 |
||||
|
||||
|
||||
|
||||
|
||||
Previous Article | Next Article
The Journal of Neuroscience, October 1, 2000, 20(19):7183-7192
Transient NMDA Receptor Inactivation Provides Long-Term Protection to Cultured Cortical Neurons from a Variety of Death Signals
Roger Tremblay, Balu Chakravarthy, Kimberley Hewitt, Joseph Tauskela, Paul Morley, Trevor Atkinson, and Jon P. Durkin Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada K1A 0R6
NMDA receptor antagonists, such as (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801), potently block glutamate-induced neuronal death in myriad in vitro cell models and effectively attenuate ischemic damage in vivo. In this report, a novel role for MK-801 and other NMDA receptor antagonists in preconditioning neurons to withstand a wide range of subsequent lethal insults is described. A brief 30 min exposure to 0.1 µM MK-801, applied up to 96 hr before a "lethal" insult, protected primary cortical neurons from a diverse group of neurotoxic agents, including NMDA,
-amyloid, staurosporine, etoposide, and oxygen-glucose deprivation. This neuroprotective preconditioning by MK-801 arose from transient NMDA receptor inactivation, because the noncompetitive NMDA receptor antagonists memantine and nylindin and the competitive antagonist AP-5 gave similar effects. MK-801 protection was dependent on new protein synthesis during the first 2 hr, but not from 2 to 5 hr, after MK-801 exposure. The MK-801 transient did not alter the ability of NMDA to trigger normally lethal [Ca2+]i influx 48 hr later, but it did block early downstream signaling events coupled to NMDA neurotoxicity, including PKC inactivation and the activation of calpain. Moreover, MK-801 protected neurons from staurosporine-induced apoptosis, although caspase activation in these cells was unimpeded. It is likely that the stress associated with transient inactivation of NMDA receptors triggered a rapid compensatory survival response that provided long-term protection from a spectrum of insults, inducing apoptotic and nonapoptotic death. The possibility that MK-801 preconditioning blocks an event common to seemingly diverse death mechanisms suggests it will be an important tool for obtaining a clearer understanding of the salient molecular events at work in neuronal death and survival pathways.
Key words: apoptosis; death signals; lethal injury; MK-801; oxygen-glucose deprivation; stress; preconditioning
Copyright © 2000 Society for Neuroscience 0270-6474/00/20197183-10$05.00/0
This article has been cited by other articles:
J. S. Tauskela, H. Fang, M. Hewitt, E. Brunette, T. Ahuja, J.-P. Thivierge, T. Comas, and G. A. R. Mealing
Elevated Synaptic Activity Preconditions Neurons against an in Vitro Model of Ischemia
J. Biol. Chem., December 12, 2008; 283(50): 34667 - 34676.
[Abstract] [Full Text] [PDF]
Q. Luo, Y. Ding, K. Watson, J. Zhang, and G.-H. Fan
N-Methyl-D-aspartate Attenuates CXCR2-Mediated Neuroprotection through Enhancing the Receptor Phosphorylation and Blocking the Receptor Recycling
Mol. Pharmacol., August 1, 2005; 68(2): 528 - 537.
[Abstract] [Full Text] [PDF]
E. A. Waxman and D. R. Lynch
N-methyl-D-aspartate Receptor Subtypes: Multiple Roles in Excitotoxicity and Neurological Disease
Neuroscientist, February 1, 2005; 11(1): 37 - 49.
[Abstract] [PDF]
A. Lionikas, D. A. Blizard, D. J. Vandenbergh, M. G. Glover, J. T. Stout, G. P. Vogler, G. E. McClearn, and L. Larsson
Genetic architecture of fast- and slow-twitch skeletal muscle weight in 200-day-old mice of the C57BL/6J and DBA/2J lineage
Physiol Genomics, December 16, 2003; 16(1): 141 - 152.
[Abstract] [Full Text] [PDF]
B. McLaughlin, K. A. Hartnett, J. A. Erhardt, J. J. Legos, R. F. White, F. C. Barone, and E. Aizenman
Caspase 3 activation is essential for neuroprotection in preconditioning
PNAS, January 21, 2003; 100(2): 715 - 720.
[Abstract] [Full Text] [PDF]
S. E. Lid, D. Gruis, R. Jung, J. A. Lorentzen, E. Ananiev, M. Chamberlin, X. Niu, R. Meeley, S. Nichols, and O.-A. Olsen
The defective kernel 1 (dek1) gene required for aleurone cell development in the endosperm of maize grains encodes a membrane protein of the calpain gene superfamily
PNAS, April 16, 2002; 99(8): 5460 - 5465.
[Abstract] [Full Text] [PDF]
S. E. Lid, D. Gruis, R. Jung, J. A. Lorentzen, E. Ananiev, M. Chamberlin, X. Niu, R. Meeley, S. Nichols, and O.-A. Olsen
The defective kernel 1 (dek1) gene required for aleurone cell development in the endosperm of maize grains encodes a membrane protein of the calpain gene superfamily
PNAS, April 16, 2002; 99(8): 5460 - 5465.
[Abstract] [Full Text] [PDF]
|
|
|
|
 |
|