JPET Introducing ALZET?ew Model 2006 Pump

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wang, C.
Right arrow Articles by Johnson, K. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wang, C.
Right arrow Articles by Johnson, K. M.

Vol. 294, Issue 1, 287-295, July 2000

Mechanisms of N-Methyl-D-aspartate-Induced Apoptosis in Phencyclidine-Treated Cultured Forebrain Neurons1

Cheng Wang, Joel A. Kaufmann2, Monica G. Sanchez-Ross and Kenneth M. Johnson

Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas

Chronic administration of phencyclidine (PCP) to rats has been demonstrated to produce a sensitized locomotor response to PCP challenge that is associated with apoptotic cell death and an up-regulation of the N-methyl-D-aspartate (NMDA) receptor. To determine the underlying mechanisms, dissociated forebrain cultures were treated for 2 days with 3 µM PCP. After washout of PCP, NMDA was added (in the presence of Mg2+) for 20 h. The uptake of a vital dye and the release of lactate dehydrogenase measured cell viability. Apoptosis was assessed by an enzyme-linked immunosorbent assay that was specific for fragmented (histone-associated) DNA and an in situ assay for nicked DNA, terminal dUTP nick-end labeling. These assays showed that the effect of a nontoxic concentration of NMDA (30 µM) became lethal to approximately one-third of the neurons after chronic (48-h) PCP treatment. This treatment also resulted in a 47% increase in NR1 subunit mRNA, suggesting that NMDA-induced neuronal cell death after chronic PCP is due to NMDA receptor up-regulation. Furthermore, exposure of PCP-treated cultures to NMDA led to increased expression of Bax and decreased expression of Bcl-XL. The Bcl-XL/Bax ratio was markedly decreased by 30 µM NMDA in the PCP-treated, but not control, cultures. Addition of superoxide dismutase and catalase prevented the decrease in Bcl-XL/Bax. This study suggests that NMDA-induced changes in Bax and/or Bcl-XL involve the formation of reactive oxygen species. By extrapolation, these data suggest that PCP-induced apoptosis in vivo may involve similar mechanisms and that cultured neurons may be a suitable model for the mechanistic study PCP toxicity in vivo.

1 This study was supported by National Institutes of Health Grant DA 02073 and the John Sealy Memorial Endowment Fund for Biomedical Research.

2 Current address: Neuroscience Graduate Program, University of Texas Medical Branch, Galveston, TX 77555-1031.

0022-3565/00/2941-0287$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Pharmacol. Rev.Home page
J. A. Lieberman, F. P. Bymaster, H. Y. Meltzer, A. Y. Deutch, G. E. Duncan, C. E. Marx, J. R. Aprille, D. S. Dwyer, X.-M. Li, S. P. Mahadik, et al.
Antipsychotic Drugs: Comparison in Animal Models of Efficacy, Neurotransmitter Regulation, and Neuroprotection
Pharmacol. Rev., September 1, 2008; 60(3): 358 - 403.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
C. Wang and W. Slikker Jr
Strategies and Experimental Models for Evaluating Anesthetics: Effects on the Developing Nervous System
Anesth. Analg., June 1, 2008; 106(6): 1643 - 1658.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
W. Slikker Jr, X. Zou, C. E. Hotchkiss, R. L. Divine, N. Sadovova, N. C. Twaddle, D. R. Doerge, A. C. Scallet, T. A. Patterson, J. P. Hanig, et al.
Ketamine-Induced Neuronal Cell Death in the Perinatal Rhesus Monkey
Toxicol. Sci., July 1, 2007; 98(1): 145 - 158.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
J. C. de Rivero Vaccari, G. P. Casey, S. Aleem, W.-M. Park, and R. A. Corriveau
NMDA receptors promote survival in somatosensory relay nuclei by inhibiting Bax-dependent developmental cell death
PNAS, November 7, 2006; 103(45): 16971 - 16976.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
C. Wang, N. Sadovova, C. Hotchkiss, X. Fu, A. C. Scallet, T. A. Patterson, J. Hanig, M. G. Paule, and W. Slikker Jr.
Blockade of N-Methyl-D-Aspartate Receptors by Ketamine Produces Loss of Postnatal Day 3 Monkey Frontal Cortical Neurons in Culture
Toxicol. Sci., May 1, 2006; 91(1): 192 - 201.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
C. Wang, J. McInnis, J. B. West, J. Bao, N. Anastasio, J. A. Guidry, Y. Ye, D. Salvemini, and K. M. Johnson
Blockade of Phencyclidine-Induced Cortical Apoptosis and Deficits in Prepulse Inhibition by M40403, a Superoxide Dismutase Mimetic
J. Pharmacol. Exp. Ther., January 1, 2003; 304(1): 266 - 271.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
J. McInnis, C. Wang, N. Anastasio, M. Hultman, Y. Ye, D. Salvemini, and K. M. Johnson
The Role of Superoxide and Nuclear Factor-kappa B Signaling in N-Methyl-D-aspartate-Induced Necrosis and Apoptosis
J. Pharmacol. Exp. Ther., May 1, 2002; 301(2): 478 - 487.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. GenomicsHome page
J. M. MARKERT, C. M. FULLER, G. Y. GILLESPIE, J. K. BUBIEN, L. A. MCLEAN, R. L. HONG, K. LEE, S. R. GULLANS, T. B. MAPSTONE, and D. J. BENOS
Differential gene expression profiling in human brain tumors
Physiol Genomics, February 7, 2001; 5(1): 21 - 33.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2000 by the American Society for Pharmacology and Experimental Therapeutics.