Neuroprotective effects of protein tyrosine phosphatase 1B inhibitor on cerebral ischemia/reperfusion in mice
Neuroprotective effects of protein tyrosine phosphatase 1B inhibitor on cerebral ischemia/reperfusion in mice
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DOI：
10.1016/j.brainres.2018.04.029
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发表时间：
2018-09-01
期刊：
影响因子：
2.9
通讯作者：
Fukunaga, Kohji
中科院分区：
文献类型：
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作者：
Sun, Meiling;Izumi, Hisanao;Fukunaga, Kohji
Akt（Protein kinase B，PKB）是一种丝氨酸/苏氨酸激酶，在细胞发育、生长和存活中起着关键作用。Akt磷酸化介导对缺血性损伤的神经保护作用。最近，开发了一种蛋白酪氨酸磷酸酶-1B（PTP 1B）抑制剂（KY-226），通过增强胰岛素信号传导来引起抗糖尿病和抗肥胖作用。之前，我们报道过非选择性PTP 1B抑制剂原钒酸钠可以在脑缺血期间拯救神经元免于迟发性神经元死亡。在这项研究中，我们证实了KY-226对缺血/再灌注（I/R）损伤的改善作用，使用小鼠大脑中动脉闭塞（MCAO）模型。ICR小鼠进行MCAO 2小时，然后再灌注。KY-226对正常小鼠血脑屏障（BBB）的通透性较差，但对缺血再灌注损伤后的小鼠血脑屏障有一定的通透性。腹膜内给予KY-226引起梗塞脑区的剂量依赖性减少并改善神经功能缺损。KY-266在再灌注后0.5 h内给药可获得神经保护作用。KY-226（10 mg/kg）还恢复了I/R损伤后降低的Akt磷酸化和eNOS磷酸化（Ser-1177）水平。此外，10 mg/kg的KY-226改善了I/R诱导的细胞外信号调节激酶（ERK）磷酸化的降低。此外，KY-226减弱了小鼠皮层中活性氧（ROS）的产生。这些结果表明，KY-226可能作为一种新的治疗缺血性中风的候选。Akt和ERK的激活可能是KY-226的神经保护机制的基础。(C)2018爱思唯尔B. V.保留所有权利。
Akt (Protein kinase B, PKB), a serine/threonine kinase, plays a critical role in cell development, growth, and survival. Akt phosphorylation mediates a neuroprotective effect against ischemic injury. Recently, a protein-tyrosine phosphatase-1B (PTP1B) inhibitor (KY-226) was developed to elicit anti-diabetic and anti-obesity effects via enhancement of insulin signaling. Previously, we reported that the nonselective PTP1B inhibitor, sodium orthovanadate, rescued neurons from delayed neuronal death during brain ischemia. In this study, we confirmed the ameliorative effects of KY-226 on ischemia/reperfusion (I/R) injury using a murine model of middle cerebral artery occlusion (MCAO). ICR mice were subjected to MCAO for 2 h followed by reperfusion. Although KY-226 permeability was poor through the blood brain barrier (BBB) of normal mice, it could penetrate through the BBB of mice after I/R insult. Intraperitoneal KY-226 administration elicited dose-dependent reductions in infarcted brain areas and improved neurological deficits. The neuroprotective effects of KY-266 were obtained when administered within 0.5 h after reperfusion. KY-226 (10 mg/kg) also restored reduced Akt phosphorylation and eNOS phosphorylation (Ser-1177) levels following I/R insult. Moreover, 10 mg/kg of KY-226 improved I/R-induced decreased extracellular signal-regulated kinase (ERK) phosphorylation. Furthermore, KY-226 attenuated the generation of reactive oxygen species (ROS) in mouse cortex. These results suggest that KY-226 may act as a novel therapeutic candidate for ischemic stroke. Activation of Akt and ERK possibly underlie the neuroprotective mechanism of KY-226. (C) 2018 Elsevier B.V. All rights reserved.