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Glibenclamide is superior to decompressive craniectomy in a rat model of malignant stroke.

ABSTRACT: Treating patients with malignant cerebral infarctions remains a major unsolved problem in medicine. Decompressive craniectomy (DC) improves the bleak outlook but is suboptimal. Using a rat model of severe ischemia/reperfusion with very high mortality due to malignant cerebral edema, we tested the hypothesis that blocking of sulfonylurea receptor 1-regulated NC(Ca-ATP) channels with glibenclamide would compare favorably to DC when reperfusion and treatment were begun 6 hours after onset of ischemia.Male Wistar rats underwent filament occlusion of the middle cerebral artery to reduce laser Doppler flowmetry perfusion signals by >75%, with filament removal plus treatment 6 hours later. In rats treated with vehicle versus glibenclamide (10 microg/kg IP plus 200 ng/h SC), we compared mortality, neurologic function, and brain swelling at 24 hours. In rats treated with DC versus glibenclamide, we compared neurologic function for 2 weeks and histologic outcomes.Compared with vehicle, glibenclamide treatment reduced 24-hour mortality from 67% to 5% and reduced hemispheric swelling at 24 hours from 21% to 8%. DC eliminated 24-hour mortality, but neurologic function during the next 2 weeks was significantly better with glibenclamide compared with DC. Watershed cortex and deep white matter were significantly better preserved with glibenclamide compared with DC.In a rat model of severe ischemia/reperfusion, with reperfusion and treatment beginning 6 hours after onset of ischemia, glibenclamide is as effective as DC in preventing death from malignant cerebral edema but is superior to DC in preserving neurologic function and the integrity of watershed cortex and deep white matter.

SUBMITTER: Simard JM

PROVIDER: S-EPMC2845311 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Glibenclamide is superior to decompressive craniectomy in a rat model of malignant stroke.

Simard J Marc JM Tsymbalyuk Natalia N Tsymbalyuk Orest O Ivanova Svetlana S Yurovsky Vladimir V Gerzanich Volodymyr V

Stroke 20100121 3

<h4>Background and purpose</h4>Treating patients with malignant cerebral infarctions remains a major unsolved problem in medicine. Decompressive craniectomy (DC) improves the bleak outlook but is suboptimal. Using a rat model of severe ischemia/reperfusion with very high mortality due to malignant cerebral edema, we tested the hypothesis that blocking of sulfonylurea receptor 1-regulated NC(Ca-ATP) channels with glibenclamide would compare favorably to DC when reperfusion and treatment were begu ...[more]

PMID: 20093633

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Project description:Purpose: Signaling pathways mediated by microRNAs (miRNAs) represent one of the mechanisms that regulate stroke progression and recovery. The goal of this study is to investigate miRNA expression signatures in freshly removed human stroke brain tissue. Methods: Human brain samples (5 stroke and 3 non-stroke samples) obtained at 48-72 hours after stroke onset during craniectomy and stroke-ectomy, were subjected to histopathological and immunofluorescence microscopy analyses. NGS sequencing was performed by Qiagen company and analyses were carried out using QIAseq miRNA Quantification workflow and RNA-seq Analysis tools within CLC Genomics Workbench (version 20.0.2). Reads were normalized for expression analysis using trimmed mean of M-values method (TMM). miRNA profiling was performed using the EdgeR in Bioconductor package. Whole transcriptome RNA-sequencing Analysis: The unmapped reads from the NGS miRNA analysis were extracted, deduplicated and mapped to the genome. Gene expressions were calculated by counting number of reads mapping to the annotated gene loci. Human miR-155 Targets RT2 Profiler PCR Array (Qiagen) was performed using 3 RNA samples per stroke and control groups. The PCR Array Data analysis was performed using an automated PCR Analysis Web Portal and GeneGlobe Data Analysis (Qiagen). Results: Human stroke brain tissue was characterized by classic ischemic changes, including significant neuronal and vascular damage, and prominent edema. The absence of monocytes and notable neutrophil infiltration indicated the early stage of leukocyte response to ischemia. miRNA NGS analysis detected 36 miRNAs with significantly aberrant expression in stroke tissue, as compared to non-stroke samples. Of these miRNAs, 19 were previously identified in stroke patient blood and CSF, while dysregulation of 16 miRNAs was newly detected in this study. Bioinformatics pathway enrichment analysis demonstrated a strong association of the identified miRNAs with stroke-related biological processes and signaling pathways Conclusions: Dysregulated miRNAs detected in our study could be regarded as potential candidates for biomarkers and/or targets for therapeutic intervention. The obtained data will serve for better understanding of the molecular basis of stroke and provide valuable information for the future functional studies in the experimental models of stroke.

Project description:IntroductionThe optimal timing for decompressive hemicraniectomy (DHC) after intravenous thrombolysis (IVT) remains unclear. This study in patients with acute ischemic stroke treated with IVT aimed to assess the safety of DHC and patient outcome.MethodsData was extracted from the Tabriz stroke registry from June 2011 up to September 2020. In all, 881 patients were treated with IVT. Among these, 23 patients underwent DH. Six patients were excluded due to symptomatic intracranial hemorrhage (parenchymal hematoma type 2 based on SITS-MOST definition) after IVT, but other types of bleeding after venous thrombolysis, including HI1, HI2, and PH1 were not excluded; so the remaining 17 patients were enrolled in the study. Functional Outcome was defined as the proportion of patients who achieved mRS score of 2-3 (moderate disability), 4-5 (severe disability), or 6 (mortality) at 90 days after stroke. mRSwas assess by trained neurologist at the hospital clinic with direct interview Safety outcome was assessed by comparison of two scans just prior to and after craniectomy. Any new hemorrhage or worsening of previous hemorrhage was reported. Parenchymal hematoma type 2, based on ECASS II definition, was considered as major surgical complication. This study was approved by the local ethics committee of the Tabriz University of Medical Sciences (Ethics Code: IR.TBZMED.REC.1398.420).ResultsAt the three-month mRS follow up, six patients (35%) had moderate and five (29%) had severe disability. The outcome of death was observed in six patients (35%).Nine of 15 patients (60%) underwent surgery in the first 48 hours after onset of symptoms. No patient over 60 years of age survived to the three-month follow up; 67% of those who were under60 years and underwent DH in the first 48 hours had favorable outcome. Hemorrhagic complication was seen in 64% of patients but none was major.ConclusionResults of this study showed that the rate of major bleeding and outcome of acute ischemic stroke patients who underwent DHC after IVT is comparable with the reported data in the literature and intentionally waiting for the fibrinolytic effects of IVT to disappear may not outweigh the benefits of DHC. Although the findings of the study should be interpreted with caution and larger studies are needed to confirm the results.

Project description:IntroductionThis study aims to assess the quality of life (QoL) in patients who have undergone decompressive craniectomy (DC) for any pathology that has caused life-threatening intracranial hypertension. Similarly, it aims to evaluate QoL perceived by caregivers or external informants. In addition to that, the last purpose is to determine which clinical or therapeutic factors could correlate with a better QoL.MethodsA single-center cross-sectional study was designed. All patients over 18 years old who underwent a supratentorial DC at our department due to intracranial hypertension of any etiology, from January 2015 to December 2021, were retrospectively selected. Patients with incomplete follow-up (under 1 year from the event or those who died) or who declined to participate in the study were excluded. QoL was assessed with SF-36 and CAVIDACE scales. The correlation between clinical and therapeutic variables and SF-36 subscales was studied with Spearman's correlation and the Mann-Whitney U-test.ResultsA total of 55 consecutive patients were recruited: 22 patients had died, three were missed for follow-up, and 15 declined to participate, thus 15 subjects were finally included. The mean follow-up was 47 months (IQR 21.5-67.5). A significant reduction in the "role physical" and "role emotional" subscales of SF-36 was observed compared with the general population. According to caregivers, a significant reduction was assigned to the "physical wellbeing" and "rights" domains. The "physical functioning" score was poorer in women, older patients, those with dominant hemisphere disease, those who required tracheostomy, and those with poor outcomes in the modified Rankin scale. A strong correlation was found between the QoL index at the CAVIDACE scale and the SF-36 subscales "physical functioning" and "role physical".ConclusionMost patients and caregivers reported acceptable QoL after DC due to a life-threatening disease. A significant reduction in SF- 36 subscales scores "role limitation due to physical problems" and "role limitation due to emotional problems" was referred by patients. According to caregivers' QoL perception, only 25% of the survey's participants showed low scores in the QoL index of the CAVIDACE scale. Only 26.7% of the patients showed mood disorders.

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Glibenclamide is superior to decompressive craniectomy in a rat model of malignant stroke.

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Glibenclamide is superior to decompressive craniectomy in a rat model of malignant stroke.

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