Sun Meiling, Izumi Hisanao, Shinoda Yasuharu, Fukunaga Kohji
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai Japan.
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai Japan.
Brain Res. 2018 Sep 1;1694:1-12. doi: 10.1016/j.brainres.2018.04.029. Epub 2018 Apr 26.
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.
Akt（蛋白激酶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，一种蛋白酪氨酸磷酸酶-1B（PTP1B）抑制剂（KY-226）被开发出来，通过增强胰岛素信号传导来产生抗糖尿病和抗肥胖作用。此前，我们报道非选择性PTP1B抑制剂原钒酸钠可使神经元在脑缺血期间免于延迟性神经元死亡。在本研究中，我们使用大脑中动脉闭塞（MCAO）小鼠模型证实了KY-226对缺血/再灌注（I/R）损伤的改善作用。将ICR小鼠进行MCAO 2小时，然后再灌注。尽管KY-226透过正常小鼠血脑屏障（BBB）的通透性较差，但在I/R损伤后它可以穿透小鼠的BBB。腹腔注射KY-226可使梗死脑区呈剂量依赖性减小，并改善神经功能缺损。在再灌注后0.5小时内给予KY-266可获得神经保护作用。KY-226（10mg/kg）还可恢复I/R损伤后降低了的Akt磷酸化和eNOS磷酸化（Ser-1177）水平。此外，10mg/kg的KY-226改善了I/R诱导的细胞外信号调节激酶（ERK）磷酸化降低的情况。此外，KY-226减弱了小鼠皮质中活性氧（ROS）的生成。这些结果表明，KY-226可能作为缺血性中风的一种新型治疗候选药物。Akt和ERK的激活可能是KY-226神经保护机制 的基础。
