Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress
Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress
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DOI：
10.1073/pnas.051606598
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发表时间：
2001-03-27
影响因子：
11.1
通讯作者：
Ghezzi, P
中科院分区：
文献类型：
--
作者：
Sirén, AL;Fratelli, M;Ghezzi, P
促红细胞生成素（EPO）通过很大程度上未知的机制促进缺氧和其他代谢损伤后的神经元存活。细胞凋亡和坏死被认为是细胞死亡的机制，两者都可能是EPO的作用靶点。本研究评估抗凋亡机制是否可以解释EPO的神经保护作用。全身施用EPO（5，000单位/kg体重，i. p.）在大鼠大脑中动脉闭塞后，24小时后显著减少梗死体积，与缺血半暗带内末端脱氧核苷酸转移酶介导的dUTP缺口末端标记神经元的数量几乎完全减少一致。在纯的和混合的神经元培养物中，EPO（0.1-10单位/ml）也抑制由血清剥夺或红藻氨酸暴露诱导的细胞凋亡。保护需要预处理，与基因表达程序的诱导一致，并且在没有EPO持续存在的情况下持续3天，（0.3单位/ml）还通过激活细胞外信号调节激酶和蛋白激酶Akt-1/蛋白激酶B保护海马神经元免于缺氧诱导的神经元死亡。EPO的作用不限于直接促进细胞存活，因为EPO在培养的神经元细胞中是营养性的但不是促有丝分裂的。这些数据表明，抑制神经细胞凋亡的基础短潜伏期脑缺血和其他脑损伤后EPO的保护作用。神经营养作用表明可能还有更长的潜伏期效应。EPO是一种临床安全的化合物，作为急性脑损伤的神经保护治疗，其评价得到进一步支持。
Erythropoietin (EPO) promotes neuronal survival after hypoxia and other metabolic insults by largely unknown mechanisms. Apoptosis and necrosis have been proposed as mechanisms of cellular demise, and either could be the target of actions of EPO. This study evaluates whether antiapoptotic mechanisms can account for the neuroprotective actions of EPO, Systemic administration of EPO (5,000 units/kg of body weight, i.p.) after middle-cerebral artery occlusion in rats dramatically reduces the volume of infarction 24 h later, in concert with an almost complete reduction in the number of terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling of neurons within the ischemic penumbra. In both pure and mixed neuronal cultures, EPO (0.1-10 units/ml) also inhibits apoptosis induced by serum deprivation or kainic acid exposure. Protection requires pretreatment, consistent with the induction of a gene expression program, and is sustained for 3 days without the continued presence of EPO, EPO (0.3 units/ml) also protects hippocampal neurons against hypoxia-induced neuronal death through activation of extracellular signal-regulated kinases and protein kinase Akt-1/protein kinase B, The action of EPO is not limited to directly promoting cell survival, as EPO is trophic but not mitogenic in cultured neuronal cells. These data suggest that inhibition of neuronal apoptosis underlies short latency protective effects of EPO after cerebral ischemia and other brain injuries. The neurotrophic actions suggest there may be longer-latency effects as well. Evaluation of EPO, a compound established as clinically safe, as neuroprotective therapy in acute brain injury is further supported.