Erythropoietin promotes regeneration of adult CNS neurons via Jak2/Stat3 and PI3K/AKT pathway activation

• Published in: Molecular and cellular neuroscience 2005-08, Vol.29 (4), p.569-579
• Main Authors: Kretz, Alexandra, Happold, Caroline J., Marticke, Julia K., Isenmann, Stefan
• Format: Article
• Language: English
• Subjects: Animals; Bcl_2; Bcl_X L; Cell Survival - drug effects; Cell Survival - physiology; Cells, Cultured; Enzyme Activation - drug effects; Enzyme Activation - physiology; EPO; Erythropoietin - metabolism; Erythropoietin - pharmacology; Female; Growth Cones - drug effects; Growth Cones - metabolism; Janus Kinase 2; Nerve Regeneration - drug effects; Nerve Regeneration - physiology; Neurites - drug effects; Neurites - metabolism; Neuroregeneration; Optic Nerve Injuries - drug therapy; Optic Nerve Injuries - metabolism; Optic Nerve Injuries - physiopathology; Phosphatidylinositol 3-Kinases - drug effects; Phosphatidylinositol 3-Kinases - metabolism; Protein-Tyrosine Kinases - drug effects; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - drug effects; Proto-Oncogene Proteins - metabolism; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Retinal Ganglion Cells - drug effects; Retinal Ganglion Cells - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Stat_proteins; Up-Regulation - drug effects; Up-Regulation - physiology
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2005.04.009

The cytokine hormone erythropoietin (EPO) has proved neuroprotective in CNS injury, and clinical trials for ischemic stroke are ongoing. The capability of EPO to restore postmitotic CNS architecture and function by fibre regeneration has not been examined. Here, we compared in vitro outgrowth capacity of adult retinal ganglion cells (RGCs) following optic nerve (ON) lesion in the presence and absence of EPO. Immediate EPO conditioning in vivo, or delayed EPO treatment of cultures with 10–10,000 IU rhEPO significantly increased numbers (2.66-fold) and length (8.31-fold) of newly generated neurites, without evoking rheological complications. EPO induced Stat3 phosphorylation in RGCs, and inhibition of Jak2/Stat3 abolished EPO-induced growth. EPO-facilitated neuritogenesis was paralleled by upregulation of Bcl-X L, a Bcl-2 homologue capable of promoting RGC regeneration. The PI3K/Akt pathway was also involved in antiapoptotic and regeneration-enhancing EPO actions. In conclusion, EPO treatment may offer a unique dual-function strategy for neuroprotection and regeneration.