Differential effects of BDNF, ADNF9, and TNFalpha on levels of NMDA receptor subunits, calcium homeostasis, and neuronal vulnerability to excitotoxicity.
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 alpha (TNFalpha), 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 TNFalpha 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-kappaB, by H7 and kappaB decoy DNA, respectively, suggest that the excitotoxic-modulating actions of BDNF are mediated by kinases, while those of ADNF9 and TNFalpha are mediated by both kinases and the transcription factor NF-kappaB. Our data show that, whereas BDNF increases neuronal responses to glutamate while ADNF9 and TNFalpha decrease the same, all three protect against excitotoxic apoptosis.
Glazner
G W
GW
Sanders-Brown Research Center on Aging, Department of Anatomy, University of Kentucky, Lexington, 40536, Kentucky, USA.
Mattson
M P
MP
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004622:Embryo, Mammalian; D018698:Glutamic Acid / Q000494:pharmacology; D006706:Homeostasis; D007700:Kinetics; D009336:Necrosis; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D019208:Brain-Derived Neurotrophic Factor; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D014409:Tumor Necrosis Factor-alpha; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002118:Calcium