Department of Pharmaceutical and Administrative Sciences, Loma Linda University, Loma Linda, CA 92350, USA.
Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA.
Int J Mol Sci. 2018 May 31;19(6):1635. doi: 10.3390/ijms19061635.
When given beyond 4.5 h of stroke onset, tissue plasminogen activator (tPA) induces deleterious side effects in the ischemic brain, notably, hemorrhagic transformation (HT). We examined the efficacy of granulocyte-colony stimulating factor (G-CSF) in reducing delayed tPA-induced HT, cerebral infarction, and neurological deficits in a thromboembolic (TE) stroke model, and whether the effects of G-CSF were sustained for longer periods of recovery. After stroke induction, rats were given intravenous saline (control), tPA (10 mg/kg), or G-CSF (300 μg/kg) + tPA 6 h after stroke. We found that G-CSF reduced delayed tPA-associated HT by 47%, decreased infarct volumes by 33%, and improved motor and neurological deficits by 15% and 25%, respectively. It also prevented delayed tPA treatment-induced mortality by 46%. Immunohistochemistry showed 1.5- and 1.8-fold enrichment of the endothelial progenitor cell (EPC) markers CD34+ and VEGFR2 in the ischemic cortex and striatum, respectively, and 1.7- and 2.8-fold increases in the expression of the vasculogenesis marker von Willebrand factor (vWF) in the ischemic cortex and striatum, respectively, in G-CSF-treated rats compared with tPA-treated animals. Flow cytometry revealed increased mobilization of CD34+ cells in the peripheral blood of rats given G-CSF. These results corroborate the efficacy of G-CSF in enhancing the therapeutic time window of tPA for stroke treatment via EPC mobilization and enhancement of vasculogenesis.
在中风发作后 4.5 小时以上给予组织型纤溶酶原激活物（tPA）会在缺血性大脑中引起有害的副作用，特别是出血性转化（HT）。我们研究了粒细胞集落刺激因子（G-CSF）在减少延迟 tPA 诱导的 HT、脑梗死和神经功能缺损方面的功效，以及 G-CSF 的作用是否能持续更长的恢复时间。中风诱导后，大鼠给予静脉注射生理盐水（对照）、tPA（10mg/kg）或 G-CSF（300μg/kg）+中风后 6 小时给予 tPA。我们发现 G-CSF 减少了延迟 tPA 相关 HT 47%，减少了梗死体积 33%，并分别改善了运动和神经功能缺损 15%和 25%，还将延迟 tPA 治疗诱导的死亡率降低了 46%。免疫组织化学显示，缺血皮质和纹状体中内皮祖细胞（EPC）标志物 CD34+和 VEGFR2 的丰度分别增加了 1.5 倍和 1.8 倍，血管生成标志物 von Willebrand 因子（vWF）的表达分别增加了 1.7 倍和 2.8 倍在 G-CSF 治疗的大鼠中比 tPA 治疗的动物。流式细胞术显示，给予 G-CSF 的大鼠外周血中 CD34+细胞的动员增加。这些结果证实了 G-CSF 通过动员 EPC 和增强血管生成来增强 tPA 治疗中风的治疗时间窗的功效。
