Differential effects of BDNF, ADNF9, and TNFα on levels of NMDA receptor subunits, calcium homeostasis, and neuronal vulnerability to excitotoxicity

Gordon W. Glazner, Mark P. Mattson

Research output: Contribution to journalArticle

Abstract

Calcium influx through N-methyl-D-aspartate (NMDA) receptors can result in neuronal apoptosis or necrosis and may play a pivotal role in neuronal death in many different neurodegenerative diseases. In the present study we employed primary neuronal cultures and three different excitoprotective factors, brain-derived neurotrophic factor (BDNF), activity-dependent neurotrophic factor (ADNF9), and tumor necrosis factor α (TNFα), to elucidate the mechanisms whereby trophic factors modify the excitotoxic process. Neurons pretreated with BDNF exhibited increased levels of the NMDA receptor subunits NR1 and NR2A, which was associated with increased calcium responses to NMDA and vulnerability to excitotoxic necrosis and reduced vulnerability to apoptosis. ADNF9 and TNFα, suppressed calcium responses to glutamate and protected neurons against both excitotoxic necrosis and apoptosis, but had no effect on levels of NMDA receptor subunits. Inhibition of phosphorylation and DNA binding of NF-κB, by H7 and κB decoy DNA, respectively, suggest that the excitotoxic-modulating actions of BDNF are mediated by kinases, while those of ADNF9 and TNFα are mediated by both kinases and the transcription factor NF-κB. Our data show that, whereas BDNF increases neuronal responses to glutamate while ADNF9 and TNFα decrease the same, all three protect against excitotoxic apoptosis. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)442-452
Number of pages11
JournalExperimental Neurology
Volume161
Issue number2
DOIs
StatePublished - Feb 2000
Externally publishedYes

Keywords

  • ADNF
  • AMPA
  • BDNF
  • Excitotoxicity
  • Glutamate
  • NF-κB
  • TNFα

ASJC Scopus subject areas

  • Neurology
  • Neuroscience(all)

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