Experimental Research in Stroke and Inflammation (ERSI) Group, Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Aging Dis. 2024 Oct 1;15(5):2191-2204. doi: 10.14336/AD.2024.0518.
Ischemic stroke represents a significant global health challenge, often resulting in death or long-term disability, particularly among the elderly, where advancing age stands as the most unmodifiable risk factor. Arising from the blockage of a brain-feeding artery, the only therapies available to date aim at removing the blood clot to restore cerebral blood flow and rescue neuronal cells from death. The prevailing treatment approach involves thrombolysis by administration of recombinant tissue plasminogen activator (tPA), albeit with a critical time constraint. Timely intervention is imperative, given that delayed thrombolysis increases tPA leakage into the brain parenchyma, causing harmful effects. Strategies to preserve tPA's vascular benefits while shielding brain cells from its toxicity have been explored. Notably, administering neuroserpin (Ns), a brain-specific tPA inhibitor, represents one such approach. Following ischemic stroke, Ns levels rise and correlate with favorable post-stroke outcomes. Studies in rodent models of focal cerebral ischemia have demonstrated the beneficial effects of Ns administration. Ns treatment maintains blood-brain barrier (BBB) integrity, reducing stroke volume. Conversely, Ns-deficient animals exhibit larger stroke injury, increased BBB permeability and enhanced microglia activation. Furthermore, Ns administration extends the therapeutic window for tPA intervention, underscoring its potential in stroke management. Remarkably, our investigation reveals the presence of Ns within extracellular vesicles (EVs), small membrane-surrounded particles released by all cells and critical for intercellular communication. EVs influence disease outcome following stroke through cargo transfer between cells. Clarifying the role of EVs containing NS could open up urgently needed novel therapeutic approaches to improve post-ischemic stroke outcome.
缺血性脑卒中是一个重大的全球健康挑战，常导致死亡或长期残疾，尤其在老年人中更为常见，因为年龄增长是最不可改变的危险因素。它是由于大脑供血动脉阻塞引起的，目前可用的治疗方法旨在清除血栓以恢复脑血流并挽救神经元细胞免于死亡。目前的治疗方法主要是通过给予重组组织型纤溶酶原激活剂（tPA）进行溶栓治疗，但存在严格的时间限制。及时干预至关重要，因为溶栓延迟会导致 tPA 漏入脑实质，产生有害影响。因此，人们探索了一些策略来保留 tPA 的血管益处，同时保护脑细胞免受其毒性影响。值得注意的是，给予神经丝氨酸蛋白酶抑制剂（Ns）是一种方法。在缺血性脑卒中后，Ns 水平升高，并与良好的脑卒中后结局相关。在局灶性脑缺血的啮齿动物模型中进行的研究表明了 Ns 给药的有益作用。Ns 治疗可维持血脑屏障（BBB）的完整性，减少脑卒中的体积。相反，Ns 缺乏的动物表现出更大的脑卒中损伤、增加的 BBB 通透性和增强的小胶质细胞激活。此外，Ns 给药可延长 tPA 干预的治疗窗口，突出了其在脑卒中管理中的潜力。值得注意的是，我们的研究发现 Ns 存在于细胞外囊泡（EVs）中，EVs 是所有细胞释放的具有膜包围的小颗粒，对细胞间通讯至关重要。EVs 通过细胞间的物质转移影响脑卒中后的疾病结局。阐明含有 Ns 的 EVs 的作用可能为改善缺血性脑卒中后的预后提供急需的新的治疗方法。
