title: Erythropoietin-mediated protection of insect brain neurons involves JAK and STAT but not PI3K transduction pathways.
abstract: The cytokine erythropoietin (Epo) initiates adaptive cellular responses to both moderate environmental challenges and tissue damaging insults in various non-hematopoietic mammalian tissues including the nervous system. Neuroprotective and neuroregenerative functions of Epo in mammals are mediated through receptor-associated Janus kinase 2 and intracellular signaling cascades that modify the transcription of Epo-regulated genes. Signal transducers and activators of transcription (STAT) and phosphoinositol-3-kinase (PI3K) represent key components of two important Epo-induced transduction pathways. Our previous study on insects revealed neuroprotective and regenerative functions of recombinant human Epo (rhEpo) similar to those in mammalian nervous tissues. Here we demonstrate that rhEpo effectively rescues primary cultured locust brain neurons from apoptotic cell death induced by hypoxia or the chemical compound H-7. The Janus kinase inhibitor AG-490 and the STAT inhibitor sc-355797 abolished protective effects of rhEpo on locust brain neurons. In contrast, inhibition of PI3K with LY294002 had no effect on rhEpo-mediated neuroprotection. The results indicate that rhEpo mediates the protection of locust brain neurons through interference with apoptotic pathways by the activation of a Janus kinase-associated receptor and STAT transcription factor(s). The involvement of similar transduction pathways in mammals and insects for the mediation of neuroprotection and support of neural regeneration by Epo indicates that an Epo/Epo receptor-like signaling system with high structural and functional similarity exists in both groups of animals. Epo-like signaling involved in tissue protection appears to be an ancient beneficial function shared by vertebrates and invertebrates.
authors.affiliation: Department of Cellular Neurobiology, Institute for Zoology, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Miljus
authors.affiliation: Department of Cellular Neurobiology, Institute for Zoology, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Heibeck
authors.affiliation: Department of Cellular Neurobiology, Institute for Zoology, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Jarrar
authors.affiliation: Department of Cellular Neurobiology, Institute for Zoology, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Micke
authors.affiliation: Department of Cellular Neurobiology, Institute for Zoology, Georg-August-University Göttingen, Göttingen, Germany; Department of Biomedical Sciences, Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA.
authors.forename: D
authors.initials: D
authors.lastname: Ostrowski
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany; DFG Center for Nanoscale Microscopy & Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Ehrenreich
authors.affiliation: Department of Cellular Neurobiology, Institute for Zoology, Georg-August-University Göttingen, Göttingen, Germany. Electronic address: rheinri1@gwdg.de.
authors.forename: R
authors.initials: R
authors.lastname: Heinrich
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000633:toxicity; D004921:Erythropoietin / Q000494:pharmacology*; D006110:Grasshoppers / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy / Q000503:physiopathology; D019476:Insect Proteins / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002867:Chromones; D004791:Enzyme Inhibitors; D004921:Erythropoietin; D019476:Insect Proteins; D053614:Janus Kinase 2; D009025:Morpholines; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D050791:STAT Transcription Factors; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
keywords: Epo; Epo receptor; EpoR; GM; H-7; JAK2; Janus kinase 2; Locusta migratoria; MAPK; PBS; PI3K; PI3K/Akt; RT; STAT; Signal transducers and activators of transcription; apoptosis; erythropoietin; gentamicin; hypoxia; insect; mitogen-activated protein kinase; phosphate-buffered saline; phosphoinositol-3-kinase; phosphoinositol-3-kinase/protein kinase B; primary brain cell culture; recombinant human Epo; rhEpo; room temperature; β common receptor; βc-R