N-methyl-D-aspartate receptor blockade induces neuronal apoptosis in cortical culture

Jee Yeon Hwang, Yang Hee Kim, Young Ho Ahn, Myung Bok Wie, Jae Young Koh

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

Whereas excessive activation of the NMDA receptor may contribute to ischemic neuronal injury, physiologic activation may promote neuronal survival under certain conditions. Consistently, it has recently been shown that NMDA antagonists induce apoptosis of central neurons in immature rats. In the present study, we have examined whether NMDA antagonists induce neuronal apoptosis also in a culture condition. Exposure of cortical cultures (DIV 10-13) to MK-801 (1-10 μM) for 48 h resulted in death of about 30-40% of neurons. Similar neuronal death was induced by exposure to other NMDA antagonists, D-AP5 and dextromethorphan. The neuronal death was dependent on the culture age; MK-801 induced much less neuronal death in younger (DIV 7) and older (DIV 16-19) cultures. The NMDA antagonist-induced neuronal death was accompanied by cell body shrinkage, nuclear fragmentation, and cleavage/activation of caspase-3. Furthermore, it was attenuated by cycloheximide and zVAD-fmk, indicating that the death occurred mainly by the apoptosis mechanism. As in several other apoptosis models, high-potassium medium blocked the NMDA antagonist-induced apoptosis, which was reversed by voltage-gated calcium channel blockers. The present results demonstrate that NMDA antagonists induce neuronal apoptosis in cortical culture, consistent with the findings obtained in immature rats. Since the activation of the voltage-gated calcium channels attenuated the NMDA antagonist-induced apoptosis, it may be another example of the 'calcium set point hypothesis'.

Original languageEnglish (US)
Pages (from-to)124-130
Number of pages7
JournalExperimental Neurology
Volume159
Issue number1
DOIs
StatePublished - Sep 1999

Keywords

  • AP-5
  • Calcium
  • Caspase
  • Dextromethorphan
  • High potassium
  • MK-801

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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