Efficacy and Safety of Platelet Glycoprotein Receptor Blockade in Aged and Comorbid Mice With Acute Experimental Stroke
Efficacy and Safety of Platelet Glycoprotein Receptor Blockade in Aged and Comorbid Mice With Acute Experimental Stroke
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DOI：
10.1161/strokeaha.115.011114
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发表时间：
2015-12-01
期刊：
影响因子：
8.3
通讯作者：
Kleinschnitz, Christoph
中科院分区：
文献类型：
--
作者：
Kraft, Peter;Schuhmann, Michael K.;Kleinschnitz, Christoph
背景和目的--尽管缺血性中风的医学和社会经济影响以及广泛的临床前研究，但缺血性中风的治疗选择有限。我们最近发现并表征了中风中血栓形成的基本步骤，并证明了抑制血小板膜糖蛋白(GP)受体Ib和VI，而不是IIb/IIIa，可以保护年轻和健康的小鼠免受缺血性神经变性的影响。目前尚不清楚这些发现是否会应用于临床。考虑到典型的中风患者是老年患者，我们的目的是分析新型临床前抗血栓药物在成年和合并急性实验性中风小鼠中的有效性和安全性。方法：我们将成年、健康、动脉粥样硬化(LDLR(-/-))、糖尿病(链脲佐菌素治疗)和高血压(RenTgMK)小鼠造成60min短暂大脑中动脉闭塞。卒中后1h分别给予抗GPVI抗体或抗GPIb或抗GPIIb/IIIa抗原结合片段治疗。以同型处理为对照。短暂性大脑中动脉闭塞24小时后，我们目测脑内出血率，并测量脑梗塞体积(用2，3，5-三苯基四氮唑氯化铵染色的脑片)和功能结果(使用Bederson和握力测试评分)。结果-GPIB和GPVI抑制对小鼠缺血性卒中有保护作用，而不增加出血并发症。相反，抑制GPIIb/IIIa不具有保护作用，反而增加了脑出血的发生率。结论-抑制血栓形成的早期步骤可以保护成年和合并中风的小鼠免受缺血性中风的影响。使用具有临床意义的小鼠品系可能会促进临床前中风研究向临床的转化。
Background and Purpose-Despite the medical and socioeconomic effect of ischemic stroke and extensive preclinical research, treatment options for ischemic stroke are limited. We recently identified and characterized essential steps of thrombus formation in stroke and demonstrated that inhibition of the platelet glycoprotein (GP) receptors Ib and VI, but not IIb/IIIa, protects young and healthy mice from ischemic neurodegeneration. Whether these findings translate to the clinic remains unclear. Considering that the typical stroke patient is elderly with comorbidity, we aimed to analyze the efficacy and safety of novel preclinical antithrombotics in adult and comorbid mice with acute experimental stroke.Methods-We subjected adult, healthy, atherosclerotic (Ldlr(-/-)), diabetic (streptozotocin treated), and hypertensive (RenTgMK) mice to a 60-minute transient middle cerebral artery occlusion. Animals were pretreated with anti-GPVI antibodies or treated 1 hour after stroke induction with anti-GPIb or anti-GPIIb/IIIa antigen-binding fragments, respectively. Isotype treatment served as control. Twenty-four hours after transient middle cerebral artery occlusion, we visually assessed the intracerebral hemorrhage rate and measured infarct volumes (using 2,3,5-triphenyltetrazolium chloride-stained brain slices) and functional outcome (using Bederson and grip-test scores).Results-GPIb and GPVI inhibition protected the mice from ischemic stroke without increasing bleeding complications. In contrast, GPIIb/IIIa inhibition was not protective but increased the intracerebral hemorrhage rate.Conclusions-Inhibition of early steps of thrombus formation protects adult and comorbid mice from ischemic stroke. The use of clinically meaningful mouse strains might improve the translation of preclinical stroke research to the clinic.