Integrin α5β1 inhibition by ATN-161 reduces neuroinflammation and is neuroprotective in ischemic stroke
Integrin α5β1 inhibition by ATN-161 reduces neuroinflammation and is neuroprotective in ischemic stroke
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DOI：
10.1177/0271678x19880161
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发表时间：
2019-10-01
影响因子：
6.3
通讯作者：
Bix, Gregory J.
中科院分区：
文献类型：
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作者：
Edwards, Danielle N.;Salmeron, Kathleen;Bix, Gregory J.
中风仍然是死亡和残疾的主要原因，治疗选择有限。内皮细胞 β(1) 整合素受体通过调节紧密连接蛋白和浸润白细胞（可能由 β 1 整合素介导）在血脑屏障 (BBB) 功能障碍中发挥直接作用。对野生型小鼠进行串联短暂性颈总动脉/大脑中动脉闭塞后，我们在再灌注后、卒中后第 1 天和 PSD2 立即腹膜内 (IP) 注射 1 mg/kg 整合素 a5b1 抑制剂 ATN-161。测定全身变化（心率、脉搏扩张和体温）。此外，通过 2,3-三苯基氯化四唑和磁共振成像确定梗塞体积和水肿，同时使用 11 点 Neuroscore 评估神经系统变化。对claudin-5、alpha 5 beta 1、IgG和CD45 + 细胞进行脑免疫组织化学分析，并对基质金属蛋白酶-9 (MMP-9)、白细胞介素 (IL)-1 beta、IV 型胶原蛋白和 CXCL12 进行定量聚合酶链反应 (qPCR)。 ATN-161 显着降低梗死周围区域的整合素 α 5 β 1 表达，但没有全身变化。 ATN-161 治疗小鼠的梗塞体积、水肿和功能缺陷均显着减少。此外，ATN-161 治疗通过保守的claudin-5、胶原蛋白IV、CXCL12 减少了 IgG 外渗到实质中，同时减少了 MMP-9 转录。此外，施用 ATN-161 后，同侧皮质中的 IL-1 β 和 CD45 + 细胞减少。总的来说，ATN-161 通过减少中风后炎症和 BBB 通透性可能成为一种有前途的新型中风疗法。
Stroke remains a leading cause of death and disability with limited therapeutic options. Endothelial cell beta(1) integrin receptors play a direct role in blood-brain barrier (BBB) dysfunction through regulation of tight junction proteins and infiltrating leukocytes, potentially mediated by beta 1 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, alpha 5 beta 1, IgG, and CD45 + cells, and quantitative polymerase chain reaction (qPCR) was performed for matrix metalloproteinase-9 (MMP-9), interleukin (IL)-1 beta, collagen IV, and CXCL12. ATN-161 significantly reduced integrin alpha 5 beta 1 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-1 beta 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.