Neuroprotective effects of erythropoietin on glutamate and nitric oxide toxicity in primary cultured retinal ganglion cells
Neuroprotective effects of erythropoietin on glutamate and nitric oxide toxicity in primary cultured retinal ganglion cells
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DOI：
10.1016/j.brainres.2005.05.037
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发表时间：
2005-07
期刊：
影响因子：
2.9
通讯作者：
Makiko Yamasaki;H. Mishima;H. Yamashita;K. Kashiwagi;K. Murata;A. Minamoto;T. Inaba
中科院分区：
文献类型：
--
作者：
Makiko Yamasaki;H. Mishima;H. Yamashita;K. Kashiwagi;K. Murata;A. Minamoto;T. Inaba
促红细胞生成素受体(EPOR)在中枢神经系统(CNS)中表达，但EPO是否在神经元中起到生存因子的作用还没有明确的共识。由于视网膜神经节细胞(RGC)死亡是几种眼病中视功能下降的常见原因，我们通过两步淘洗的方法分离RGC，探讨EPO是否可能有助于保护RGC免受谷氨酸和一氧化氮(NO)诱导的细胞毒性。以脑源性神经营养因子(BDNF)为阳性对照。EPOR mRNA在分离的RGCs中表达，EPOR蛋白在正常和缺血视网膜RGCs上表达。与BDNF相比，EPO对原代培养的RGCs在无血清培养条件下的存活率影响较小。在这些细胞中，BDNF而不是EPO下调了Bim的表达，Bim是一个促凋亡的Bcl-2家族成员，在细胞因子介导的细胞生存中发挥关键作用，这表明这种差异可能是一种机制。当视网膜节细胞与谷氨酸或NO生成剂共同培养时，视网膜节细胞的存活受到影响，细胞内的Bcl2表达减少。EPO和BDNF均能显著减少谷氨酸和NO诱导的RGC死亡。与此相一致的是，这些因素逆转了Bcl2的表达。这些发现表明，EPO可能是一种有效的神经保护性治疗药物，用于治疗以RGC死亡为特征的眼部疾病。
Erythropoietin receptor (EpoR) is expressed in the central nervous system (CNS), however, no clear consensus has been obtained whether Epo acts as a prosurvival factor in neurons. Because retinal ganglion cell (RGC) death is a common cause of reduced visual function in several ocular diseases, we explored whether Epo might potentially be beneficial in protecting RGCs from glutamate and nitric oxide (NO)-induced cytotoxicity, using isolated RGCs by a two-step panning method. Brain-derived neurotrophic factor (BDNF) was used as a positive control. EpoR mRNA was expressed in isolated RGCs, and EpoR protein was expressed on the RGCs in the normal and ischemic retinas. Epo had less potential to improve the survival of primary RGCs in serum-free medium than BDNF. In these cells, BDNF, but not Epo, downregulated the expression of Bim, a proapoptotic Bcl-2 family member that plays a key role in cytokine-mediated cell survival, suggesting a possible mechanism for this difference. When RGCs were cultured with glutamate or an NO-generating reagent, the survival of RGCs was compromised, and Bcl-2 expression was decreased in these cells. Both Epo and BDNF significantly reduced RGC death induced by glutamate and NO. In agreement with this, these factors reversed the Bcl-2 expression. These findings suggest that Epo may be a potent neuroprotective therapeutic agent for the treatment of ocular diseases that are characterized by RGC death.