In vivo evidence that erythropoietin protects neurons from ischemic damage
In vivo evidence that erythropoietin protects neurons from ischemic damage
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DOI：
10.1073/pnas.95.8.4635
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发表时间：
1998-04-14
影响因子：
11.1
通讯作者：
Sasaki, R
中科院分区：
文献类型：
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作者：
Sakanaka, M;Wen, TC;Sasaki, R
由肾脏和肝脏（胎儿）产生的促红细胞生成素（EPO）刺激红细胞生成。在中枢神经系统，神经元表达EPO受体（EPOR），星形胶质细胞产生EPO。EPO已被证明可以保护原代培养的神经元免受n -甲基- d -天冬氨酸（NMDA）受体介导的谷氨酸毒性。在这里，我们报告了EPO保护神经元免受缺血诱导的细胞死亡的体内证据。向沙鼠侧脑室输注EPO可预防缺血性学习障碍，并可保护海马CA1神经元免受致死性缺血性损伤。外源性EPO的神经保护作用也通过海马CA1区突触计数得到证实。将可溶性EPOR（一种能够与配体结合的细胞外结构域）输注到给予轻度缺血治疗的动物体内，不会产生神经元损伤，但会导致神经元变性和学习能力受损，而输注热变性的可溶性EPOR则不会造成损害，这表明内源性脑EPO对神经元存活至关重要。EPO在神经元培养中的存在并没有抑制NMDA受体介导的细胞内Ca2+的增加，但却使神经元免于no诱导的死亡。综上所述，EPO可能通过减少no介导的自由基形成或拮抗其毒性来发挥其神经保护作用。
Erythropoietin (EPO) produced by the kidney and the liver (in fetuses) stimulates erythropoiesis. In the central nervous system, neurons express EPO receptor (EPOR) and astrocytes produce EPO. EPO has been shown to protect primary cultured neurons from N-methyl-D-aspartate (NMDA) receptor-mediated glutamate toxicity, Here we report in vivo evidence that EPO protects neurons against ischemia-induced cell death. Infusion of EPO into the lateral ventricles of gerbils prevented ischemia-induced learning disability and rescued hippocampal CA1 neurons from lethal ischemic damage. The neuroprotective action of exogenous EPO was also confirmed by counting synapses in the hippocampal CA1 region. Infusion of soluble EPOR (an extracellular domain capable of binding with the ligand) into animals given a mild ischemic treatment that did not produce neuronal damage, caused neuronal degeneration and impaired learning ability, whereas infusion of the heat-denatured soluble EPOR was not detrimental, demonstrating that the endogenous brain EPO is crucial for neuronal survival. The presence of EPO in neuron cultures did not repress a NMDA receptor mediated increase in intracellular Ca2+, but rescued the neurons from NO-induced death. Taken together EPO may exert its neuroprotective effect by reducing the NO-mediated formation of free radicals or antagonizing their toxicity.