Neurobiology of Disease (Jul 2004)
Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain
- Henrik H Hansen,
- Tim Briem,
- Mark Dzietko,
- Marco Sifringer,
- Alexander Voss,
- Wojciech Rzeski,
- Barbara Zdzisinska,
- Friederike Thor,
- Rolf Heumann,
- Andrzej Stepulak,
- Petra Bittigau,
- Chrysanthy Ikonomidou
Affiliations
- Henrik H Hansen
- Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Neuroscience Research Center, Charité, Humboldt University, 10117 Berlin, Germany; Department of Pharmacology, The Danish University of Pharmaceutical Sciences, DK-2100 Copenhagen, Denmark; Department of Neonatology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Sklodowska University, Lublin, Poland; Molecular Neurobiochemistry, Ruhr University, Bochum, Germany; Department of Biochemistry and Molecular Biology, University School of Medicine, Lublin, Poland
- Tim Briem
- Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Neuroscience Research Center, Charité, Humboldt University, 10117 Berlin, Germany; Department of Pharmacology, The Danish University of Pharmaceutical Sciences, DK-2100 Copenhagen, Denmark; Department of Neonatology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Sklodowska University, Lublin, Poland; Molecular Neurobiochemistry, Ruhr University, Bochum, Germany; Department of Biochemistry and Molecular Biology, University School of Medicine, Lublin, Poland
- Mark Dzietko
- Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Neuroscience Research Center, Charité, Humboldt University, 10117 Berlin, Germany; Department of Pharmacology, The Danish University of Pharmaceutical Sciences, DK-2100 Copenhagen, Denmark; Department of Neonatology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Sklodowska University, Lublin, Poland; Molecular Neurobiochemistry, Ruhr University, Bochum, Germany; Department of Biochemistry and Molecular Biology, University School of Medicine, Lublin, Poland
- Marco Sifringer
- Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Neuroscience Research Center, Charité, Humboldt University, 10117 Berlin, Germany; Department of Pharmacology, The Danish University of Pharmaceutical Sciences, DK-2100 Copenhagen, Denmark; Department of Neonatology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Sklodowska University, Lublin, Poland; Molecular Neurobiochemistry, Ruhr University, Bochum, Germany; Department of Biochemistry and Molecular Biology, University School of Medicine, Lublin, Poland
- Alexander Voss
- Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Neuroscience Research Center, Charité, Humboldt University, 10117 Berlin, Germany; Department of Pharmacology, The Danish University of Pharmaceutical Sciences, DK-2100 Copenhagen, Denmark; Department of Neonatology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Sklodowska University, Lublin, Poland; Molecular Neurobiochemistry, Ruhr University, Bochum, Germany; Department of Biochemistry and Molecular Biology, University School of Medicine, Lublin, Poland
- Wojciech Rzeski
- Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Neuroscience Research Center, Charité, Humboldt University, 10117 Berlin, Germany; Department of Pharmacology, The Danish University of Pharmaceutical Sciences, DK-2100 Copenhagen, Denmark; Department of Neonatology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Sklodowska University, Lublin, Poland; Molecular Neurobiochemistry, Ruhr University, Bochum, Germany; Department of Biochemistry and Molecular Biology, University School of Medicine, Lublin, Poland
- Barbara Zdzisinska
- Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Neuroscience Research Center, Charité, Humboldt University, 10117 Berlin, Germany; Department of Pharmacology, The Danish University of Pharmaceutical Sciences, DK-2100 Copenhagen, Denmark; Department of Neonatology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Sklodowska University, Lublin, Poland; Molecular Neurobiochemistry, Ruhr University, Bochum, Germany; Department of Biochemistry and Molecular Biology, University School of Medicine, Lublin, Poland
- Friederike Thor
- Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Neuroscience Research Center, Charité, Humboldt University, 10117 Berlin, Germany; Department of Pharmacology, The Danish University of Pharmaceutical Sciences, DK-2100 Copenhagen, Denmark; Department of Neonatology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Sklodowska University, Lublin, Poland; Molecular Neurobiochemistry, Ruhr University, Bochum, Germany; Department of Biochemistry and Molecular Biology, University School of Medicine, Lublin, Poland
- Rolf Heumann
- Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Neuroscience Research Center, Charité, Humboldt University, 10117 Berlin, Germany; Department of Pharmacology, The Danish University of Pharmaceutical Sciences, DK-2100 Copenhagen, Denmark; Department of Neonatology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Sklodowska University, Lublin, Poland; Molecular Neurobiochemistry, Ruhr University, Bochum, Germany; Department of Biochemistry and Molecular Biology, University School of Medicine, Lublin, Poland
- Andrzej Stepulak
- Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Neuroscience Research Center, Charité, Humboldt University, 10117 Berlin, Germany; Department of Pharmacology, The Danish University of Pharmaceutical Sciences, DK-2100 Copenhagen, Denmark; Department of Neonatology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Sklodowska University, Lublin, Poland; Molecular Neurobiochemistry, Ruhr University, Bochum, Germany; Department of Biochemistry and Molecular Biology, University School of Medicine, Lublin, Poland
- Petra Bittigau
- Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Neuroscience Research Center, Charité, Humboldt University, 10117 Berlin, Germany; Department of Pharmacology, The Danish University of Pharmaceutical Sciences, DK-2100 Copenhagen, Denmark; Department of Neonatology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Sklodowska University, Lublin, Poland; Molecular Neurobiochemistry, Ruhr University, Bochum, Germany; Department of Biochemistry and Molecular Biology, University School of Medicine, Lublin, Poland
- Chrysanthy Ikonomidou
- Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Neuroscience Research Center, Charité, Humboldt University, 10117 Berlin, Germany; Department of Pharmacology, The Danish University of Pharmaceutical Sciences, DK-2100 Copenhagen, Denmark; Department of Neonatology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, 13353 Berlin, Germany; Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Sklodowska University, Lublin, Poland; Molecular Neurobiochemistry, Ruhr University, Bochum, Germany; Department of Biochemistry and Molecular Biology, University School of Medicine, Lublin, Poland
- Journal volume & issue
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Vol. 16,
no. 2
pp. 440 – 453
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.
