title: Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain.
abstract: The developing rodent brain is vulnerable to pharmacological blockade of N-methyl-d-aspartate (NMDA) receptors which can lead to severe and disseminated apoptotic neurodegeneration. Here, we show that systemic administration of the NMDA receptor antagonist MK801 to 7-day-old rats leads to impaired activity of extracellular signal-regulated kinase 1/2 (ERK1/2) and reduces levels of phosphorylated cAMP-responsive element binding protein (CREB) in brain regions which display severe apoptotic neurodegeneration. Impaired ERK1/2 and CREB activity were temporally paralleled by sustained depletion of neurotrophin expression, particularly brain-derived neurotrophic factor (BDNF). BDNF supplementation fully prevented MK801-induced neurotoxicity in immature neuronal cultures and transgenic constitutive activation of Ras was associated with marked protection against MK801-induced apoptotic neuronal death. These data indicate that uncoupling of NMDA receptors from the ERK1/2-CREB signaling pathway in vivo results in massive apoptotic deletion of neurons in the developing rodent brain.
authors.affiliation: Department of Pediatric Neurology,Campus Virchow Klinikum, and Neuroscience Research Center, Charité, Humboldt University, 10117, Berlin, Germany. henrik.hansen@charite.de
authors.forename: Henrik H
authors.initials: HH
authors.lastname: Hansen
authors.forename: Tim
authors.initials: T
authors.lastname: Briem
authors.forename: Mark
authors.initials: M
authors.lastname: Dzietko
authors.forename: Marco
authors.initials: M
authors.lastname: Sifringer
authors.forename: Alexander
authors.initials: A
authors.lastname: Voss
authors.forename: Wojciech
authors.initials: W
authors.lastname: Rzeski
authors.forename: Barbara
authors.initials: B
authors.lastname: Zdzisinska
authors.forename: Friederike
authors.initials: F
authors.lastname: Thor
authors.forename: Rolf
authors.initials: R
authors.lastname: Heumann
authors.forename: Andrzej
authors.initials: A
authors.lastname: Stepulak
authors.forename: Petra
authors.initials: P
authors.lastname: Bittigau
authors.forename: Chrysanthy
authors.initials: C
authors.lastname: Ikonomidou
mesh_terms: D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006179:Gyrus Cinguli / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology*; D009414:Nerve Growth Factors / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D018691:Excitatory Amino Acid Antagonists; D009414:Nerve Growth Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins