarcts were identified by hematoxylin and eosin staining and quantified with image analysis software. Immunohistochemical localization of microglia and macrophages was performed using Iba1 staining, and the expression of inflammatory markers was measured after 24 hours of reperfusion by quantitative reverse transcription-polymerase chain reaction.myeloid-specific MR knockout resulted in a 65% reduction in infarct volume (P=0.005) after middle cerebral artery occlusion. This was accompanied by a significant reduction in activated microglia and macrophages in the ischemic core. Furthermore, myeloid-specific MR knockout suppressed classically activated M1 macrophage markers tumor necrosis factor-?, interleukin-1?, monocyte chemoattractant protein-1, macrophage inflammatory protein-1?, and interleukin-6 at the same time as partially preserving the induction of alternatively activated, M2, markers Arg1, and Ym1.these data demonstrate that myeloid MR activation exacerbates stroke and identify myeloid MR as a critical target for MR antagonists. Furthermore, these data indicate that MR activation has an important role in controlling immune cell function during the inflammatory response to stroke.

SUBMITTER: Frieler RA

PROVIDER: S-EPMC3042719 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Myeloid-specific deletion of the mineralocorticoid receptor reduces infarct volume and alters inflammation during cerebral ischemia.

Frieler Ryan A RA Meng He H Duan Sheng Zhong SZ Berger Stefan S Schütz Günther G He Yangdong Y Xi Guohua G Wang Michael M MM Mortensen Richard M RM

Stroke 20101124 1

<h4>Background and purpose</h4>mineralocorticoid receptor (MR) antagonists have protective effects in rodent models of ischemic stroke, but the cell type-specific actions of these drugs are unknown. In the present study, we examined the contribution of myeloid cell MR during focal cerebral ischemia using myeloid-specific MR knockout mice.<h4>Methods</h4>myeloid-specific MR knockout mice were subjected to transient (90 minutes) middle cerebral artery occlusion followed by 24 hours reperfusion (n= ...[more]

PMID: 21106954

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Project description:Patients who have large cerebral infarctions may not be good candidates for endovascular treatment. Various methods for determining infarct volume have been used in clinical studies. We evaluated the effectiveness of several methods for measuring infarct volume, especially regarding futile outcomes despite endovascular treatment.Patients with acute ischemic stroke in unilateral anterior circulation territory who were treated with intra-arterial thrombectomy were included. For assessing infarct volume, the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) scoring system was applied to images obtained by noncontrast computed tomography (NCCT), postcontrast CT (PCCT), and diffusion-weighted imaging (DWI). DWI stroke volume was semiquantitatively measured with the manually outlined hyperintense lesion. Infarct core volume was calculated with a threshold apparent diffusion coefficient value of 600?×?10?mm/s. Intraclass correlation coefficients (ICC) were estimated to assess inter-reader reliability for ASPECTS scoring and DWI stroke volume. Receiver operating characteristic (ROC) curve analyses, and univariable and multivariable comparative analyses, were performed with each evaluation method to predict futile outcome (modified Rankin Scale score 5-6).The mean age of the included 79 patients was 65.1?±?15.7 years. Among them, 55 (69.6%) patients demonstrated successful reperfusion after intra-arterial thrombectomy, but 34 (43.0%) patients had futile outcomes. Inter-reader agreement was excellent for measurement of the DWI stroke volume (ICC, 0.973), DWI ASPECTS (0.940), and PCCT ASPECTS (0.859), but was moderate for NCCT ASPECTS (0.694). Regarding prediction of futile outcomes, area under ROC curve was 0.551 on NCCT ASPECTS and it was significantly smaller than that in PCCT ASPECTS (area under ROC 0.651, P?=?0.030), DWI ASPECTS (0.733, P?=?0.003), DWI stroke volume (0.702, P?=?0.022), and infarct core volume (0.702, P?=?0.021). Besides old age and high National Institutes of Health Stroke Scale score on admission, MRI parameters such as DWI ASPECTS and infarct core volume indicating large volumes were independently associated with futile outcomes in multivariable analyses.DWI ASPECTS can be a good parameter predicting futility, which is easily measured and has high prediction power.

Project description:ObjectiveWe investigated (1) the associations of pre-stroke aspirin use with thrombus burden, infarct volume, hemorrhagic transformation, early neurological deterioration (END), and functional outcome, and (2) whether stroke subtypes modify these associations in first-ever ischemic stroke.MethodsThis multicenter magnetic resonance imaging (MRI)-based study included 5,700 consecutive patients with acute first-ever ischemic stroke, who did not undergo intravenous thrombolysis or endovascular thrombectomy, from May 2011 through February 2014. Propensity score-based augmented inverse probability weighting was performed to estimate adjusted effects of pre-stroke aspirin use.ResultsThe mean age was 67 years (41% women), and 15.9% (n = 907) were taking aspirin before stroke. Pre-stroke aspirin use (vs nonuse) was significantly related to a reduced infarct volume (by 30%), particularly in large artery atherosclerosis stroke (by 45%). In cardioembolic stroke, pre-stroke aspirin use was associated with a ~50% lower incidence of END (adjusted difference = -5.4%, 95% confidence interval [CI] = -8.9 to -1.9). Thus, pre-stroke aspirin use was associated with ~30% higher likelihood of favorable outcome (3-month modified Rankin Scale score < 3), particularly in large artery atherosclerosis stroke and cardioembolic stroke (adjusted difference = 7.2%, 95% CI = 1.8 to 12.5 and adjusted difference = 6.4%, 95% CI = 1.7 to 11.1, respectively). Pre-stroke aspirin use (vs nonuse) was associated with 85% less frequent cerebral thrombus-related susceptibility vessel sign (SVS) in large artery atherosclerosis stroke (adjusted difference = -1.4%, 95% CI = -2.1 to -0.8, p < 0.001) and was associated with ~40% lower SVS volumes, particularly in cardioembolic stroke (adjusted difference = -0.16 cm3 , 95% CI = -0.29 to -0.02, p = 0.03). Moreover, pre-stroke aspirin use was not significantly associated with hemorrhagic transformation (adjusted difference = -1.1%, p = 0.09).InterpretationPre-stroke aspirin use associates with improved functional independence in patients with first-ever ischemic large arterial stroke by reducing infarct volume and/or END, likely by decreasing thrombus burden, without increased risk of hemorrhagic transformation. ANN NEUROL 2021;90:763-776.

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Myeloid-specific deletion of the mineralocorticoid receptor reduces infarct volume and alters inflammation during cerebral ischemia.

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Myeloid-specific deletion of the mineralocorticoid receptor reduces infarct volume and alters inflammation during cerebral ischemia.

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