Department of Neuroscience, University of Kentucky, Lexington, USA.
Department of Physiology, University of Kentucky, Lexington, USA.
J Cereb Blood Flow Metab. 2020 Aug;40(8):1695-1708. doi: 10.1177/0271678X19880161. Epub 2019 Oct 1.
Stroke remains a leading cause of death and disability with limited therapeutic options. Endothelial cell β integrin receptors play a direct role in blood-brain barrier (BBB) dysfunction through regulation of tight junction proteins and infiltrating leukocytes, potentially mediated by β1 integrins. Following tandem transient common carotid artery/middle cerebral artery occlusion on wild-type mice, we administered the integrin a5b1 inhibitor, ATN-161, intraperitoneal (IP) injection at 1 mg/kg acutely after reperfusion, on post-stroke day (PSD)1 and PSD2. Systemic changes (heart rate, pulse distension, and body temperature) were determined. Additionally, infarct volume and edema were determined by 2,3-triphenyltetrazolium chloride and magnetic resonance imaging, while neurological changes were evaluated using an 11-point Neuroscore. Brain immunohistochemistry was performed for claudin-5, α5β1, IgG, and CD45 + cells, and quantitative polymerase chain reaction (qPCR) was performed for matrix metalloproteinase-9 (MMP-9), interleukin (IL)-1β, collagen IV, and CXCL12. ATN-161 significantly reduced integrin α5β1 expression in the surrounding peri-infarct region with no systemic changes. Infarct volume, edema, and functional deficit were significantly reduced in ATN-161-treated mice. Furthermore, ATN-161 treatment reduced IgG extravasation into the parenchyma through conserved claudin-5, collagen IV, CXCL12 while reducing MMP-9 transcription. Additionally, IL-1β and CD45 + cells were reduced in the ipsilateral cortex following ATN-161 administration. Collectively, ATN-161 may be a promising novel stroke therapy by reducing post-stroke inflammation and BBB permeability.
中风仍然是导致死亡和残疾的主要原因，治疗选择有限。内皮细胞β整合素受体通过调节紧密连接蛋白和浸润白细胞在血脑屏障（BBB）功能障碍中发挥直接作用，这可能是由β1 整合素介导的。在野生型小鼠串联短暂性颈总动脉/大脑中动脉闭塞后，我们在再灌注后立即给予整合素 a5b1 抑制剂 ATN-161，剂量为 1mg/kg，腹腔内（IP）注射，在中风后第 1 天（PSD1）和 PSD2 时各注射 1 次。系统变化（心率、脉搏扩张和体温）被确定。此外，通过 2,3-三苯基四唑氯化物和磁共振成像确定梗死体积和水肿，通过 11 分神经评分评估神经变化。进行脑免疫组织化学检测紧密连接蛋白-5、α5β1、IgG 和 CD45+细胞，并进行定量聚合酶链反应（qPCR）检测基质金属蛋白酶-9（MMP-9）、白细胞介素（IL）-1β、胶原 IV 和 CXCL12。ATN-161 可显著减少周围梗死区的整合素α5β1 表达，无系统变化。ATN-161 治疗可显著减少梗死体积、水肿和功能缺陷。此外，ATN-161 治疗可通过保守的紧密连接蛋白-5、胶原 IV、CXCL12 减少 IgG 向实质内的渗漏，同时减少 MMP-9 的转录。此外，ATN-161 给药后同侧皮质中的 IL-1β 和 CD45+细胞减少。综上所述，ATN-161 可能通过减少中风后的炎症和 BBB 通透性成为一种有前途的新型中风治疗方法。
