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17?-Estradiol attenuates hematoma expansion through estrogen receptor ?/silent information regulator 1/nuclear factor-kappa b pathway in hyperglycemic intracerebral hemorrhage mice.

ABSTRACT: 17?-estradiol (E2) has been reported to reduce bleeding and brain injury in experimental intracerebral hemorrhage (ICH) model. However, it is not clear if E2 can prevent early hematoma expansion (HE) induced by hyperglycemia in acute ICH. The aim of this study is to evaluate the effects of E2 on HE and its potential mechanisms in hyperglycemic ICH mice.Two hundred, 8-week-old male CD1 mice were used. ICH was performed by collagenase injection. 50% dextrose (8 mL/kg) was injected intraperitoneally 3 hours after ICH to induce acute HE (normal saline was used as control). The time course of HE was measured 6, 24, and 72 hours after ICH. Two dosages (100 and 300 ?g/kg) of E2 were administrated 1 hour after ICH intraperitoneally. Neurobehavioral deficits, hemorrhage volume, blood glucose level, and blood-brain barrier disruption were measured. To study the mechanisms of E2, estrogen receptor ? (ER?) inhibitor methyl-piperidino-pyrazole, silent information regulator 1 (Sirt1) siRNA was administered, respectively. Protein expression of ER?, Sirt1, and acetylated nuclear factor-kappa B, and activity of matrix metalloproteinases-9 were detected.Hyperglycemia enhanced HE and deteriorated neurological deficits after ICH from 6 hours after ICH. E2 treatment prevented blood-brain barrier disruption and improved neurological deficits 24 and 72 hours after ICH. E2 reduced HE by activating its receptor ER?, decreasing the expression of Sirt1, deacelylation of nuclear factor-kappa B, and inhibiting the activity of matrix metalloproteinases-9. ER? inhibitor methyl-piperidino-pyrazole and Sirt1 siRNA removed these effects of E2.E2 treatment prevented hyperglycemia-enhanced HE and improved neurological deficits in ICH mice mediated by ER?/Sirt1/nuclear factor-kappa B pathway. E2 may serve as an alternative treatment to decrease early HE after ICH.

SUBMITTER: Zheng Y

PROVIDER: S-EPMC4308513 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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17β-Estradiol attenuates hematoma expansion through estrogen receptor α/silent information regulator 1/nuclear factor-kappa b pathway in hyperglycemic intracerebral hemorrhage mice.

Zheng Yun Y Hu Qin Q Manaenko Anatol A Zhang Yang Y Peng Yan Y Xu Liang L Tang Junjia J Tang Jiping J Zhang John H JH

Stroke 20141218 2

<h4>Background and purpose</h4>17β-estradiol (E2) has been reported to reduce bleeding and brain injury in experimental intracerebral hemorrhage (ICH) model. However, it is not clear if E2 can prevent early hematoma expansion (HE) induced by hyperglycemia in acute ICH. The aim of this study is to evaluate the effects of E2 on HE and its potential mechanisms in hyperglycemic ICH mice.<h4>Methods</h4>Two hundred, 8-week-old male CD1 mice were used. ICH was performed by collagenase injection. 50% d ...[more]

PMID: 25523052

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Project description:BACKGROUND:Hematoma expansion (HE) after intracerebral hemorrhage (ICH) is associated with worse outcome. Lobar ICHs are known to have better outcomes compared to deep ICH; however, it is unclear whether there are HE differences between these locations. We sought to investigate the hypothesis that lobar ICH has less HE compared to deep ICH. METHODS:Primary ICH patients admitted between 2009 and 2016 were included in a prospective single-center ICH cohort study. Patients with preceding anticoagulant use, coagulopathy on admission labs, or presenting after 24?h from symptom onset were excluded. Lobar and deep ICH patients with baseline and follow-up computed tomography (CT) (within 24?h of admission CT) were evaluated. HE was defined primarily as relative growth >?33% given expected baseline hematoma volume differences between locations. Other commonly utilized definitions of HE: >?6 mL, and >?33% or >?6 mL, were additionally assessed. Multivariable logistic regression was used to assess the association of ICH location with HE while adjusting for previously identified covariates of HE. RESULTS:There were 59 lobar and 143 deep ICH patients analyzed. Lobar ICH patients had significantly larger baseline hematoma volumes, lower admission systolic blood pressure, and longer times to admission CT compared to deep ICH. Multivariable logistic regression revealed an association of lobar ICH with lower odds of HE (>?33%) [odds ratio (OR) 0.32; 95% confidence interval (CI) 0.11-0.93; p?=?0.04] compared to deep ICH after adjusting for baseline ICH volume, blood pressure, and time to CT. Secondary analysis did not identify an association of lobar ICH with HE defined as >?6 mL (adjusted OR 1.44; 95% CI 0.59-3.50; p?=?0.41) or >?33% or >?6 mL (adjusted OR 0.71; 95% CI 0.29-1.70; p?=?0.44). CONCLUSION:We identified less HE in lobar compared to deep ICH. The use of absolute growth thresholds in defining HE may be limited when assessing groups with largely different baseline hematoma sizes. Further study is required to replicate our findings and investigate mechanisms for HE differences between lobar and deep ICH locations.

Project description:Background and objectiveThe aim of this study was to evaluate the impact of radiographic cerebral small vessel disease (CSVD) on the severity of acute intracerebral hemorrhage (ICH) as measured by: ICH volume, hematoma expansion, and extension of intraventricular hemorrhage (IVH).MethodsCSVD was determined on baseline computed tomography (CT) scans of patients from the Ethnic and Racial Variations of Intracerebral Hemorrhage study through the extent of leukoaraiosis and cerebral atrophy using visual rating scales. The associations of leukoaraiosis and atrophy with ICH volume, hematoma expansion, IVH presence, and severity of IVH were tested using multivariable regression models. Secondary analyses were stratified by hemorrhage location. Bonferroni correction was applied to correct for multiple testing.ResultsA total of 2579 patients (mean age 61.7 years, 59% male) met inclusion criteria. Median ICH volume was 10.5 (Interquartile range [IQR] 4.0-25.3) mL. IVH was detected in 971 patients (38%). Neither leukoaraiosis nor atrophy was associated with hematoma expansion. Increasing grades of leukoaraiosis were associated with increased risk of IVH in a dose-dependent manner, while cerebral atrophy was inversely associated with IVH (both P for trend < 0.001). Increasing grades of global atrophy were dose-dependently associated with lower ICH volumes (ß (95% Confidence Interval [CI]) - 0.30[- 0.46, - 0.14], - 0.33[- 0.49, - 0.17], - 0.40[- 0.60, - 0.20], and - 0.54[- 0.76, - 0.32], for grades 1, 2, 3 and 4 compared to 0; all P < 0.001). The associations of leukoaraiosis with ICH volume were consistent with those of atrophy, albeit not meeting statistical significance.ConclusionsLeukoaraiosis and cerebral atrophy appear to have opposing associations with ICH severity. Cerebral atrophy correlates with smaller ICH volume and decreased risk and severity of IVH, while leukoaraiosis is associated with increased risk of IVH. Whether these observations reflect overlapping or divergent underlying mechanisms requires further study.

Dataset Information

17?-Estradiol attenuates hematoma expansion through estrogen receptor ?/silent information regulator 1/nuclear factor-kappa b pathway in hyperglycemic intracerebral hemorrhage mice.

Publications

17β-Estradiol attenuates hematoma expansion through estrogen receptor α/silent information regulator 1/nuclear factor-kappa b pathway in hyperglycemic intracerebral hemorrhage mice.

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