Department of Clinical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
J Cell Physiol. 2019 Nov;234(11):20533-20545. doi: 10.1002/jcp.28653. Epub 2019 Apr 26.
The only Food and Drug Administration-approved treatment for acute ischemic stroke is tissue plasminogen activator, and the discovery of novel therapeutic targets is critical. Here, we found orosomucoid (ORM), an acute-phase protein mainly produced by the liver, might act as a treatment candidate for an ischemic stroke. The results showed that ORM2 is the dominant subtype in mice normal brain tissue. After middle cerebral artery occlusion (MCAO), the level of ORM2 is significantly increased in the ischemic penumbra compared with the contralateral normal brain tissue, whereas ORM1 knockout did not affect the infarct size. Exogenous ORM could significantly decrease infarct size and neurological deficit score. Inspiringly, the best administration time point was at 4.5 and 6 hr after MCAO. ORM could markedly decrease the Evans blue extravasation, and improve blood-brain barrier-associated proteins expression in the ischemic penumbra of MACO mice and oxygen-glucose deprivation (OGD)-treated bEnd3 cells. Meanwhile, ORM could significantly alleviate inflammation by inhibiting the production of interleukin 1β (IL-1β), IL-6, and tumor necrosis factor α (TNF-α), reduce oxidative stress by improving the balance of malondialdehyde (MDA) and superoxide dismutase (SOD), inhibit apoptosis by decreasing caspase-3 activity in ischemic penumbra of MCAO mice and OGD-treated bEnd.3 cells. Because of its protective role at multiple levels, ORM might be a promising therapeutic target for ischemic stroke.
唯一获得美国食品和药物管理局批准用于急性缺血性脑卒中的治疗方法是组织纤溶酶原激活物，因此发现新的治疗靶点至关重要。在这里，我们发现急性反应蛋白（ORM），一种主要由肝脏产生的急性期蛋白，可能成为缺血性脑卒中的治疗候选物。结果表明，ORM2 是正常小鼠脑组织中的主要亚型。大脑中动脉闭塞（MCAO）后，与对侧正常脑组织相比，缺血半影区 ORM2 的水平显著升高，而 ORM1 敲除则不影响梗死面积。外源性 ORM 可显著减小梗死面积和神经功能缺损评分。令人鼓舞的是，最佳给药时间点是 MCAO 后 4.5 和 6 小时。ORM 可显著减少 Evans 蓝渗出，并改善 MCAO 小鼠缺血半影区和氧葡萄糖剥夺（OGD）处理的 bEnd3 细胞中与血脑屏障相关的蛋白表达。同时，ORM 可通过抑制白细胞介素 1β（IL-1β）、IL-6 和肿瘤坏死因子α（TNF-α）的产生来显著抑制炎症，通过改善丙二醛（MDA）和超氧化物歧化酶（SOD）的平衡来减轻氧化应激，通过降低缺血半影区的 caspase-3 活性和 OGD 处理的 bEnd.3 细胞来抑制细胞凋亡。由于 ORM 在多个水平上具有保护作用，因此它可能是缺血性脑卒中的一个有前途的治疗靶点。
