Nasal administration of osteopontin peptide mimetics confers neuroprotection in stroke
Nasal administration of osteopontin peptide mimetics confers neuroprotection in stroke
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DOI：
10.1038/jcbfm.2008.17
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发表时间：
2008-06-01
影响因子：
6.3
通讯作者：
Stenzel-Poore, Mary P.
中科院分区：
文献类型：
--
作者：
Doyle, Kristian P.;Yang, Tao;Stenzel-Poore, Mary P.
骨桥蛋白（OPN）是一种具有精氨酸、甘氨酸、天冬氨酸（RGD）结构的分泌型糖蛋白，可与细胞整合素受体结合并通过整合素受体传递信号。我们以前已经表明，骨桥蛋白在缺血环境中增强神经元的存活。在这里，我们试图增加OPN的神经保护效力，并改进递送方法，目的是确定人类中风的治疗方法。我们发现，凝血酶裂解骨桥蛋白提高了其连接整合素受体的能力，并提高了其在缺血模型中的神经保护能力。凝血酶裂解的OPN是一种比未经处理的分子有效两倍的神经保护剂。我们还测试了OPN是否可以鼻内给药，发现它通过鼻内递送有效地靶向大脑。此外，经凝血酶处理的OPN的鼻内给药赋予针对缺血性脑损伤的保护作用。产生基于位于凝血酶切割位点的N或C末端的肽序列的骨桥蛋白模拟物，并在缺血模型中进行测试。用连续较短的N-末端肽和磷酸化的C-末端肽治疗提供了针对缺血性损伤的显著神经保护。这些发现表明，OPN模拟物为开发治疗中风的新药提供了希望。
Osteopontin (OPN), a large secreted glycoprotein with an arginine, glycine, aspartate (RGD) motif, can bind and signal through cellular integrin receptors. We have shown previously that OPN enhances neuronal survival in the setting of ischemia. Here, we sought to increase the neuroprotective potency of OPN and improve the method of delivery with the goal of identifying a treatment for stroke in humans. We show that thrombin cleavage of OPN improves its ability to ligate integrin receptors and its neuroprotective capacity in models of ischemia. Thrombin-cleaved OPN is a twofold more effective neuroprotectant than the untreated molecule. We also tested whether OPN could be administered intranasally and found that it is efficiently targeted to the brain via intranasal delivery. Furthermore, intranasal administration of thrombin-treated OPN confers protection against ischemic brain injury. Osteopontin mimetics based on the peptide sequences located either N or C terminal to the thrombin cleavage site were generated and tested in models of ischemia. Treatment with successively shorter N-terminal peptides and a phosphorylated C-terminal peptide provided significant neuroprotection against ischemic injury. These findings show that OPN mimetics offer promise for development into new drugs for the treatment of stroke.