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The role of NMDA receptor upregulation in phencyclidine-induced cortical apoptosis in organotypic culture.
Biochem Pharmacol. 2005 May 01; 69(9):1373-83.BP

Abstract

Phencyclidine (PCP) is an N-methyl-D-aspartate receptor (NMDAR) antagonist known to cause selective neurotoxicity in the cortex following subchronic administration. The purpose of this study was to test the hypothesis that upregulation of the NMDAR plays a role in PCP-induced apoptotic cell death. Corticostriatal slice cultures were used to determine the effects of NMDAR subunit antisense oligodeoxynucleotides (ODNs) on PCP-induced apoptosis and NMDAR upregulation. NR1, NR2A or NR2B antisense ODNs were incubated alone or with PCP for 48h. One day following washout, it was observed that PCP treatment caused an increase in NR1, NR2A and Bax polypeptides in the cortex, but had no effect on Bcl-xL. These increases were associated with an increase in cortical histone-associated DNA fragments. Co-incubation of PCP with either NR1 or NR2A antisense significantly reduced PCP-induced apoptosis, while neither NR2B antisense ODN nor NR1 sense ODN used as a control had an effect. This effect was exactly correlated with the ability of the antisense ODNs to prevent PCP-induced upregulation of NR subunit proteins and the pro-apoptotic protein, Bax. That is, western analysis showed that antisense ODNs directed against either NR1 or NR2A prevented PCP-induced increases in Bax in addition to preventing the upregulation of the respective receptor proteins. On the other hand, the NR2B antisense ODN had no effect on either NR2B protein or on Bax. These data suggest that NR1 and NR2A antisense ODNs offer neuroprotection from apoptosis, and that upregulation of the NR1 and NR2A subunits following PCP administration is at least partly responsible for the observed apoptotic DNA fragmentation.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555-1031, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

15826608

Citation

Wang, Cheng, et al. "The Role of NMDA Receptor Upregulation in Phencyclidine-induced Cortical Apoptosis in Organotypic Culture." Biochemical Pharmacology, vol. 69, no. 9, 2005, pp. 1373-83.
Wang C, Fridley J, Johnson KM. The role of NMDA receptor upregulation in phencyclidine-induced cortical apoptosis in organotypic culture. Biochem Pharmacol. 2005;69(9):1373-83.
Wang, C., Fridley, J., & Johnson, K. M. (2005). The role of NMDA receptor upregulation in phencyclidine-induced cortical apoptosis in organotypic culture. Biochemical Pharmacology, 69(9), 1373-83.
Wang C, Fridley J, Johnson KM. The Role of NMDA Receptor Upregulation in Phencyclidine-induced Cortical Apoptosis in Organotypic Culture. Biochem Pharmacol. 2005 May 1;69(9):1373-83. PubMed PMID: 15826608.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The role of NMDA receptor upregulation in phencyclidine-induced cortical apoptosis in organotypic culture. AU - Wang,Cheng, AU - Fridley,Jared, AU - Johnson,Kenneth M, PY - 2005/01/18/received PY - 2005/02/14/revised PY - 2005/02/24/accepted PY - 2005/4/14/pubmed PY - 2005/5/25/medline PY - 2005/4/14/entrez SP - 1373 EP - 83 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 69 IS - 9 N2 - Phencyclidine (PCP) is an N-methyl-D-aspartate receptor (NMDAR) antagonist known to cause selective neurotoxicity in the cortex following subchronic administration. The purpose of this study was to test the hypothesis that upregulation of the NMDAR plays a role in PCP-induced apoptotic cell death. Corticostriatal slice cultures were used to determine the effects of NMDAR subunit antisense oligodeoxynucleotides (ODNs) on PCP-induced apoptosis and NMDAR upregulation. NR1, NR2A or NR2B antisense ODNs were incubated alone or with PCP for 48h. One day following washout, it was observed that PCP treatment caused an increase in NR1, NR2A and Bax polypeptides in the cortex, but had no effect on Bcl-xL. These increases were associated with an increase in cortical histone-associated DNA fragments. Co-incubation of PCP with either NR1 or NR2A antisense significantly reduced PCP-induced apoptosis, while neither NR2B antisense ODN nor NR1 sense ODN used as a control had an effect. This effect was exactly correlated with the ability of the antisense ODNs to prevent PCP-induced upregulation of NR subunit proteins and the pro-apoptotic protein, Bax. That is, western analysis showed that antisense ODNs directed against either NR1 or NR2A prevented PCP-induced increases in Bax in addition to preventing the upregulation of the respective receptor proteins. On the other hand, the NR2B antisense ODN had no effect on either NR2B protein or on Bax. These data suggest that NR1 and NR2A antisense ODNs offer neuroprotection from apoptosis, and that upregulation of the NR1 and NR2A subunits following PCP administration is at least partly responsible for the observed apoptotic DNA fragmentation. SN - 0006-2952 UR - https://www.unboundmedicine.com/medline/citation/15826608/The_role_of_NMDA_receptor_upregulation_in_phencyclidine_induced_cortical_apoptosis_in_organotypic_culture_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(05)00122-X DB - PRIME DP - Unbound Medicine ER -