The role of NMDA receptor upregulation in phencyclidine-induced cortical apoptosis in organotypic culture

Cheng Wang, Jared Fridley, Kenneth M. Johnson

Research output: Contribution to journalArticle

39 Citations (Scopus)

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 48 h. 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.

Original languageEnglish (US)
Pages (from-to)1373-1383
Number of pages11
JournalBiochemical Pharmacology
Volume69
Issue number9
DOIs
StatePublished - May 1 2005

Fingerprint

Phencyclidine
Oligodeoxyribonucleotides
N-Methyl-D-Aspartate Receptors
Up-Regulation
Apoptosis
Apoptosis Regulatory Proteins
DNA
Protein Subunits
DNA Fragmentation
Cell death
Cell culture
Histones
Proteins
Cell Death
Peptides
aspartic acid receptor

Keywords

  • Antisense
  • Apoptosis
  • Bax
  • Cortex
  • N-Methyl-d-aspartate receptor
  • Phencyclidine

ASJC Scopus subject areas

  • Pharmacology

Cite this

The role of NMDA receptor upregulation in phencyclidine-induced cortical apoptosis in organotypic culture. / Wang, Cheng; Fridley, Jared; Johnson, Kenneth M.

In: Biochemical Pharmacology, Vol. 69, No. 9, 01.05.2005, p. 1373-1383.

Research output: Contribution to journalArticle

Wang, Cheng ; Fridley, Jared ; Johnson, Kenneth M. / The role of NMDA receptor upregulation in phencyclidine-induced cortical apoptosis in organotypic culture. In: Biochemical Pharmacology. 2005 ; Vol. 69, No. 9. pp. 1373-1383.
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