Abstract：
Intracerebral hemorrhage (ICH) is a significant public health matter that has no effective treatment. ICH-induced destruction of the blood-brain barrier (BBB) leads to neurological deterioration. Astrocytic sonic hedgehog (SHH) alleviates brain injury by maintaining the integrity of the BBB after ICH. Silent information regulator 1 (SIRT1) is neuroprotective in several central nervous system diseases via BBB regulation. It is also a possible influential factor of the SHH signaling pathway. Nevertheless, the role of SIRT1 on BBB and the underlying pathological process associated with the SHH signaling pathway after ICH remain unclear. We established an intracerebral hemorrhagic mouse model by collagenase injection. SRT1720 (a selective agonist of SIRT1) was used to evaluate the effect of SIRT1 on BBB integrity after ICH. SIRT1 expression was reduced in the mouse brain after ICH. SRT1720 attenuated neurobehavioral impairments and brain edema of ICH mouse. After ICH induction, SRT1720 improved BBB integrity and tight junction expressions in the mouse brain. The SHH signaling pathway-related factors smoothened and glioma-associated oncogene homolog-1 were increased with the intervention of SRT1720, while cyclopamine (a specific inhibitor of the SHH signaling pathway) reversed these effects. These findings suggest that SIRT1 protects from ICH by altering BBB permeability and tight junction expression levels. This process is associated with the SHH signaling pathway, suggesting that SIRT1 may be a potential therapeutic target for ICH.
摘要：
脑出血（ICH）是一个重要的公共卫生问题，没有有效的治疗方法。ICH诱导的血脑屏障（BBB）破坏导致神经系统恶化。星形细胞声波刺猬（SHH）通过维持ICH后BBB的完整性来减轻脑损伤。沉默信息调节因子1（SIRT1）通过BBB调节在几种中枢神经系统疾病中具有神经保护作用。它也是SHH信号通路的可能影响因素。然而，SIRT1对ICH后BBB的作用以及与SHH信号通路相关的潜在病理过程仍不清楚.我们通过胶原酶注射建立了脑出血小鼠模型。SRT1720（SIRT1的选择性激动剂）用于评估SIRT1对ICH后BBB完整性的影响。ICH后小鼠脑中SIRT1表达降低。SRT1720减轻ICH小鼠的神经行为障碍和脑水肿。ICH诱导后,SRT1720改善了小鼠脑中的BBB完整性和紧密连接表达。在SRT1720的干预下，SHH信号通路相关因子平滑化和神经胶质瘤相关癌基因同源物1增加，而环巴胺（SHH信号通路的特异性抑制剂）逆转了这些作用。这些发现表明SIRT1通过改变BBB通透性和紧密连接表达水平保护免受ICH。这个过程与SHH信号通路有关,提示SIRT1可能是ICH的潜在治疗靶点.
