Erythropoietin prevents early and late neuronal demise through modulation of Akt1 and induction of caspase 1, 3, and 8

Abstract

Erythropoietin (EPO) modulates primarily the proliferation of immature erythroid precursors, but little is known of the potential protective mechanisms of EPO in the central nervous system. We therefore examined the ability of EPO to modulate a series of death-related cellular pathways during anoxia and free radical induced neuronal degeneration. Neuronal injury was evaluated by trypan blue, DNA fragmentation, membrane phosphatidylserine exposure, protein kinase B phosphorylation, cysteine protease activity, mitochondrial membrane potential, and mitogen-activated protein (MAP) kinase phosphorylation. We demonstrate that constitutive neuronal EPO is insufficient to prevent cellular injury, but that signaling through the EPO receptor remains biologically responsive to exogenous EPO administration. Exogenous EPO is both necessary and sufficient to prevent acute genomic DNA destruction and subsequent phagocytosis through membrane PS exposure, because neuronal protection by EPO is completely abolished by co-treatment with an anti-EPO neutralizing antibody. Through pathways that involve the initial activation of protein kinase B, EPO maintains mitochondrial membrane potential. Subsequently, EPO inhibits caspase 8-, caspase 1-, and caspase 3-like activities linked to cytochrome c release through mechanisms that are independent from the MAP kinase systems of p38 and JNK. Elucidating some of the novel neuroprotective pathways employed by EPO may further the development of new therapeutic strategies for neurodegenerative disorders.

促红细胞生成素对1-甲基-4-苯基吡啶损伤的 Pc12 细胞的保护作用

“…The neuroprtective effect of EPO reached maximum at 1 U/mL, while obviously decreased at larger doses. In accordance with others found in various cell culture models of neuronal cell death [13,16] , the survivalpromoting action of EPO followed a bell-shaped doseresponse curve in our in vitro paradigm. Increasing EPO concentration in the cell culture medium above an optimal of Bcl-2 in the MPP + -treated group was significantly decreased compared with the control group.…”

“…Studies in vitro provided informations related to the molecular pathways involved in EPO action. These data showed that EPO may have a direct protective role against a variety of neurotoxic insults, such as hypoxic conditions [11] , glutamate toxicity [12] , free-radical injury [13] , and exposure to neurotoxicants [14] . In addition, EPO receptor is abundantly expressed in adult dopaminergic neurons [15] , suggesting a direct effect of EPO on neurons.…”

Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen–glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures

“…In the brain, EPO is highly expressed in development (Buemi et al, 2002;Nagai et al, 2001). In the mature brain, expression of EPO appears to be upregulated by oxidative or nitrosative stress (Bernaudin et al, 1999(Bernaudin et al, , 2000Chong et al, 2003;Digicaylioglu et al, 1995). Within the brain, functional EPORs are expressed by different cell types such as neurons, glial cells and brain capillary endothelial cells (Genc et al, 2004a,b), while the main source of EPO within the CNS itself appears to be the astroglial cells (Bernaudin et al, 2000;Digicaylioglu et al, 1995;Juul et al, 1998;Marti et al, 1996;Masuda et al, 1993).…”

Erythropoietin inhibits apoptosis induced by photodynamic therapy in ovarian cancer cells

“…The activation of Akt signal transduction mediates the antiapoptotic effects of erythropoietin in primary human erythroid progenitor cells (41), in vascular endothelial cells (42), and in neural tissue (43). A recent study showed the association between erythropoietin and dose-dependent inhibition of apoptosis in response to Taxol treatment and serum starvation of rodent mammary adenocarcinoma (R3230) cells in vitro (44).…”