title: Prolonged activation of ERK triggers glutamate-induced apoptosis of astrocytes: neuroprotective effect of FK506.
abstract: Although, astrocytes are more resistant than neurons to ischemic injury, astrocyte death has been demonstrated in animal models of brain ischemia. Astrocytes death after ischemia/reperfusion may strongly affect neuronal survival because of the absence of their trophic and metabolic support to neurons, and astrocytic glutamate uptake. Early signals involved in astrocytes death are poorly understood. We demonstrated enhanced and mostly cytoplasmic activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) during glutamate-induced apoptosis of cultured astrocytes. Treatment with UO126, inhibitor of MEK1, threo-beta-benzyloxyaspartic acid, glutamate transporter inhibitor, and FK506, a cytoprotective drug prevented ERK activation and glutamate-induced apoptosis. Over-expression of ERK dual specificity phosphatases 5 and 6 reduced apoptosis in transfected astrocytes. Prolonged ERK1/2 activation was observed in ischemic brain: in the nucleus and cytoplasm of astrocytes in the cerebral cortex, and exclusively in the cytoplasm of astrocytes in the striatum. Global gene expression profiling in the cortex revealed that FK506 blocks middle cerebral artery occlusion-induced expression of numerous genes associated with ERK signaling pathway and apoptosis. The results demonstrate a pro-apoptotic role of sustained activation of ERK1/2 signaling in glutamate-induced death of astrocytes and the ability of FK506 to block both ERK activation and astrocytic cell death in vitro and in ischemic brains.
authors.affiliation: Laboratory of Transcription Regulation, The Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Szydlowska
authors.forename: Agata
authors.initials: A
authors.lastname: Gozdz
authors.forename: Michal
authors.initials: M
authors.lastname: Dabrowski
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Zawadzka
authors.forename: Bozena
authors.initials: B
authors.lastname: Kaminska
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism / Q000633:toxicity; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D027322:Amino Acid Transport System X-AG; D002070:Butadienes; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D009570:Nitriles; C113580:U 0126; D018698:Glutamic Acid; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D016559:Tacrolimus