title: Erythropoietin increases neuronal NDPKA expression, and NDPKA up-regulation as well as exogenous application protects cortical neurons from in vitro ischemia-related insults.
abstract: Using proteomics, we identified nucleoside diphosphate kinase A (NDPKA; also known as NME/NM23 nucleoside diphosphate kinase 1: NME1) to be up-regulated in primary cortical neuronal cultures by erythropoietin (EPO) preconditioning. To investigate a neuroprotective role of NDPKA in neurons, we used a RNAi construct to knock-down and an adenoviral vector to overexpress the protein in cortical neuronal cultures prior to exposure to three ischemia-related injury models; excitotoxicity (L-glutamic acid), oxidative stress (hydrogen peroxide), and in vitro ischemia (oxygen-glucose deprivation). NDPKA down-regulation had no effect on neuronal viability following injury. By contrast, NDPKA up-regulation increased neuronal survival in all three-injury models. Similarly, treatment with NDPKA recombinant protein increased neuronal survival, but only against in vitro ischemia and excitotoxicity. These findings indicate that the NDPKA protein may confer a neuroprotective advantage following injury. Furthermore, as exogenous NDPKA protein was neuroprotective, it suggests that a cell surface receptor may be activated by NDPKA leading to a protective cell-signaling response. Taken together both NDPKAs intracellular and extracellular neuroprotective actions suggest that the protein is a legitimate therapeutic target for the design of drugs to limit neuronal death following stroke and other forms of brain injury.
authors.affiliation: Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, WA, 6009, Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Teoh
authors.forename: Sherif
authors.initials: S
authors.lastname: Boulos
authors.forename: Joanne
authors.initials: J
authors.lastname: Chieng
authors.forename: Neville W
authors.initials: NW
authors.lastname: Knuckey
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Meloni
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000517:prevention & control; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004921:Erythropoietin / Q000494:pharmacology / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009701:Nucleoside-Diphosphate Kinase / Q000096:biosynthesis* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D018696:Neuroprotective Agents; D004921:Erythropoietin; D009701:Nucleoside-Diphosphate Kinase; C576766:nucleoside diphosphate kinase, rat