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Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain.
Neurobiol Dis. 2004 Jul; 16(2):440-53.ND

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+Show Affiliations

Department of Pediatric Neurology,Campus Virchow Klinikum, and Neuroscience Research Center, Charité, Humboldt University, 10117, Berlin, Germany. henrik.hansen@charite.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15193300

Citation

Hansen, Henrik H., et al. "Mechanisms Leading to Disseminated Apoptosis Following NMDA Receptor Blockade in the Developing Rat Brain." Neurobiology of Disease, vol. 16, no. 2, 2004, pp. 440-53.
Hansen HH, Briem T, Dzietko M, et al. Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain. Neurobiol Dis. 2004;16(2):440-53.
Hansen, H. H., Briem, T., Dzietko, M., Sifringer, M., Voss, A., Rzeski, W., Zdzisinska, B., Thor, F., Heumann, R., Stepulak, A., Bittigau, P., & Ikonomidou, C. (2004). Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain. Neurobiology of Disease, 16(2), 440-53.
Hansen HH, et al. Mechanisms Leading to Disseminated Apoptosis Following NMDA Receptor Blockade in the Developing Rat Brain. Neurobiol Dis. 2004;16(2):440-53. PubMed PMID: 15193300.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain. AU - Hansen,Henrik H, AU - Briem,Tim, AU - Dzietko,Mark, AU - Sifringer,Marco, AU - Voss,Alexander, AU - Rzeski,Wojciech, AU - Zdzisinska,Barbara, AU - Thor,Friederike, AU - Heumann,Rolf, AU - Stepulak,Andrzej, AU - Bittigau,Petra, AU - Ikonomidou,Chrysanthy, PY - 2004/01/04/received PY - 2004/03/16/revised PY - 2004/03/22/accepted PY - 2004/6/15/pubmed PY - 2004/8/17/medline PY - 2004/6/15/entrez SP - 440 EP - 53 JF - Neurobiology of disease JO - Neurobiol Dis VL - 16 IS - 2 N2 - 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. SN - 0969-9961 UR - https://www.unboundmedicine.com/medline/citation/15193300/Mechanisms_leading_to_disseminated_apoptosis_following_NMDA_receptor_blockade_in_the_developing_rat_brain_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969996104000749 DB - PRIME DP - Unbound Medicine ER -