The protective effects of plasma gelsolin on stroke outcome in rats.

Huong T Le, Aaron C Hirko, Jeffrey S Thinschmidt, Maria Grant, Zhimin Li, Joanna Peris, Michael A King, Jeffrey A Hughes, Sihong Song
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引用次数: 28

Abstract

Background: To date, recombinant tissue plasminogen activator (rtPA) is the only approved drug for ischemic stroke. It is intravenously administered functioning as a thrombolytic agent and is used to obtain reperfusion of the affected area of the brain. Excitotoxicity, inflammation and apoptosis are all involved in delayed neuronal death following stroke and offer multiple opportunities to intervene with neuroprotective agents. Gelsolin (GSN) is an actin- and calcium-binding protein mediating the disassembly of actin filaments and activity of calcium channels. It also functions as a regulator of apoptosis and inflammatory responses. This study tests the hypothesis that increasing the concentration of the form of GSN known as plasma GSN (pGSN) near an infarct will provide neuroprotection following ischemic stroke.

Methods: We induced middle cerebral artery occlusion (MCAO) in male rats via intracranial injection of endothelin-1 (ET-1), a potent vasoconstrictor, and then treated with local delivery of pGSN. Whole brain laser Doppler perfusion imaging was performed through the skull to assess MCAO effectiveness. Cylinder and vibrissae tests evaluated sensorimotor function before and 72 h after MCAO. Infarct volumes were examined 72 h after MCAO via 2, 3, 5-triphenyltetrazolium chloride (TTC) assay.

Results: Estimates of relative cerebral perfusion were significantly decreased in all groups receiving MCAO with no differences detected between treatments. Despite equivalent initial strokes, the infarct volume of the pGSN treatment group was significantly reduced compared with the untreated MCAO rats at 72 h. ET-1 induced significant deficits in both cylinder and vibrissae tests while pGSN significantly limited these deficits.

Conclusion: Gelsolin could be a promising drug for protection against neurodegeneration following ischemic stroke.

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血浆凝胶对大鼠脑卒中预后的保护作用。
背景:迄今为止,重组组织型纤溶酶原激活剂(rtPA)是唯一被批准用于缺血性脑卒中的药物。它作为一种溶栓剂进行静脉注射,并用于获得脑受影响区域的再灌注。兴奋性毒性、炎症和细胞凋亡都与脑卒中后延迟性神经元死亡有关,并为神经保护剂干预提供了多种机会。Gelsolin (GSN)是一种肌动蛋白和钙结合蛋白,介导肌动蛋白丝的分解和钙通道的活性。它还可以调节细胞凋亡和炎症反应。本研究验证了一种假设,即在梗死区附近增加血浆GSN (pGSN)的浓度将提供缺血性卒中后的神经保护。方法:通过颅内注射强效血管收缩剂内皮素-1 (ET-1)诱导雄性大鼠大脑中动脉闭塞(MCAO),然后局部给药pGSN。经颅骨行全脑激光多普勒灌注显像,评价MCAO的有效性。在MCAO前和术后72 h,用圆柱体和触电测试评估感觉运动功能。MCAO 72h后,通过2,3,5 -三苯四唑氯(TTC)法检测梗死体积。结果:所有接受MCAO治疗的组的相对脑灌注估计值均显著降低,治疗间无差异。尽管初始卒中相同,但与未治疗的MCAO大鼠相比,pGSN治疗组在72 h时的梗死体积显着减少。ET-1在圆柱体和阴茎试验中均引起显著缺陷,而pGSN显著限制了这些缺陷。结论:Gelsolin是一种很有前景的抗缺血性脑卒中神经退行性变药物。
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