Fukuta Tatsuya, Asai Tomohiro, Yanagida Yosuke, Namba Mio, Koide Hiroyuki, Shimizu Kosuke, Oku Naoto
Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Japan; and.
Japan Society for the Promotion of Science, Tokyo, Japan.
FASEB J. 2017 May;31(5):1879-1890. doi: 10.1096/fj.201601209R. Epub 2017 Jan 12.
For ischemic stroke treatment, extension of the therapeutic time window (TTW) of thrombolytic therapy with tissue plasminogen activator (tPA) and amelioration of secondary ischemia/reperfusion (I/R) injury are most desirable. Our previous studies have indicated that liposomal delivery of neuroprotectants into an ischemic region is effective for stroke treatment. In the present study, for solving the above problems in the clinical setting, the usefulness of combination therapy with tPA and liposomal fasudil (fasudil-Lip) was investigated in ischemic stroke model rats with photochemically induced thrombosis, with clots that were dissolved by tPA. Treatment with tPA 3 h after occlusion markedly increased blood-brain barrier permeability and activated matrix metalloproteinase (MMP)-2 and -9, which are involved in cerebral hemorrhage. However, an intravenous administration of fasudil-Lip before tPA markedly suppressed the increase in permeability and the MMP activation stemming from tPA. The combination treatment showed significantly larger neuroprotective effects, even in the case of delayed tPA administration compared with each treatment alone or the tPA/fasudil-treated group. These findings suggest that treatment with fasudil-Lip before tPA could decrease the risk of tPA-derived cerebral hemorrhage and extend the TTW of tPA and that the combination therapy could be a useful therapeutic option for ischemic stroke.-Fukuta, T., Asai, T., Yanagida, Y., Namba, M., Koide, H., Shimizu, K., Oku, N. Combination therapy with liposomal neuroprotectants and tissue plasminogen activator for treatment of ischemic stroke.
对于缺血性脑卒中的治疗，最理想的是延长组织型纤溶酶原激活剂（tPA）溶栓治疗的治疗时间窗（TTW），并减轻继发性缺血/再灌注（I/R）损伤。我们之前的研究表明，将神经保护剂通过脂质体递送至缺血区域对脑卒中治疗有效。在本研究中，为了解决临床环境中的上述问题，我们在光化学诱导血栓形成的缺血性脑卒中模型大鼠中研究了tPA与脂质体法舒地尔（法舒地尔脂质体）联合治疗的有效性，血栓可被tPA溶解。闭塞后3小时给予tPA治疗显著增加了血脑屏障通透性，并激活了与脑出血有关的基质金属蛋白酶（MMP）-2和-9。然而，在给予tPA之前静脉注射法舒地尔脂质体可显著抑制由tPA引起的通透性增加和MMP激活。联合治疗显示出显著更大的神经保护作用，即使在tPA延迟给药的情况下，与单独的每种治疗或tPA/法舒地尔治疗组相比也是如此。这些发现表明，在tPA之前给予法舒地尔脂质体治疗可降低tPA引起脑出血的风险，并延长tPA的TTW，并且联合治疗可能是缺血性脑卒中的一种有用治疗选择。-深田，T.，浅井，T.，柳田，Y.，难波，M.，小出，H.，清水，K.，奥库，N.脂质体神经保护剂与组织型纤溶酶原激活剂联合治疗缺血性脑卒中。
