title: EPO-dependent activation of PI3K/Akt/FoxO3a signalling mediates neuroprotection in in vitro and in vivo models of Parkinson's disease.
abstract: Erythropoietin (EPO) may become a potential therapeutic candidate for the treatment of the neurodegenerative disorder -- Parkinson's disease (PD), since EPO has been found to prevent neuron apoptosis through the activation of cell survival signalling. However, the underlying mechanisms of how EPO exerts its neuroprotective effect are not fully elucidated. Here we investigated the mechanism by which EPO suppressed 6-hydroxydopamine (6-OHDA)-induced neuron death in in vitro and in vivo models of PD. EPO knockdown conferred 6-OHDA-induced cytotoxicity. This effect was reversed by EPO administration. Treatment of PC12 cells with EPO greatly diminished the toxicity induced by 6-OHDA in a dose- and time-dependent manner. EPO effectively reduced apoptosis of striatal neurons and induced a significant improvement on the neurological function score in the rat models of PD. Furthermore, EPO increased the expression of phosphorylated Akt and phosphorylated FoxO3a, and abrogated the 6-OHDA-induced dysregulation of Bcl-2, Bax and Caspase-3 in PC12 cells and in striatal neurons. Meanwhile, the EPO-dependent neuroprotection was notably reversed by pretreatment with LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K). Our data suggest that PI3K/Akt/FoxO3a signalling pathway may be a possible mechanism involved in the neuroprotective effect of EPO in PD.
authors.affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jia
authors.forename: Shi-Jing
authors.initials: SJ
authors.lastname: Mo
authors.forename: Qi-Qi
authors.initials: QQ
authors.lastname: Feng
authors.forename: Ma-Li
authors.initials: ML
authors.lastname: Zhan
authors.forename: Li-Si
authors.initials: LS
authors.lastname: OuYang
authors.forename: Jia-Chang
authors.initials: JC
authors.lastname: Chen
authors.forename: Yu-Xin
authors.initials: YX
authors.lastname: Ma
authors.forename: Jia-Jia
authors.initials: JJ
authors.lastname: Wu
authors.forename: Wan-Long
authors.initials: WL
authors.lastname: Lei
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004921:Erythropoietin / Q000494:pharmacology / Q000627:therapeutic use*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008124:Locomotion; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016627:Oxidopamine / Q000633:toxicity; D016716:PC12 Cells; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D002867:Chromones; D004921:Erythropoietin; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009025:Morpholines; D018696:Neuroprotective Agents; D016627:Oxidopamine; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C499515:FOXO3 protein, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one