Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan.
Institute for Environment and Gender Specific Medicine, Juntendo University School of Medicine, Chiba, Japan.
PLoS One. 2018 May 24;13(5):e0198039. doi: 10.1371/journal.pone.0198039. eCollection 2018.
Loss of integrity of the blood-brain barrier (BBB) in ischemic stroke victims initiates a devastating cascade of events causing brain damage. Maintaining the BBB is important to preserve brain function in ischemic stroke. Unfortunately, recombinant tissue plasminogen activator (tPA), the only effective fibrinolytic treatment at the acute stage of ischemic stroke, also injures the BBB and increases the risk of brain edema and secondary hemorrhagic transformation. Thus, it is important to identify compounds that maintain BBB integrity in the face of ischemic injury in patients with stroke. We previously demonstrated that intravenously injected phosphorylated recombinant heat shock protein 27 (prHSP27) protects the brains of mice with transient middle cerebral artery occlusion (tMCAO), an animal stroke-model. Here, we determined whether prHSP27, in addition to attenuating brain injury, also decreases BBB damage in hyperglycemic tMCAO mice that had received tPA. After induction of hyperglycemia and tMCAO, we examined 4 treatment groups: 1) bovine serum albumin (BSA), 2) prHSP27, 3) tPA, 4) tPA plus prHSP27. We examined the effects of prHSP27 by comparing the BSA and prHSP27 groups and the tPA and tPA plus prHSP27 groups. Twenty-four hours after injection, prHSP27 reduced infarct volume, brain swelling, neurological deficits, the loss of microvessel proteins and endothelial cell walls, and mortality. It also reduced the rates of hemorrhagic transformation, extravasation of endogenous IgG, and MMP-9 activity, signs of BBB damage. Therefore, prHSP27 injection attenuated brain damage and preserved the BBB in tPA-injected, hyperglycemic tMCAO experimental stroke-model mice, in which the BBB is even more severely damaged than in simple tMCAO mice. The attenuation of brain damage and BBB disruption in the presence of tPA suggests the effectiveness of prHSP27 and tPA as a combination therapy. prHSP27 may be a novel therapeutic agent for ischemic stroke patients whose BBBs are injured following tPA injections.
血脑屏障（BBB）在缺血性中风患者中的完整性丧失会引发一系列破坏性事件，导致脑损伤。保持 BBB 的完整性对于保护缺血性中风患者的脑功能很重要。不幸的是，重组组织纤溶酶原激活物（tPA）是缺血性中风急性阶段唯一有效的溶栓治疗药物，它也会损伤 BBB，并增加脑水肿和继发性出血转化的风险。因此，在中风患者中，识别在面对缺血性损伤时能维持 BBB 完整性的化合物非常重要。我们之前的研究表明，静脉注射磷酸化重组热休克蛋白 27（prHSP27）可保护短暂性大脑中动脉闭塞（tMCAO）模型小鼠的大脑，这种动物中风模型。在这里，我们确定了 prHSP27 是否除了减轻脑损伤外，还可以减少接受 tPA 治疗的高血糖 tMCAO 小鼠的 BBB 损伤。在诱导高血糖和 tMCAO 后，我们检查了 4 个治疗组：1）牛血清白蛋白（BSA），2）prHSP27，3）tPA，4）tPA+prHSP27。我们通过比较 prHSP27 组和 BSA 组以及 tPA 组和 tPA+prHSP27 组来检查 prHSP27 的作用。注射后 24 小时，prHSP27 降低了梗死体积、脑水肿、神经功能缺损、微血管蛋白和内皮细胞壁的丢失以及死亡率。它还降低了出血转化、内源性 IgG 漏出和 MMP-9 活性的比率，这些都是 BBB 损伤的迹象。因此，prHSP27 注射减轻了 tPA 注射的高血糖 tMCAO 实验性中风模型小鼠的脑损伤并保护了 BBB，其中 BBB 的损伤比单纯 tMCAO 小鼠更为严重。在存在 tPA 的情况下，脑损伤和 BBB 破坏的减轻表明 prHSP27 和 tPA 联合治疗的有效性。prHSP27 可能是一种新型治疗药物，适用于接受 tPA 注射后 BBB 受损的缺血性中风患者。
