Pub Date : 2024-06-01Epub Date: 2023-02-27DOI: 10.1007/s12975-023-01142-8
Jian Chen, Cheng-Gang Li, Li-Xuan Yang, Yi Qian, Li-Wen Zhu, Pin-Yi Liu, Xiang Cao, Ye Wang, Min-Sheng Zhu, Yun Xu
Cerebral small vessel disease (CSVD) is the most common progressive vascular disease that causes vascular dementia. Aging and hypertension are major contributors to CSVD, but the pathophysiological mechanism remains unclear, mainly due to the lack of an ideal animal model. Our previous study revealed that vascular smooth muscle cell (VSMC)-specific myosin phosphatase target subunit 1 (MYPT1) knockout (MYPT1SMKO) leads to constant hypertension, prompting us to explore whether hypertensive MYPT1SMKO mice can be considered a novel CSVD animal model. Here, we found that MYPT1SMKO mice displayed age-dependent CSVD-like neurobehaviors, including decreased motion speed, anxiety, and cognitive decline. MYPT1SMKO mice exhibited remarkable white matter injury compared with control mice, as shown by the more prominent loss of myelin at 12 months of age. Additionally, MYPT1SMKO mice were found to exhibit CSVD-like small vessel impairment, including intravascular hyalinization, perivascular space enlargement, and microbleed and blood-brain barrier (BBB) disruption. Last, our results revealed that the brain of MYPT1SMKO mice was characterized by an exacerbated inflammatory microenvironment, which is similar to patients with CSVD. In light of the above structural and functional phenotypes that closely mimic the conditions of human CSVD, we suggest that MYPT1SMKO mice are a novel age- and hypertension-dependent animal model of CSVD.
{"title":"MYPT1<sup>SMKO</sup> Mice Function as a Novel Spontaneous Age- and Hypertension-Dependent Animal Model of CSVD.","authors":"Jian Chen, Cheng-Gang Li, Li-Xuan Yang, Yi Qian, Li-Wen Zhu, Pin-Yi Liu, Xiang Cao, Ye Wang, Min-Sheng Zhu, Yun Xu","doi":"10.1007/s12975-023-01142-8","DOIUrl":"10.1007/s12975-023-01142-8","url":null,"abstract":"<p><p>Cerebral small vessel disease (CSVD) is the most common progressive vascular disease that causes vascular dementia. Aging and hypertension are major contributors to CSVD, but the pathophysiological mechanism remains unclear, mainly due to the lack of an ideal animal model. Our previous study revealed that vascular smooth muscle cell (VSMC)-specific myosin phosphatase target subunit 1 (MYPT1) knockout (MYPT1<sup>SMKO</sup>) leads to constant hypertension, prompting us to explore whether hypertensive MYPT1<sup>SMKO</sup> mice can be considered a novel CSVD animal model. Here, we found that MYPT1<sup>SMKO</sup> mice displayed age-dependent CSVD-like neurobehaviors, including decreased motion speed, anxiety, and cognitive decline. MYPT1<sup>SMKO</sup> mice exhibited remarkable white matter injury compared with control mice, as shown by the more prominent loss of myelin at 12 months of age. Additionally, MYPT1<sup>SMKO</sup> mice were found to exhibit CSVD-like small vessel impairment, including intravascular hyalinization, perivascular space enlargement, and microbleed and blood-brain barrier (BBB) disruption. Last, our results revealed that the brain of MYPT1<sup>SMKO</sup> mice was characterized by an exacerbated inflammatory microenvironment, which is similar to patients with CSVD. In light of the above structural and functional phenotypes that closely mimic the conditions of human CSVD, we suggest that MYPT1<sup>SMKO</sup> mice are a novel age- and hypertension-dependent animal model of CSVD.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10780693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Intracerebral hemorrhage (ICH) is a severe cerebrovascular disease, which impairs patients' white matter even after timely clinical interventions. Indicated by studies in the past decade, ICH-induced white matter injury (WMI) is closely related to neurological deficits; however, its underlying mechanism and pertinent treatment are yet insufficient. We gathered two datasets (GSE24265 and GSE125512), and by taking an intersection among interesting genes identified by weighted gene co-expression networks analysis, we determined target genes after differentially expressing genes in two datasets. Additional single-cell RNA-seq analysis (GSE167593) helped locate the gene in cell types. Furthermore, we established ICH mice models induced by autologous blood or collagenase. Basic medical experiments and diffusion tensor imaging were applied to verify the function of target genes in WMI after ICH. Through intersection and enrichment analysis, gene SLC45A3 was identified as the target one, which plays a key role in the regulation of oligodendrocyte differentiation involving in fatty acid metabolic process, etc. after ICH, and single-cell RNA-seq analysis also shows that it mainly locates in oligodendrocytes. Further experiments verified overexpression of SLC45A3 ameliorated brain injury after ICH. Therefore, SLC45A3 might serve as a candidate therapeutic biomarker for ICH-induced WMI, and overexpression of it may be a potential approach for injury attenuation.
脑出血(ICH)是一种严重的脑血管疾病,即使经过及时的临床干预,患者的脑白质仍会受损。近十年来的研究表明,ICH 引起的脑白质损伤(WMI)与神经功能缺损密切相关,但其潜在机制和相关治疗方法尚不充分。我们收集了两个数据集(GSE24265 和 GSE125512),通过加权基因共表达网络分析发现的有趣基因之间的交集,确定了两个数据集中差异表达基因后的靶基因。额外的单细胞 RNA-seq分析(GSE167593)帮助我们确定了该基因在细胞类型中的位置。此外,我们还建立了由自体血或胶原酶诱导的 ICH 小鼠模型。应用基础医学实验和弥散张量成像来验证目标基因在 ICH 后 WMI 中的功能。通过交叉和富集分析,SLC45A3基因被确定为靶基因,该基因在ICH后少突胶质细胞分化调控中起关键作用,参与脂肪酸代谢过程等,单细胞RNA-seq分析也表明该基因主要定位于少突胶质细胞。进一步的实验证实,过表达 SLC45A3 可改善 ICH 后的脑损伤。因此,SLC45A3 可作为 ICH 诱导的 WMI 的候选治疗生物标志物,而过表达它可能是减轻损伤的一种潜在方法。
{"title":"SLC45A3 Serves as a Potential Therapeutic Biomarker to Attenuate White Matter Injury After Intracerebral Hemorrhage.","authors":"Yi Zhang, Hanhai Zeng, Feiyang Lou, Xiaoxiao Tan, Xiaotong Zhang, Gao Chen","doi":"10.1007/s12975-023-01145-5","DOIUrl":"10.1007/s12975-023-01145-5","url":null,"abstract":"<p><p>Intracerebral hemorrhage (ICH) is a severe cerebrovascular disease, which impairs patients' white matter even after timely clinical interventions. Indicated by studies in the past decade, ICH-induced white matter injury (WMI) is closely related to neurological deficits; however, its underlying mechanism and pertinent treatment are yet insufficient. We gathered two datasets (GSE24265 and GSE125512), and by taking an intersection among interesting genes identified by weighted gene co-expression networks analysis, we determined target genes after differentially expressing genes in two datasets. Additional single-cell RNA-seq analysis (GSE167593) helped locate the gene in cell types. Furthermore, we established ICH mice models induced by autologous blood or collagenase. Basic medical experiments and diffusion tensor imaging were applied to verify the function of target genes in WMI after ICH. Through intersection and enrichment analysis, gene SLC45A3 was identified as the target one, which plays a key role in the regulation of oligodendrocyte differentiation involving in fatty acid metabolic process, etc. after ICH, and single-cell RNA-seq analysis also shows that it mainly locates in oligodendrocytes. Further experiments verified overexpression of SLC45A3 ameliorated brain injury after ICH. Therefore, SLC45A3 might serve as a candidate therapeutic biomarker for ICH-induced WMI, and overexpression of it may be a potential approach for injury attenuation.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11106206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9099612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2023-06-06DOI: 10.1007/s12975-023-01154-4
Mangmang Xu, Yuyi Zhu, Xindi Song, Xuelian Zhong, Xinxin Yu, Deren Wang, Yajun Cheng, Wendan Tao, Bo Wu, Ming Liu
In intracerebral hemorrhage (ICH) with pathology-proven etiology, we performed a systematic review and meta-analysis to elucidate the association between cerebral amyloid angiopathy (CAA) and arteriolosclerosis, and directly compared MRI and pathological changes of markers of cerebral small vessel disease (CSVD). Studies enrolling primary ICH who had received an etiological diagnosis through biopsy or autopsy were searched using Ovid MEDLINE, PubMed, and Web of Science from inception to June 8, 2022. We extracted pathological changes of CSVD for each patient whenever available. Patients were grouped into CAA + arteriolosclerosis, strict CAA, and strict arteriolosclerosis subgroups. Of 4155 studies identified, 28 studies with 456 ICH patients were included. The frequency of lobar ICH (p<0.001) and total microbleed number (p=0.015) differed among patients with CAA + arteriolosclerosis, strict CAA, and strict arteriolosclerosis. Concerning pathology, severe CAA was associated with arteriolosclerosis (OR 6.067, 95% CI 1.107-33.238, p=0.038), although this association was not statistically significant after adjusting for age and sex. Additionally, the total microbleed number (median 15 vs. 0, p=0.006) was higher in ICH patients with CAA evidence than those without CAA. The pathology of CSVD imaging markers was mostly investigated in CAA-ICH. There was inconsistency concerning CAA severity surrounding microbleeds. Small diffusion-weighted imaging lesions could be matched to acute microinfarct histopathologically. Studies that directly correlated MRI and pathology of lacunes, enlarged perivascular spaces, and atrophy were scarce. Arteriolosclerosis might be associated with severe CAA. The pathological changes of CSVD markers by ICH etiology are needed to be investigated further.
我们对病理确诊的脑出血(ICH)进行了系统回顾和荟萃分析,以阐明脑淀粉样血管病(CAA)与动脉硬化之间的关联,并直接比较了脑小血管病(CSVD)标记物的磁共振成像和病理变化。我们使用 Ovid MEDLINE、PubMed 和 Web of Science 检索了从开始到 2022 年 6 月 8 日期间纳入通过活检或尸检获得病因诊断的原发性 ICH 的研究。我们提取了每位患者 CSVD 的病理变化。患者被分为CAA+动脉硬化、严格CAA和严格动脉硬化亚组。在已确定的 4155 项研究中,有 28 项研究共纳入了 456 名 ICH 患者。大叶 ICH 的频率(p
{"title":"Pathological Changes of Small Vessel Disease in Intracerebral Hemorrhage: a Systematic Review and Meta-analysis.","authors":"Mangmang Xu, Yuyi Zhu, Xindi Song, Xuelian Zhong, Xinxin Yu, Deren Wang, Yajun Cheng, Wendan Tao, Bo Wu, Ming Liu","doi":"10.1007/s12975-023-01154-4","DOIUrl":"10.1007/s12975-023-01154-4","url":null,"abstract":"<p><p>In intracerebral hemorrhage (ICH) with pathology-proven etiology, we performed a systematic review and meta-analysis to elucidate the association between cerebral amyloid angiopathy (CAA) and arteriolosclerosis, and directly compared MRI and pathological changes of markers of cerebral small vessel disease (CSVD). Studies enrolling primary ICH who had received an etiological diagnosis through biopsy or autopsy were searched using Ovid MEDLINE, PubMed, and Web of Science from inception to June 8, 2022. We extracted pathological changes of CSVD for each patient whenever available. Patients were grouped into CAA + arteriolosclerosis, strict CAA, and strict arteriolosclerosis subgroups. Of 4155 studies identified, 28 studies with 456 ICH patients were included. The frequency of lobar ICH (p<0.001) and total microbleed number (p=0.015) differed among patients with CAA + arteriolosclerosis, strict CAA, and strict arteriolosclerosis. Concerning pathology, severe CAA was associated with arteriolosclerosis (OR 6.067, 95% CI 1.107-33.238, p=0.038), although this association was not statistically significant after adjusting for age and sex. Additionally, the total microbleed number (median 15 vs. 0, p=0.006) was higher in ICH patients with CAA evidence than those without CAA. The pathology of CSVD imaging markers was mostly investigated in CAA-ICH. There was inconsistency concerning CAA severity surrounding microbleeds. Small diffusion-weighted imaging lesions could be matched to acute microinfarct histopathologically. Studies that directly correlated MRI and pathology of lacunes, enlarged perivascular spaces, and atrophy were scarce. Arteriolosclerosis might be associated with severe CAA. The pathological changes of CSVD markers by ICH etiology are needed to be investigated further.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11106194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9576826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2023-03-10DOI: 10.1007/s12975-023-01146-4
Xueyan Feng, Hui Fang, Bonaventure Y M Ip, Ka Lung Chan, Shuang Li, Xuan Tian, Lina Zheng, Yuying Liu, Linfang Lan, Haipeng Liu, Jill Abrigo, Sze Ho Ma, Florence S Y Fan, Vincent H L Ip, Yannie O Y Soo, Vincent C T Mok, Bo Song, Thomas W Leung, Yuming Xu, Xinyi Leng
Artery-to-artery embolism (AAE) is a common stroke mechanism in intracranial atherosclerotic disease (ICAD), associated with a considerable risk of recurrent stroke. We aimed to investigate cerebral hemodynamic features associated with AAE in symptomatic ICAD. Patients with anterior-circulation, symptomatic ICAD confirmed in CT angiography (CTA) were recruited. We classified probable stroke mechanisms as isolated parent artery atherosclerosis occluding penetrating artery, AAE, hypoperfusion, and mixed mechanisms, largely based on infarct topography. CTA-based computational fluid dynamics (CFD) models were built to simulate blood flow across culprit ICAD lesions. Translesional pressure ratio (PR = Pressurepost-stenotic/Pressurepre-stenotic) and wall shear stress ratio (WSSR = WSSstenotic-throat/WSSpre-stenotic) were calculated, to reflect the relative, translesional changes of the two hemodynamic metrics. Low PR (PR ≤ median) and high WSSR (WSSR ≥ 4th quartile) respectively indicated large translesional pressure and elevated WSS upon the lesion. Among 99 symptomatic ICAD patients, 44 had AAE as a probable stroke mechanism, 13 with AAE alone and 31 with coexisting hypoperfusion. High WSSR was independently associated with AAE (adjusted OR = 3.90; P = 0.022) in multivariate logistic regression. There was significant WSSR-PR interaction on the presence of AAE (P for interaction = 0.013): high WSSR was more likely to associate with AAE in those with low PR (P = 0.075), but not in those with normal PR (P = 0.959). Excessively elevated WSS in ICAD might increase the risk of AAE. Such association was more prominent in those with large translesional pressure gradient. Hypoperfusion, commonly coexisting with AAE, might be a therapeutic indicator for secondary stroke prevention in symptomatic ICAD with AAE.
{"title":"Cerebral Hemodynamics Underlying Artery-to-Artery Embolism in Symptomatic Intracranial Atherosclerotic Disease.","authors":"Xueyan Feng, Hui Fang, Bonaventure Y M Ip, Ka Lung Chan, Shuang Li, Xuan Tian, Lina Zheng, Yuying Liu, Linfang Lan, Haipeng Liu, Jill Abrigo, Sze Ho Ma, Florence S Y Fan, Vincent H L Ip, Yannie O Y Soo, Vincent C T Mok, Bo Song, Thomas W Leung, Yuming Xu, Xinyi Leng","doi":"10.1007/s12975-023-01146-4","DOIUrl":"10.1007/s12975-023-01146-4","url":null,"abstract":"<p><p>Artery-to-artery embolism (AAE) is a common stroke mechanism in intracranial atherosclerotic disease (ICAD), associated with a considerable risk of recurrent stroke. We aimed to investigate cerebral hemodynamic features associated with AAE in symptomatic ICAD. Patients with anterior-circulation, symptomatic ICAD confirmed in CT angiography (CTA) were recruited. We classified probable stroke mechanisms as isolated parent artery atherosclerosis occluding penetrating artery, AAE, hypoperfusion, and mixed mechanisms, largely based on infarct topography. CTA-based computational fluid dynamics (CFD) models were built to simulate blood flow across culprit ICAD lesions. Translesional pressure ratio (PR = Pressure<sub>post-stenotic</sub>/Pressure<sub>pre-stenotic</sub>) and wall shear stress ratio (WSSR = WSS<sub>stenotic-throat</sub>/WSS<sub>pre-stenotic</sub>) were calculated, to reflect the relative, translesional changes of the two hemodynamic metrics. Low PR (PR ≤ median) and high WSSR (WSSR ≥ 4th quartile) respectively indicated large translesional pressure and elevated WSS upon the lesion. Among 99 symptomatic ICAD patients, 44 had AAE as a probable stroke mechanism, 13 with AAE alone and 31 with coexisting hypoperfusion. High WSSR was independently associated with AAE (adjusted OR = 3.90; P = 0.022) in multivariate logistic regression. There was significant WSSR-PR interaction on the presence of AAE (P for interaction = 0.013): high WSSR was more likely to associate with AAE in those with low PR (P = 0.075), but not in those with normal PR (P = 0.959). Excessively elevated WSS in ICAD might increase the risk of AAE. Such association was more prominent in those with large translesional pressure gradient. Hypoperfusion, commonly coexisting with AAE, might be a therapeutic indicator for secondary stroke prevention in symptomatic ICAD with AAE.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9090513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cerebral small vessel disease (CSVD) is a common disease that seriously endangers people's health, and is easily overlooked by both patients and clinicians due to its near-silent onset. Dynamic functional connectivity (DFC) is a new concept focusing on the dynamic features and patterns of brain networks that represents a powerful tool for gaining novel insight into neurological diseases. To assess alterations in DFC in CSVD patients, and the correlation of DFC with cognitive function. We enrolled 35 CSVD patients and 31 normal control subjects (NC). Resting-state functional MRI (rs-fMRI) with a sliding-window approach and k-means clustering based on independent component analysis (ICA) was used to evaluate DFC. The temporal properties of fractional windows and the mean dwell time in each state, as well as the number of transitions between each pair of DFC states, were calculated. Additionally, we assessed the functional connectivity (FC) strength of the dynamic states and the associations of altered neuroimaging measures with cognitive performance. A dynamic analysis of all included subjects suggested four distinct functional connectivity states. Compared with the NC group, the CSVD group had more fractional windows and longer mean dwell times in state 4 characterized by sparse FC both inter-network and intra-networks. Additionally, the CSVD group had a reduced number of windows and shorter mean dwell times compared to the NC group in state 3 characterized by highly positive FC between the somatomotor and visual networks, and negative FC in the basal ganglia and somatomotor and visual networks. The number of transitions between state 2 and state 3 and between state 3 and state 4 was significantly reduced in the CSVD group compared to the NC group. Moreover, there was a significant difference in the FC strength between the two groups, and the altered temporal properties of DFC were significantly related to cognitive performance. Our study indicated that CSVD is characterized by altered temporal properties in DFC that may be sensitive neuroimaging biomarkers for early disease identification. Further study of DFC alterations could help us to better understand the progressive dysfunction of networks in CSVD patients.
{"title":"Alterations in Dynamic Functional Connectivity in Patients with Cerebral Small Vessel Disease.","authors":"Futao Chen, Qian Chen, Yajing Zhu, Cong Long, Jiaming Lu, Yaoxian Jiang, Xin Zhang, Bing Zhang","doi":"10.1007/s12975-023-01148-2","DOIUrl":"10.1007/s12975-023-01148-2","url":null,"abstract":"<p><p>Cerebral small vessel disease (CSVD) is a common disease that seriously endangers people's health, and is easily overlooked by both patients and clinicians due to its near-silent onset. Dynamic functional connectivity (DFC) is a new concept focusing on the dynamic features and patterns of brain networks that represents a powerful tool for gaining novel insight into neurological diseases. To assess alterations in DFC in CSVD patients, and the correlation of DFC with cognitive function. We enrolled 35 CSVD patients and 31 normal control subjects (NC). Resting-state functional MRI (rs-fMRI) with a sliding-window approach and k-means clustering based on independent component analysis (ICA) was used to evaluate DFC. The temporal properties of fractional windows and the mean dwell time in each state, as well as the number of transitions between each pair of DFC states, were calculated. Additionally, we assessed the functional connectivity (FC) strength of the dynamic states and the associations of altered neuroimaging measures with cognitive performance. A dynamic analysis of all included subjects suggested four distinct functional connectivity states. Compared with the NC group, the CSVD group had more fractional windows and longer mean dwell times in state 4 characterized by sparse FC both inter-network and intra-networks. Additionally, the CSVD group had a reduced number of windows and shorter mean dwell times compared to the NC group in state 3 characterized by highly positive FC between the somatomotor and visual networks, and negative FC in the basal ganglia and somatomotor and visual networks. The number of transitions between state 2 and state 3 and between state 3 and state 4 was significantly reduced in the CSVD group compared to the NC group. Moreover, there was a significant difference in the FC strength between the two groups, and the altered temporal properties of DFC were significantly related to cognitive performance. Our study indicated that CSVD is characterized by altered temporal properties in DFC that may be sensitive neuroimaging biomarkers for early disease identification. Further study of DFC alterations could help us to better understand the progressive dysfunction of networks in CSVD patients.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11106163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9183987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2023-04-24DOI: 10.1007/s12975-023-01152-6
Ruth D Lee, Yi-Je Chen, Hai M Nguyen, Latika Singh, Connor J Dietrich, Benjamin R Pyles, Yanjun Cui, Jonathan R Weinstein, Heike Wulff
Senicapoc, a small molecule inhibitor of the calcium-activated potassium channel KCa3.1, was safe and well-tolerated in clinical trials for sickle cell anemia. We previously reported proof-of-concept data suggesting that both pharmacological inhibition and genetic deletion of KCa3.1 reduces infarction and improves neurologic recovery in rodents by attenuating neuroinflammation. Here we evaluated the potential of repurposing senicapoc for ischemic stroke. In cultured microglia, senicapoc inhibited KCa3.1 currents with an IC50 of 7 nM, reduced Ca2+ signaling induced by the purinergic agonist ATP, suppressed expression of pro-inflammatory cytokines and enzymes (iNOS and COX-2), and prevented induction of the inflammasome component NLRP3. When transient middle cerebral artery occlusion (tMCAO, 60 min) was induced in male C57BL/6 J mice, twice daily administration of senicapoc at 10 and 40 mg/kg starting 12 h after reperfusion dose-dependently reduced infarct area determined by T2-weighted magnetic resonance imaging (MRI) and improved neurological deficit on day 8. Ultra-high-performance liquid chromatography/mass spectrometry analysis of total and free brain concentrations demonstrated sufficient KCa3.1 target engagement. Senicapoc treatment significantly reduced microglia/macrophage and T cell infiltration and activation and attenuated neuronal death. A different treatment paradigm with senicapoc started at 3 h and MRI on day 3 and day 8 revealed that senicapoc reduces secondary infarct growth and suppresses expression of inflammation markers, including T cell cytokines in the brain. Lastly, we demonstrated that senicapoc does not impair the proteolytic activity of tissue plasminogen activator (tPA) in vitro. We suggest that senicapoc could be repurposed as an adjunctive immunocytoprotective agent for combination with reperfusion therapy for ischemic stroke.
{"title":"Repurposing the K<sub>Ca</sub>3.1 Blocker Senicapoc for Ischemic Stroke.","authors":"Ruth D Lee, Yi-Je Chen, Hai M Nguyen, Latika Singh, Connor J Dietrich, Benjamin R Pyles, Yanjun Cui, Jonathan R Weinstein, Heike Wulff","doi":"10.1007/s12975-023-01152-6","DOIUrl":"10.1007/s12975-023-01152-6","url":null,"abstract":"<p><p>Senicapoc, a small molecule inhibitor of the calcium-activated potassium channel KCa3.1, was safe and well-tolerated in clinical trials for sickle cell anemia. We previously reported proof-of-concept data suggesting that both pharmacological inhibition and genetic deletion of KCa3.1 reduces infarction and improves neurologic recovery in rodents by attenuating neuroinflammation. Here we evaluated the potential of repurposing senicapoc for ischemic stroke. In cultured microglia, senicapoc inhibited KCa3.1 currents with an IC<sub>50</sub> of 7 nM, reduced Ca<sup>2+</sup> signaling induced by the purinergic agonist ATP, suppressed expression of pro-inflammatory cytokines and enzymes (iNOS and COX-2), and prevented induction of the inflammasome component NLRP3. When transient middle cerebral artery occlusion (tMCAO, 60 min) was induced in male C57BL/6 J mice, twice daily administration of senicapoc at 10 and 40 mg/kg starting 12 h after reperfusion dose-dependently reduced infarct area determined by T2-weighted magnetic resonance imaging (MRI) and improved neurological deficit on day 8. Ultra-high-performance liquid chromatography/mass spectrometry analysis of total and free brain concentrations demonstrated sufficient KCa3.1 target engagement. Senicapoc treatment significantly reduced microglia/macrophage and T cell infiltration and activation and attenuated neuronal death. A different treatment paradigm with senicapoc started at 3 h and MRI on day 3 and day 8 revealed that senicapoc reduces secondary infarct growth and suppresses expression of inflammation markers, including T cell cytokines in the brain. Lastly, we demonstrated that senicapoc does not impair the proteolytic activity of tissue plasminogen activator (tPA) in vitro. We suggest that senicapoc could be repurposed as an adjunctive immunocytoprotective agent for combination with reperfusion therapy for ischemic stroke.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11106165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9424822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vulnerable plaque is closely related to the occurrence of ischemic stroke. Therefore, early accurate identification of plaque vulnerability is crucial in risk stratification. In the development of vulnerable plaques, the change of the adventitia is earlier than that of the intima. Currently, researchers focused on the ultrasound detection of intraplaque and intima, but adventitia was often ignored in the examination. Real-time elastography technology (RTE) provides an estimation of adventitia stiffness, and contrast-enhanced ultrasound (CEUS) provides the quantification of adventitial VV. Therefore, we aimed to evaluate the value of adventitia in the early diagnosis of plaque vulnerability by combining CEUS and RTE based on histopathology. Rabbit carotid atherosclerosis models were established, and CEUS and RTE were performed. Normalized maximal video-intensity enhancement (MVE) was calculated to quantify adventitial VV density, and strain values were acquired to evaluate the adventitial elasticity. After removal of the lesion lumen, histological analysis of each excised plaque and adventitia was performed, and vulnerable plaques (n = 32) and stable group (n = 13) were distinguished. Normalized MVE of the adventitial VV and adventitial strain values in the vulnerable group was significantly higher than those in the stable group. Normalized MVE and strain values had a positive linear correlation with histological findings. Normalized MVE of the adventitial VV combined with adventitial strain values could identify plaque vulnerability with the area under the curve of 0.913 (sensitivity 90% and specificity 97%). Accordingly, the multimodal ultrasound detection strategy of adventitia has a high diagnostic value for early plaque vulnerability.
{"title":"Real-time Elastography and Contrast-Enhanced Ultrasound for Evaluating Adventitia in the Early Diagnosis of Vulnerable Plaques: an Exploratory Study Based on Histopathology.","authors":"Yingnan Wu, Xiaoying Li, Zhenzhen Wang, Shuang Zhang, Yanan Feng, Litao Sun","doi":"10.1007/s12975-023-01141-9","DOIUrl":"10.1007/s12975-023-01141-9","url":null,"abstract":"<p><p>Vulnerable plaque is closely related to the occurrence of ischemic stroke. Therefore, early accurate identification of plaque vulnerability is crucial in risk stratification. In the development of vulnerable plaques, the change of the adventitia is earlier than that of the intima. Currently, researchers focused on the ultrasound detection of intraplaque and intima, but adventitia was often ignored in the examination. Real-time elastography technology (RTE) provides an estimation of adventitia stiffness, and contrast-enhanced ultrasound (CEUS) provides the quantification of adventitial VV. Therefore, we aimed to evaluate the value of adventitia in the early diagnosis of plaque vulnerability by combining CEUS and RTE based on histopathology. Rabbit carotid atherosclerosis models were established, and CEUS and RTE were performed. Normalized maximal video-intensity enhancement (MVE) was calculated to quantify adventitial VV density, and strain values were acquired to evaluate the adventitial elasticity. After removal of the lesion lumen, histological analysis of each excised plaque and adventitia was performed, and vulnerable plaques (n = 32) and stable group (n = 13) were distinguished. Normalized MVE of the adventitial VV and adventitial strain values in the vulnerable group was significantly higher than those in the stable group. Normalized MVE and strain values had a positive linear correlation with histological findings. Normalized MVE of the adventitial VV combined with adventitial strain values could identify plaque vulnerability with the area under the curve of 0.913 (sensitivity 90% and specificity 97%). Accordingly, the multimodal ultrasound detection strategy of adventitia has a high diagnostic value for early plaque vulnerability.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10809557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Analysis of a National Institutes of Health (NIH) trial shows that cigarette smoking protected tissue plasminogen activator (tPA)-treated patients from hemorrhage transformation (HT); however, the underlying mechanism is not clear. Damage to the integrity of the blood-brain barrier (BBB) is the pathological basis of HT. Here, we investigated the molecular events of BBB damage after acute ischemic stroke (AIS) using in vitro oxygen-glucose deprivation (OGD) and in vivo mice middle cerebral artery occlusion (MCAO) models. Our results showed that the permeability of bEND.3 monolayer endothelial cells was significantly increased after being exposed to OGD for 2 h. Mice were subjected to 90-min ischemia with 45-min reperfusion, and BBB integrity was significantly damaged, accompanied by tight junction protein occludin degradation, downregulation of microRNA-21 (miR-21), transforming growth factor-β (TGF-β), phosphorylated Smad (p-Smad), plasminogen activator inhibitor-1 (PAI-1), and the upregulation of PDZ and LIM domain protein 5 (Pdlim5), an adaptor protein that has been shown to regulate TGF-β-Smad3 pathway. In addition, pretreatment with two-week nicotine significantly reduced AIS-induced BBB damage and its associated protein dysregulation via downregulating Pdlim5. Notably, AIS did not significantly induce BBB damage in Pdlim5 deficit mice, but overexpression of Pdlim5 in the striatum with adeno-associated virus produced BBB damage and associated protein dysregulation which could be ameliorated by two-week nicotine pretreatment. More important, AIS induced a significant miR-21 decrease, and miR-21 mimics treatment decreased AIS-induced BBB damage by decreasing Pdlim5. Together, these results demonstrate that nicotine treatment alleviates the AIS-compromised integrity of BBB by regulating Pdlim5.
{"title":"Nicotine Treatment Ameliorates Blood-Brain Barrier Damage After Acute Ischemic Stroke by Regulating Endothelial Scaffolding Protein Pdlim5.","authors":"Xiaoyan Hu, Jiali Dong, Panpan Geng, Yanyun Sun, Weihong Du, Xiaoyun Zhao, Qian Wang, Changqing Liu, Xiaona Wang, Yushan Liu, Wenlan Liu, Hongqiang Cheng, Wei Wang, Xinchun Jin","doi":"10.1007/s12975-023-01158-0","DOIUrl":"10.1007/s12975-023-01158-0","url":null,"abstract":"<p><p>Analysis of a National Institutes of Health (NIH) trial shows that cigarette smoking protected tissue plasminogen activator (tPA)-treated patients from hemorrhage transformation (HT); however, the underlying mechanism is not clear. Damage to the integrity of the blood-brain barrier (BBB) is the pathological basis of HT. Here, we investigated the molecular events of BBB damage after acute ischemic stroke (AIS) using in vitro oxygen-glucose deprivation (OGD) and in vivo mice middle cerebral artery occlusion (MCAO) models. Our results showed that the permeability of bEND.3 monolayer endothelial cells was significantly increased after being exposed to OGD for 2 h. Mice were subjected to 90-min ischemia with 45-min reperfusion, and BBB integrity was significantly damaged, accompanied by tight junction protein occludin degradation, downregulation of microRNA-21 (miR-21), transforming growth factor-β (TGF-β), phosphorylated Smad (p-Smad), plasminogen activator inhibitor-1 (PAI-1), and the upregulation of PDZ and LIM domain protein 5 (Pdlim5), an adaptor protein that has been shown to regulate TGF-β-Smad3 pathway. In addition, pretreatment with two-week nicotine significantly reduced AIS-induced BBB damage and its associated protein dysregulation via downregulating Pdlim5. Notably, AIS did not significantly induce BBB damage in Pdlim5 deficit mice, but overexpression of Pdlim5 in the striatum with adeno-associated virus produced BBB damage and associated protein dysregulation which could be ameliorated by two-week nicotine pretreatment. More important, AIS induced a significant miR-21 decrease, and miR-21 mimics treatment decreased AIS-induced BBB damage by decreasing Pdlim5. Together, these results demonstrate that nicotine treatment alleviates the AIS-compromised integrity of BBB by regulating Pdlim5.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9515149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2023-03-17DOI: 10.1007/s12975-023-01147-3
Mariam Nour Eldine, Maryam Alhousseini, Wared Nour-Eldine, Hussein Noureldine, Kunal V Vakharia, Paul R Krafft, Mohammad Hassan A Noureldine
Germinal matrix hemorrhage (GMH) can be a fatal condition responsible for the death of 1.7% of all neonates in the USA. The majority of GMH survivors develop long-term sequalae with debilitating comorbidities. Higher grade GMH is associated with higher mortality rates and higher prevalence of comorbidities. The pathophysiology of GMH can be broken down into two main titles: faulty hemodynamic autoregulation and structural weakness at the level of tissues and cells. Prematurity is the most significant risk factor for GMH, and it predisposes to both major pathophysiological mechanisms of the condition. Secondary brain injury is an important determinant of survival and comorbidities following GMH. Mechanisms of brain injury secondary to GMH include apoptosis, necrosis, neuroinflammation, and oxidative stress. This review will have a special focus on the mechanisms of oxidative stress following GMH, including but not limited to inflammation, mitochondrial reactive oxygen species, glutamate toxicity, and hemoglobin metabolic products. In addition, this review will explore treatment options of GMH, especially targeted therapy.
{"title":"The Role of Oxidative Stress in the Progression of Secondary Brain Injury Following Germinal Matrix Hemorrhage.","authors":"Mariam Nour Eldine, Maryam Alhousseini, Wared Nour-Eldine, Hussein Noureldine, Kunal V Vakharia, Paul R Krafft, Mohammad Hassan A Noureldine","doi":"10.1007/s12975-023-01147-3","DOIUrl":"10.1007/s12975-023-01147-3","url":null,"abstract":"<p><p>Germinal matrix hemorrhage (GMH) can be a fatal condition responsible for the death of 1.7% of all neonates in the USA. The majority of GMH survivors develop long-term sequalae with debilitating comorbidities. Higher grade GMH is associated with higher mortality rates and higher prevalence of comorbidities. The pathophysiology of GMH can be broken down into two main titles: faulty hemodynamic autoregulation and structural weakness at the level of tissues and cells. Prematurity is the most significant risk factor for GMH, and it predisposes to both major pathophysiological mechanisms of the condition. Secondary brain injury is an important determinant of survival and comorbidities following GMH. Mechanisms of brain injury secondary to GMH include apoptosis, necrosis, neuroinflammation, and oxidative stress. This review will have a special focus on the mechanisms of oxidative stress following GMH, including but not limited to inflammation, mitochondrial reactive oxygen species, glutamate toxicity, and hemoglobin metabolic products. In addition, this review will explore treatment options of GMH, especially targeted therapy.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9180543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2023-03-03DOI: 10.1007/s12975-023-01144-6
Teppei Komatsu, Hiroki Ohta, Naoki Takakura, Junichi Hata, Tomomichi Kitagawa, Yuta Kurashina, Hiroaki Onoe, Hirotaka James Okano, Yasuyuki Iguchi
The failure of neuroprotective treatment-related clinical trials, including stem cell therapies, may be partially due to a lack of suitable animal models. We have developed a stem cell-implantable radiopaque hydrogel microfiber that can survive for a long time in vivo. The microfiber is made of barium alginate hydrogel containing zirconium dioxide, fabricated in a dual coaxial laminar flow microfluidic device. We aimed to develop a novel focal stroke model using this microfiber. Using male Sprague-Dawley rats (n=14), a catheter (inner diameter, 0.42 mm; outer diameter, 0.55 mm) was navigated from the caudal ventral artery to the left internal carotid artery using digital subtraction angiography. A radiopaque hydrogel microfiber (diameter, 0.4 mm; length, 1 mm) was advanced through the catheter by slow injection of heparinized physiological saline to establish local occlusion. Both 9.4-T magnetic resonance imaging at 3 and 6 h and 2% 2,3,5-triphenyl tetrazolium chloride staining at 24 h after stroke model creation were performed. Neurological deficit score and body temperature were measured. The anterior cerebral artery-middle cerebral artery bifurcation was selectively embolized in all rats. Median operating time was 4 min (interquartile range [IQR], 3-8 min). Mean infarct volume was 388 mm3 (IQR, 354-420 mm3) at 24 h after occlusion. No infarction of the thalamus or hypothalamus was seen. Body temperature did not change significantly over time (P = 0.204). However, neurological deficit scores before and at 3, 6, and 24 h after model creation differed significantly (P < 0.001). We present a novel rat model of focal infarct restricted to the middle cerebral artery territory using a radiopaque hydrogel microfiber positioned under fluoroscopic guidance. By comparing the use of stem cell-containing versus non-containing fibers in this stroke model, it would be possible to determine the efficacy of "pure" cell transplantation in treating stroke.
{"title":"A Novel Rat Model of Embolic Cerebral Ischemia Using a Cell-Implantable Radiopaque Hydrogel Microfiber.","authors":"Teppei Komatsu, Hiroki Ohta, Naoki Takakura, Junichi Hata, Tomomichi Kitagawa, Yuta Kurashina, Hiroaki Onoe, Hirotaka James Okano, Yasuyuki Iguchi","doi":"10.1007/s12975-023-01144-6","DOIUrl":"10.1007/s12975-023-01144-6","url":null,"abstract":"<p><p>The failure of neuroprotective treatment-related clinical trials, including stem cell therapies, may be partially due to a lack of suitable animal models. We have developed a stem cell-implantable radiopaque hydrogel microfiber that can survive for a long time in vivo. The microfiber is made of barium alginate hydrogel containing zirconium dioxide, fabricated in a dual coaxial laminar flow microfluidic device. We aimed to develop a novel focal stroke model using this microfiber. Using male Sprague-Dawley rats (n=14), a catheter (inner diameter, 0.42 mm; outer diameter, 0.55 mm) was navigated from the caudal ventral artery to the left internal carotid artery using digital subtraction angiography. A radiopaque hydrogel microfiber (diameter, 0.4 mm; length, 1 mm) was advanced through the catheter by slow injection of heparinized physiological saline to establish local occlusion. Both 9.4-T magnetic resonance imaging at 3 and 6 h and 2% 2,3,5-triphenyl tetrazolium chloride staining at 24 h after stroke model creation were performed. Neurological deficit score and body temperature were measured. The anterior cerebral artery-middle cerebral artery bifurcation was selectively embolized in all rats. Median operating time was 4 min (interquartile range [IQR], 3-8 min). Mean infarct volume was 388 mm<sup>3</sup> (IQR, 354-420 mm<sup>3</sup>) at 24 h after occlusion. No infarction of the thalamus or hypothalamus was seen. Body temperature did not change significantly over time (P = 0.204). However, neurological deficit scores before and at 3, 6, and 24 h after model creation differed significantly (P < 0.001). We present a novel rat model of focal infarct restricted to the middle cerebral artery territory using a radiopaque hydrogel microfiber positioned under fluoroscopic guidance. By comparing the use of stem cell-containing versus non-containing fibers in this stroke model, it would be possible to determine the efficacy of \"pure\" cell transplantation in treating stroke.</p>","PeriodicalId":23237,"journal":{"name":"Translational Stroke Research","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10824860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}