Xing Gebeili, Zhao Tianman, Zhang Xiyue, Li He, Li Xiuping, Cui Pan, Li Minshu, Li Daojing, Zhang Nan, Jiang Wei
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
Department of Neurology, Inner Mongolia People's Hospital, Hohhot, China.
Front Cell Neurosci. 2020 Dec 3;14:575690. doi: 10.3389/fncel.2020.575690. eCollection 2020.
: Intracerebral hemorrhage (ICH) is a fatal subtype of stroke that lacks effective therapy. Blood-brain barrier (BBB) damage is a hallmark of ICH-induced brain injury that leads to edema formation, leukocytes infiltration, influx of blood components into the perihematomal (PHE) region, and eventually brain injury. Astrocytes are essential for the formation and maintenance of the BBB by providing secreted molecules that contribute to the association between these cells. Sonic hedgehog (SHH) derived from astrocytes promotes the maturity and integrity of the BBB by upregulating tight junctions (TJs) in brain capillary endothelial cells (ECs). However, the effect of SHH on BBB in ICH has not been investigated. : Cyclopamine (CYC) is a potent, selective inhibitor that specifically blocks the SHH signaling pathway. Here, we used pharmacological inhibitions (CYC and its derivatives) to determine a critical role of the SHH signaling pathway in promoting BBB integrity after ICH by mechanisms of regulating the TJ proteins and . : The expression of astrocytic SHH was upregulated in mouse brains after ICH. Compared with the vehicle-treated group, inhibition of the SHH signaling pathway with CYC and its derivatives treatments aggravated neurological function deficits, brain edema, hematoma volume, and BBB impairment by downregulating TJs in ECs through the SHH-Gli-1 axis and . : SHH signaling pathway at the level of the BBB provides a barrier-promoting effect, suggesting that the SHH signaling pathway may function as a potential therapeutic target for restoring BBB function in ICH.
脑出血（ICH）是一种缺乏有效治疗方法的致命性中风亚型。血脑屏障（BBB）损伤是ICH所致脑损伤的一个标志，会导致水肿形成、白细胞浸润、血液成分流入血肿周围（PHE）区域，并最终导致脑损伤。星形胶质细胞通过提供有助于这些细胞间联系的分泌分子，对BBB的形成和维持至关重要。源自星形胶质细胞的音猬因子（SHH）通过上调脑毛细血管内皮细胞（ECs）中的紧密连接（TJs）来促进BBB的成熟和完整性。然而，SHH在ICH中对BBB的作用尚未得到研究。环杷明（CYC）是一种强效、选择性抑制剂，可特异性阻断SHH信号通路。在此，我们使用药理学抑制方法（CYC及其衍生物），通过调节TJ蛋白[具体蛋白名称缺失]和[具体蛋白名称缺失]的机制，来确定SHH信号通路在ICH后促进BBB完整性中的关键作用。ICH后小鼠脑内星形胶质细胞SHH的表达上调。与载体处理组相比，用CYC及其衍生物处理抑制SHH信号通路，会通过SHH - Gli - 1轴[具体轴相关内容缺失]和[具体轴相关内容缺失]下调ECs中的TJs，从而加重神经功能缺损、脑水肿、血肿体积和BBB损伤。BBB水平的SHH信号通路具有促进屏障的作用，这表明SHH信号通路可能作为恢复ICH中BBB功能的潜在治疗靶点。
