Erythropoietin fosters both intrinsic and extrinsic neuronal protection through modulation of microglia, Akt1, Bad, and caspase-mediated pathways
Erythropoietin fosters both intrinsic and extrinsic neuronal protection through modulation of microglia, Akt1, Bad, and caspase-mediated pathways
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DOI：
10.1038/sj.bjp.0705161
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发表时间：
2003-03-01
影响因子：
7.3
通讯作者：
Maiese, K
中科院分区：
文献类型：
--
作者：
Chong, ZZ;Kang, JQ;Maiese, K
促红细胞生成素（EPO）在造血系统中起着重要作用，但EPO作为神经保护剂和抗炎介质的功能需要进一步定义。因此，我们研究了在原代神经元和脑小胶质细胞自由基损伤过程中EPO介导保护作用的细胞机制，通过台盼蓝、DNA片段化、磷脂酰丝氨酸（PS）暴露、Akt 1磷酸化、Bad磷酸化、线粒体膜电位和半胱氨酸蛋白酶活性评价神经元损伤。通过增殖细胞核抗原和PS受体表达来评估小胶质细胞的活化。EPO提供内在的神经元保护，其对于防止急性基因组DNA破坏和随后的膜PS暴露是必要的和足够的，因为EPO的保护作用通过与抗EPO中和抗体共治疗而完全消除。EPO的外源性保护作用通过抑制脑小胶质细胞活化和抑制小胶质细胞PS受体的表达，以防止神经元的吞噬作用。在小胶质细胞趋化性方面，EPO主要通过调节caspase 1来调节小胶质细胞活化所必需的神经元凋亡膜PS暴露。EPO通过下游调节线粒体膜电位、细胞色素c释放和caspase 1、3来增加Akt 1活性、磷酸化Bad并维持神经元核DNA完整性。和8-样活性。阐明EPO的内在和外在保护途径，介导神经元完整性和炎性小胶质细胞活化，可能会促进针对急性神经元损伤的未来疗法的发展。英国药理学杂志（2003）138，1107-1118。doi：10.1038/sj.bjp.0705161
Erythropoietin (EPO) plays a significant role in the hematopoietic system, but the function of EPO as a neuroprotectant and anti‐inflammatory mediator requires further definition. We therefore examined the cellular mechanisms that mediate protection by EPO during free radical injury in primary neurons and cerebral microglia.Neuronal injury was evaluated by trypan blue, DNA fragmentation, phosphatidylserine (PS) exposure, Akt1 phosphorylation, Bad phosphorylation, mitochondrial membrane potential, and cysteine protease activity. Microglial activation was assessed through proliferating cell nuclear antigen and PS receptor expression.EPO provides intrinsic neuronal protection that is both necessary and sufficient to prevent acute genomic DNA destruction and subsequent membrane PS exposure, since protection by EPO is completely abolished by cotreatment with an anti‐EPO neutralizing antibody.Extrinsic protection by EPO is offered through the inhibition of cerebral microglial activation and the suppression of microglial PS receptor expression for the prevention of neuronal phagocytosis. In regards to microglial chemotaxis, EPO modulates neuronal poptotic membrane PS exposure necessary for microglial activation primarily through the regulation of caspase 1.EPO increases Akt1 activity, phosphorylates Bad, and maintains neuronal nuclear DNA integrity through the downstream modulation of mitochrondrial membrane potential, cytochrome c release, and caspase 1, 3, and 8‐like activities.Elucidating the intrinsic and extrinsic protective pathways of EPO that mediate both neuronal integrity and inflammatory microglial activation may enhance the development of future therapies directed against acute neuronal injury.British Journal of Pharmacology(2003)138, 1107–1118. doi:10.1038/sj.bjp.0705161