Role of serum- and glucocorticoid-inducible kinases in stroke.
Role of serum- and glucocorticoid-inducible kinases in stroke.
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DOI：
10.1111/jnc.13650
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发表时间：
2016-07
影响因子：
4.7
通讯作者：
Xiong ZG
中科院分区：
文献类型：
--
作者：
Inoue K;Leng T;Yang T;Zeng Z;Ueki T;Xiong ZG
血清和糖皮质激素诱导的激酶1（SGK 1）的表达增加可以诱导应激和生长因子在哺乳动物中，并在癌症，糖尿病和高血压中发挥重要作用。最近的一项研究表明，SGK 1活性可以恢复中风模型中的损伤。为了进一步研究SGK在缺血性脑损伤中的作用，我们研究了SGK抑制剂如何影响体内卒中结局和体外神经毒性。比较了成年小鼠大脑中动脉闭塞（MCAO），随后再灌注24小时，在存在或不存在SGK抑制剂的情况下的脑体积。采用体外培养的皮层神经元进行神经毒性试验、电生理记录和荧光钙成像，以评价其潜在机制。与我们的预期相反，在正常和糖尿病条件下，在MCAO前30分钟给予SGK抑制剂gsk 650394或EMD 638683时，卒中引起的梗死体积显著减少。SGK抑制剂可降低N-甲基-D-天冬氨酸（NMDA）受体介导的神经毒性，NMDA受体是导致卒中细胞死亡的主要因素。SGK抑制剂也可改善培养神经元内Ca ~（2+）浓度升高和NMDA电流峰值。此外，SGK抑制剂gsk 650394降低Nedd 4 -2的磷酸化并抑制电压门控钠电流。这些观察结果表明，SGK活性加重中风损害，SGK抑制剂可能是有用的候选人的治疗干预。
Increased expression of serum- and glucocorticoid-inducible kinase 1 (SGK1) can be induced by stress and growth factors in mammals, and plays an important role in cancer, diabetes and hypertension. A recent work suggested that SGK1 activity restores damage in a stroke model. To further investigate the role of SGKs in ischemic brain injury, we examined how SGK inhibitors influence stroke outcome in vivo and neurotoxicity in vitro. Infarct volumes were compared in adult mice with middle cerebral artery occlusion (MCAO), followed by 24 h reperfusion, in the absence or presence of SGK inhibitors. Neurotoxicity assay, electrophysiological recording and fluorescence Ca2+ imaging were carried out using cultured cortical neurons to evaluate the underlying mechanisms. Contrary to our expectation, infarct volume by stroke decreased significantly when SGK inhibitor, gsk650394 or EMD638683, was administrated 30 min before MCAO under normal and diabetic conditions. SGK inhibitors reduced neurotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors, a leading factor responsible for cell death in stroke. SGK inhibitors also ameliorated Ca2+ increase and peak amplitude of NMDA current in cultured neurons. In addition, SGK inhibitor gsk650394 decreased phosphorylation of Nedd4-2 and inhibited voltage-gated sodium currents. These observations suggest that SGK activity exacerbates stroke damage and that SGK inhibitors may be useful candidates for therapeutic intervention.