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The excitoprotective effect of N-methyl-D-aspartate receptors is mediated by a brain-derived neurotrophic factor autocrine loop in cultured hippocampal neurons.
J Neurochem. 2005 Aug; 94(3):713-22.JN

Abstract

The neuroprotective effect and molecular mechanisms underlying preconditioning with N-methyl-D-aspartate (NMDA) in cultured hippocampal neurons have not been described. Pre-incubation with subtoxic concentrations of the endogenous neurotransmitter glutamate protects vulnerable neurons against NMDA receptor-mediated excitotoxicity. As a result of physiological preconditioning, NMDA significantly antagonizes the neurotoxicity resulting from subsequent exposure to an excitotoxic concentration of glutamate. The protective effect of glutamate or NMDA is time- and concentration-dependent, suggesting that sufficient agonist and time are required to establish an intracellular neuroprotective state. In these cells, the TrkB ligand, brain-derived neurotrophic factor (BDNF) attenuates glutamate toxicity. Therefore, we tested the hypothesis that NMDA protects neurons via a BDNF-dependent mechanism. Exposure of hippocampal cultures to a neuroprotective concentration of NMDA (50 microM) evoked the release of BDNF within 2 min without attendant changes in BDNF protein or gene expression. The accumulated increase of BDNF in the medium is followed by an increase in the phosphorylation (activation) of TrkB receptors and a later increase in exon 4-specific BDNF mRNA. The neuroprotective effect of NMDA was attenuated by pre-incubation with a BDNF-blocking antibody and TrkB-IgG, a fusion protein known to inhibit the activity of extracellular BDNF, suggesting that BDNF plays a major role in NMDA-mediated survival. These results demonstrate that low level stimulation of NMDA receptors protect neurons against glutamate excitotoxicity via a BDNF autocrine loop in hippocampal neurons and suggest that activation of neurotrophin signaling pathways plays a key role in the neuroprotection of NMDA.

Authors+Show Affiliations

Department of Neurology and Division of Neuroscience, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

16000165

Citation

Jiang, Xueying, et al. "The Excitoprotective Effect of N-methyl-D-aspartate Receptors Is Mediated By a Brain-derived Neurotrophic Factor Autocrine Loop in Cultured Hippocampal Neurons." Journal of Neurochemistry, vol. 94, no. 3, 2005, pp. 713-22.
Jiang X, Tian F, Mearow K, et al. The excitoprotective effect of N-methyl-D-aspartate receptors is mediated by a brain-derived neurotrophic factor autocrine loop in cultured hippocampal neurons. J Neurochem. 2005;94(3):713-22.
Jiang, X., Tian, F., Mearow, K., Okagaki, P., Lipsky, R. H., & Marini, A. M. (2005). The excitoprotective effect of N-methyl-D-aspartate receptors is mediated by a brain-derived neurotrophic factor autocrine loop in cultured hippocampal neurons. Journal of Neurochemistry, 94(3), 713-22.
Jiang X, et al. The Excitoprotective Effect of N-methyl-D-aspartate Receptors Is Mediated By a Brain-derived Neurotrophic Factor Autocrine Loop in Cultured Hippocampal Neurons. J Neurochem. 2005;94(3):713-22. PubMed PMID: 16000165.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The excitoprotective effect of N-methyl-D-aspartate receptors is mediated by a brain-derived neurotrophic factor autocrine loop in cultured hippocampal neurons. AU - Jiang,Xueying, AU - Tian,Feng, AU - Mearow,Karen, AU - Okagaki,Peter, AU - Lipsky,Robert H, AU - Marini,Ann M, Y1 - 2005/07/05/ PY - 2005/7/8/pubmed PY - 2005/9/20/medline PY - 2005/7/8/entrez SP - 713 EP - 22 JF - Journal of neurochemistry JO - J Neurochem VL - 94 IS - 3 N2 - The neuroprotective effect and molecular mechanisms underlying preconditioning with N-methyl-D-aspartate (NMDA) in cultured hippocampal neurons have not been described. Pre-incubation with subtoxic concentrations of the endogenous neurotransmitter glutamate protects vulnerable neurons against NMDA receptor-mediated excitotoxicity. As a result of physiological preconditioning, NMDA significantly antagonizes the neurotoxicity resulting from subsequent exposure to an excitotoxic concentration of glutamate. The protective effect of glutamate or NMDA is time- and concentration-dependent, suggesting that sufficient agonist and time are required to establish an intracellular neuroprotective state. In these cells, the TrkB ligand, brain-derived neurotrophic factor (BDNF) attenuates glutamate toxicity. Therefore, we tested the hypothesis that NMDA protects neurons via a BDNF-dependent mechanism. Exposure of hippocampal cultures to a neuroprotective concentration of NMDA (50 microM) evoked the release of BDNF within 2 min without attendant changes in BDNF protein or gene expression. The accumulated increase of BDNF in the medium is followed by an increase in the phosphorylation (activation) of TrkB receptors and a later increase in exon 4-specific BDNF mRNA. The neuroprotective effect of NMDA was attenuated by pre-incubation with a BDNF-blocking antibody and TrkB-IgG, a fusion protein known to inhibit the activity of extracellular BDNF, suggesting that BDNF plays a major role in NMDA-mediated survival. These results demonstrate that low level stimulation of NMDA receptors protect neurons against glutamate excitotoxicity via a BDNF autocrine loop in hippocampal neurons and suggest that activation of neurotrophin signaling pathways plays a key role in the neuroprotection of NMDA. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/16000165/The_excitoprotective_effect_of_N_methyl_D_aspartate_receptors_is_mediated_by_a_brain_derived_neurotrophic_factor_autocrine_loop_in_cultured_hippocampal_neurons_ L2 - https://doi.org/10.1111/j.1471-4159.2005.03200.x DB - PRIME DP - Unbound Medicine ER -