Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain

Autor: 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
Jazyk: angličtina
Rok vydání: 2004
Předmět:
Zdroj: Neurobiology of Disease, Vol 16, Iss 2, Pp 440-453 (2004)
Druh dokumentu: article
ISSN: 1095-953X
DOI: 10.1016/j.nbd.2004.03.013
Popis: 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.
Databáze: Directory of Open Access Journals
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