Wu Xiaomei, Su Jianyou, Chen Lei, Ma Baodong, Gu Xiaosu, Zhu Li
Department of Neurochemistry, Institute for Nautical Medicine, Nantong University, 9 Seyuan Road, Nantong, 226019, China.
Medical Laboratory Center, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, China.
Cell Mol Neurobiol. 2015 Oct;35(7):943-52. doi: 10.1007/s10571-015-0189-3. Epub 2015 Apr 14.
RTP801 (also known as REDD1), a stress-related protein, is induced by several environmental stresses such as ischemia and cigarette smoke. Although ischemia can dramatically up-regulate RTP801 expression in brain ischemia, up to now, the exact relation between RTP801 and neuronal death in ischemia is poorly understood. In the current study, using oxygen and glucose deprivation as an in vitro ischemic model in primary cultured cortical neurons, we found that the expression of RTP801 increased progressively with prolongation of ischemic duration, in which the expression of RTP801 is positively correlated with the release of lactate dehydrogenase (LDH) in neurons, and knockdown of RTP801 promoted neuronal survival in ischemia-reperfusion. It was further found that ginkgolide B (GB) could significantly increase cell viability and decrease LDH release, and at the same time reduce the levels of RTP801 mRNA and protein in neurons after ischemia and reperfusion. Moreover, GB-induced reduction in expression of RTP801 was blocked by application of LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K). These results demonstrate that RTP801 could play a detrimental role on neurons in ischemia, and GB might protect neurons against ischemic injury by inhibiting RTP801 expression via PI3K pathway.
RTP801（也称为REDD1）是一种与应激相关的蛋白质，可由多种环境应激因素诱导产生，如局部缺血和香烟烟雾。尽管在脑缺血中局部缺血可显著上调RTP801的表达，但迄今为止，RTP801与缺血性神经元死亡的确切关系仍不清楚。在本研究中，我们以氧糖剥夺作为原代培养皮层神经元的体外缺血模型，发现RTP801的表达随着缺血时间的延长而逐渐增加，其中RTP801的表达与神经元中乳酸脱氢酶（LDH）的释放呈正相关，敲低RTP801可促进缺血再灌注时神经元的存活。进一步发现，银杏内酯B（GB）可显著提高细胞活力并减少LDH释放，同时降低缺血再灌注后神经元中RTP801 mRNA和蛋白的水平。此外，应用磷脂酰肌醇3激酶（PI3K）的特异性抑制剂LY294002可阻断GB诱导的RTP801表达降低。这些结果表明，RTP801可能在缺血时对神经元起有害作用，而GB可能通过PI3K途径抑制RTP801表达来保护神经元免受缺血性损伤。
