![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
H Manev, M Favaron, A Guidotti and E Costa
Fidia-Georgetown Institute for the Neurosciences, Georgetown 4niversity, Washington, DC 20007.
The mechanism of delayed neurotoxicity, triggered by glutamate, was studied in 7-8-day-old primary cultures of rat cerebellar granule cells. Treatment of cultures for 15 min with 50 microM glutamate in Mg2+ -free medium, followed by removal of the excitoxin, resulted in neuronal death, which started to appear 2-3 hr after the termination of glutamate treatment. The number of dead neurons increased gradually in the next few hours and 80-85% of neurons were found dead 24 hr later. Antagonists of N-methyl-D-aspartate-sensitive glutamate receptors (phencyclidine) or 1.2 mM MgCl2, but not the antagonist of N-methyl-D- asparatate-insensitive glutamate receptors (6-cyano-7-nitroquinoxaline- 2,3-dione), abolished the neurotoxic effect of kainate. Development of glutamate-induced neuronal death depends strongly on Ca2+. Removal of extracellular Ca2+ (with 1mM ethyleneglycol-bis-(beta-aminoethyl ether)- N,N,N',N'-tetraacetic acid) immediately after the termination of glutamate exposure and before the appearance of the early signs of neuronal death (post-glutamate period) dramatically reduced neuronal degeneration. Neurotoxic concentrations of glutamate induced sustained increase of 45Ca2+ uptake in the post-glutamate period. The delayed increase of 45Ca2+ uptake, as well as the delayed neurotoxicity, were not affected by post-glutamate treatment with phencyclidine, dibenzocyclohepteneimine; DL-2-amino-5-phosphonovalerate, or MgCl2 or with voltage-dependent Ca2+ channel blockers (nitrendipine, verapamil, diltiazem). Neurotoxic concentrations of glutamate also induced a delayed sustained increase of [3H]phorbol-12,13-dibutyrate binding, reflecting an increased translocation of protein kinase C (PKC) from cytosol to the cell membrane during the post-glutamate period. Pretreatment of neurons with the ganglioside GT1b (trisialosylgangliotetraglycosylceramide), followed by removal of free GT1b from the incubation medium, prevented PKC translocation, the sustained increase of 45Ca2+ uptake in the post-glutamate period, and the delayed neuronal death. We suggest that the sustained activation and translocation of PKC primed by glutamate receptor stimulation may be the triggering event causing the protracted increase of neuronal Ca2+ influx. This influx is insensitive to voltage-dependent Ca2+ channel blockers and glutamate receptor antagonists. It appears that this delayed increase of Ca2+ influx may be important in causing neuronal death.
This article has been cited by other articles:
|
|
 |
|
  A. T. E. Hartwick, C. M. Hamilton, and W. H. Baldridge Glutamatergic calcium dynamics and deregulation of rat retinal ganglion cells J. Physiol., July 15, 2008; 586(14): 3425 - 3446. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Schubert and D. Piasecki Oxidative Glutamate Toxicity Can Be a Component of the Excitotoxicity Cascade J. Neurosci., October 1, 2001; 21(19): 7455 - 7462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Connor and R. J. Cormier Cumulative Effects of Glutamate Microstimulation on Ca2+ Responses of CA1 Hippocampal Pyramidal Neurons in Slice J Neurophysiol, January 1, 2000; 83(1): 90 - 98. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. G. Nicholls and S. L. Budd Mitochondria and Neuronal Survival Physiol Rev, January 1, 2000; 80(1): 315 - 360. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Kiedrowski Elevated Extracellular K+ Concentrations Inhibit N-Methyl-D-Aspartate-Induced Ca2+ Influx and Excitotoxicity Mol. Pharmacol., October 1, 1999; 56(4): 737 - 743. [Abstract] [Full Text]
|
|
|
|
 |
|
 F. W. Berman and T. F. Murray Brevetoxins Cause Acute Excitotoxicity in Primary Cultures of Rat Cerebellar Granule Neurons J. Pharmacol. Exp. Ther., July 1, 1999; 290(1): 439 - 444. [Abstract] [Full Text]
|
|
|
|
|
|
S. V. Bhave, L. Ghoda, and P. L. Hoffman Brain-Derived Neurotrophic Factor Mediates the Anti-Apoptotic Effect of NMDA in Cerebellar Granule Neurons: Signal Transduction Cascades and Site of Ethanol Action J. Neurosci., May 1, 1999; 19(9): 3277 - 3286. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. F. Castilho, O. Hansson, M. W. Ward, S. L. Budd, and D. G. Nicholls Mitochondrial Control of Acute Glutamate Excitotoxicity in Cultured Cerebellar Granule Cells J. Neurosci., December 15, 1998; 18(24): 10277 - 10286. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. X. Zhang, R. Rubin, and T. A. Rooney N-Methyl-D-aspartate Inhibits Apoptosis through Activation of Phosphatidylinositol 3-Kinase in Cerebellar Granule Neurons. A ROLE FOR INSULIN RECEPTOR SUBSTRATE-1 IN THE NEUROTROPHIC ACTION OF N-METHYL-D-ASPARTATE AND ITS INHIBITION BY ETHANOL J. Biol. Chem., October 9, 1998; 273(41): 26596 - 26602. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Lipton and P. Nicotera {blacksquare} REVIEW : Excitotoxicity, Free Radicals, Necrosis, and Apoptosis Neuroscientist, September 1, 1998; 4(5): 345 - 352. [Abstract] [PDF]
|
|
|
|
|
|
L. Zirpel, W. R. Lippe, and E. W Rubel Activity-Dependent Regulation of [Ca2+]i in Avian Cochlear Nucleus Neurons: Roles of Protein Kinases A and C and Relation to Cell Death J Neurophysiol, May 1, 1998; 79(5): 2288 - 2302. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Du, K. R. Bales, R. C. Dodel, E. Hamilton-Byrd, J. W. Horn, D. L. Czilli, L. K. Simmons, B. Ni, and S. M. Paul Activation of a caspase 3-related cysteine protease is required for glutamate-mediated apoptosis of cultured cerebellar granule neurons PNAS, October 14, 1997; 94(21): 11657 - 11662. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kawasaki, T. Morooka, S. Shimohama, J. Kimura, T. Hirano, Y. Gotoh, and E. Nishida Activation and Involvement of p38 Mitogen-activated Protein Kinase in Glutamate-induced Apoptosis in Rat Cerebellar Granule Cells J. Biol. Chem., July 25, 1997; 272(30): 18518 - 18521. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. X. Chen, K. L. Perkins, D. W. Choi, and R. K. S. Wong Secondary Activation of a Cation Conductance Is Responsible for NMDA Toxicity in Acutely Isolated Hippocampal Neurons J. Neurosci., June 1, 1997; 17(11): 4032 - 4036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Montoliu, M. Llansola, C. Cucarella, S. Grisolía, and V. Felipo Activation of the Metabotropic Glutamate Receptor mGluR5 Prevents Glutamate Toxicity in Primary Cultures of Cerebellar Neurons J. Pharmacol. Exp. Ther., May 1, 1997; 281(2): 643 - 647. [Abstract] [Full Text]
|
|
|
|
|
|
M.-S. Rioult-Pedotti Intrinsic NMDA-Induced Oscillations in Motoneurons of an Adult Vertebrate Spinal Cord Are Masked by Inhibition J Neurophysiol, February 1, 1997; 77(2): 717 - 730. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
