CREB and NF-kappaB transcription factors regulate sensitivity to excitotoxic and oxidative stress induced neuronal cell death.
1. Glutamate-NMDA receptor excitotoxicity and oxidative stress are two common mechanisms associated with most neurodegenerative diseases. We hypothesize that the vital state of neurons is regulated in part by two key transcription factors, CREB and NF-kappaB. To test this hypothesis we used hippocampal-entorhinal cortex slice cultures. 2. Glutamate neurotoxicity and oxidative stress neurotoxicity, using hydrogen peroxide (H(2)O(2)) are both associated with a decrease in CREB DNA binding and an increase in NF-kappaB DNA binding. 3. Agents that modulate CREB and NF-kappaB DNA-binding activity alter neurotoxicity. Rolipram, a phosphodiesterase IV inhibitor, increased CREB DNA binding activity and decreased toxicity, whereas TNFalpha, increased NF-kappaB DNA-binding activity and increased neurotoxicity to both glutamate and H(2)O(2). Ethanol decreased CREB and increased NF-kappaB DNA-binding activity and increased neurotoxicity to both glutamate and H(2)O(2). 4. Brain-derived neurotrophic factor (BDNF) is a transcriptionally regulated trophic factor whose expression follows sensitivity to toxicity suggesting it is one of the transcriptionally regulated factors that contributes to neuronal vitality secondary to the balance of CREB-NF-kappaB-activated transcription. Together these studies suggest that neurotoxicity through glutamate-NMDA receptors or oxidative stress is dependent upon CREB and NF-kappaB DNA transcription that regulates vitality of neurons.
Zou
Jian
J
The Bowles Center For Alcohol Studies, Department of Pharmacology, School of Medicine, CB#7178, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7178, USA.
Crews
Fulton
F
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018696:Neuroprotective Agents / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology*; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009498:Neurotoxins; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D018698:Glutamic Acid; D006861:Hydrogen Peroxide