Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Academy of Forensic Science, Shanghai, China.
Department of Forensic Medicine, Medical School of Soochow University, Suzhou, China.
Stress. 2020 May;23(3):338-348. doi: 10.1080/10253890.2019.1678023. Epub 2019 Oct 18.
Growing evidences have shown that patients recovering from stroke experience high and unremitting stress. Chronic restraint stress (CRS) has been found to exacerbate neurological impairments in an experimental focal cortical ischemia model. However, there have been no studies reporting the effect and mechanism of CRS on intracerebral hemorrhage (ICH). This study aimed to evaluate the effect of CRS on a mouse ICH model. Adult male C57BL mice were subjected to infusion of collagenase IV (to induce ICH) or saline (for sham) into the left striatum. After ICH, animals were stressed with application of CRS protocol for 21 days. Our results showed that CRS significantly exacerbated neurological deficits (Garcia test, corner turn test, and wire grip test) and the ipsilateral brain atrophy and reduced body weight gain after ICH. Immunofluorescence staining indicated that CRS exerted significant suppressive effects on neuron, astrocyte, vascular endothelial cell and pericyte and excessively activated microglia post ICH. All of the key cellular components mentioned above are involved in the neurovascular unit (NVU) remodeling in the peri-hemorrhagic region after ICH. Western blot results showed that matrix metalloproteinase (MMP)-9 and tight junction (TJ) proteins including zonula occludens-1, occludin and claudin-5 were increased after ICH, but MMP-9 protein was further up-regulated and TJ-related proteins were down-regulated by CRS. In addition, ICH-induced activation of endoplasmic reticulum stress and apoptosis were further strengthened by CRS. Collectively, CRS exacerbates neurological deficits and disrupts the remodeling of the peri-hemorrhagic NVU after ICH, which may be associated with TJ proteins degradation and excessive activation of MMP-9 and endoplasmic reticulum stress-apoptosis.LAY SUMMARYCRS exacerbates neurological deficits and disrupts the remodeling of the NVU in the recovery stage after ICH, which suggest that monitoring chronic stress levels in patients recovering from ICH may merit consideration in the future.
越来越多的证据表明，中风后康复的患者经历着高度且持续的压力。慢性束缚应激（CRS）已被发现会加重实验性皮质局灶性缺血模型中的神经损伤。然而，目前还没有研究报道 CRS 对脑出血（ICH）的影响和机制。本研究旨在评估 CRS 对小鼠 ICH 模型的影响。成年雄性 C57BL 小鼠接受 IV 型胶原酶（诱导 ICH）或生理盐水（假手术）注入左侧纹状体。ICH 后，动物接受 CRS 方案 21 天应激。我们的结果表明，CRS 显著加重了神经功能缺损（Garcia 测试、转角测试和线握力测试）和 ICH 后对侧大脑萎缩和体重减轻。免疫荧光染色表明，CRS 在 ICH 后对神经元、星形胶质细胞、血管内皮细胞和周细胞以及过度激活的小胶质细胞产生了显著的抑制作用。上述所有关键细胞成分均参与 ICH 后出血周围区的神经血管单元（NVU）重塑。Western blot 结果表明，基质金属蛋白酶（MMP）-9 和紧密连接（TJ）蛋白，包括闭锁蛋白-1、occludin 和 claudin-5，在 ICH 后增加，但 MMP-9 蛋白进一步上调，TJ 相关蛋白下调由 CRS 引起。此外，CRS 进一步增强了 ICH 诱导的内质网应激和细胞凋亡的激活。综上所述，CRS 加重了 ICH 后神经功能缺损，并破坏了出血周围 NVU 的重塑，这可能与 TJ 蛋白降解和 MMP-9 过度激活以及内质网应激-凋亡有关。
