Skip to main content
SpringerLink
Log in

CREB and NF-κB Transcription Factors Regulate Sensitivity to Excitotoxic and Oxidative Stress Induced Neuronal Cell Death

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Summary

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-κB. To test this hypothesis we used hippocampal–entorhinal cortex slice cultures.

2. Glutamate neurotoxicity and oxidative stress neurotoxicity, using hydrogen peroxide (H2O2) are both associated with a decrease in CREB DNA binding and an increase in NF-κB DNA binding.

3. Agents that modulate CREB and NF-κB DNA-binding activity alter neurotoxicity. Rolipram, a phosphodiesterase IV inhibitor, increased CREB DNA binding activity and decreased toxicity, whereas TNFα, increased NF-κB DNA-binding activity and increased neurotoxicity to both glutamate and H2O2. Ethanol decreased CREB and increased NF-κB DNA-binding activity and increased neurotoxicity to both glutamate and H2O2.

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-κB-activated transcription. Together these studies suggest that neurotoxicity through glutamate–NMDA receptors or oxidative stress is dependent upon CREB and NF-κB DNA transcription that regulates vitality of neurons.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.
Fig. 7.
Fig. 8.
Fig. 9.
Fig. 10.
Fig. 11.
Fig. 12.
Fig. 13.

Similar content being viewed by others

REFERENCES

  • Bison, S., and Crews, F. (2003). Alcohol withdrawal increases neuropeptide Y immunoreactivity in rat brain. Alcohol Clin. Exp. Res. 27:1173–1183.

    Article  PubMed  CAS  Google Scholar 

  • Buntinx, M., Stinissen, P., Steels, P., Ameloot, M., and Raus, J. (2002). Immune-mediated oligodendrocyte injury in multiple sclerosis: Molecular mechanisms and therapeutic interventions. Crit. Rev. Immunol. 22:391–424.

    PubMed  CAS  Google Scholar 

  • Carlezon, W. A., Jr., Duman, R. S., and Nestler, E. J. (2005). The many faces of CREB. Trends Neurosci. 28:436–445.

    Article  PubMed  CAS  Google Scholar 

  • Chandler, L. J., Sumners, C., and Crews, F. T. (1993). Ethanol inhibits NMDA receptor-mediated excitotoxicity in rat primary neuronal cultures. Alcohol Clin. Exp. Res. 17:54–60.

    Article  PubMed  CAS  Google Scholar 

  • Chao, C. C., Molitor, T. W., and Hu, S. (1993). Neuroprotective role of IL-4 against activated microglia. J. Immunol. 151:1473–1481.

    PubMed  CAS  Google Scholar 

  • Cheng, B., Christakos, S., and Mattson, M. P. (1994). Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis. Neuron. 12:139–153.

    Article  PubMed  CAS  Google Scholar 

  • Cicchetti, F., Brownell, A. L., Williams, K., Chen, Y. I., Livni, E., and Isacson, O. (2002). Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging. Eur. J. Neurosci. 15:991–998.

    Article  PubMed  CAS  Google Scholar 

  • Crews, F. T., Waage, H. G., Wilkie, M. B., and Lauder, J. M. (1999). Ethanol pretreatment enhances NMDA excitotoxicity in biogenic amine neurons: Protection by brain derived neurotrophic factor. Alcohol Clin. Exp. Res. 23:1834–1842.

    Article  PubMed  CAS  Google Scholar 

  • Crews, F. T., Collins, M. A., Dlugos, C., Littleton, J., Wilkins, L., Neafsey, E. J., Pentney, R., Snell, L. D., Tabakoff, B., Zou, J., and Noronha, A. (2004). Alcohol-induced neurodegeneration: When, where and why? Alcohol Clin. Exp. Res. 28:350–364.

    Article  PubMed  Google Scholar 

  • Datta, K., Babbar, P., Srivastava, T., Sinha, S., and Chattopadhyay, P. (2002). p53 dependent apoptosis in glioma cell lines in response to hydrogen peroxide induced oxidative stress. Int. J. Biochem. Cell Biol. 34:148–157.

    Article  PubMed  CAS  Google Scholar 

  • Emch, G. S., Hermann, G. E., and Rogers, R. C. (2000), TNF-alpha activates solitary nucleus neurons responsive to gastric distension. Am. J. Physiol. Gastrointest Liver Physiol. 279:G582–G586.

    PubMed  CAS  Google Scholar 

  • Emch, G. S., Hermann, G. E., and Rogers, R. C. (2001). TNF-alpha-induced c-Fos generation in the nucleus of the solitary tract is blocked by NBQX and MK-801. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281:R1394–1400.

    PubMed  CAS  Google Scholar 

  • Finkbeiner, S., Tavazoie, S. F., Maloratsky, A., Jacobs, K. M., Harris, K. M., and Greenberg, M. E. (1997). CREB: A major mediator of neuronal neurotrophin responses. Neuron. 19:1031–1047.

    Article  PubMed  CAS  Google Scholar 

  • Flohe, L., Brigelius-Flohe, R., Saliou, C., Traber, M. G., and Packer, L. (1997). Redox regulation of NF-kappa B activation. Free Radic. Biol. Med. 22:1115–1126.

    Article  PubMed  CAS  Google Scholar 

  • Fukuchi, M., Tabuchi, A., and Tsuda, M. (2005). Transcriptional regulation of neuronal genes and its effect on neural functions: Cumulative mRNA expression of PACAP and BDNF genes controlled by calcium and cAMP signals in neurons. J. Pharmacol. Sci. 98:212–218.

    Article  PubMed  CAS  Google Scholar 

  • Ghosh, S., May, M. J., and Kopp, E. B. (1998). NF-kappa B and Rel proteins: Evolutionarily conserved mediators of immune responses. Annu. Rev. Immunol. 16:225–260.

    Article  PubMed  CAS  Google Scholar 

  • Grilli, M., and Memo, M. (1999). Possible role of NF-kappaB and p53 in the glutamate-induced pro-apoptotic neuronal pathway. Cell Death Differ. 6:22–27.

    Article  PubMed  CAS  Google Scholar 

  • Hara, T., Hamada, J., Yano, S., Morioka, M., Kai, Y., and Ushio, Y. (2003). CREB is required for acquisition of ischemic tolerance in gerbil hippocampal CA1 region. J. Neurochem. 86:805–814.

    Article  PubMed  CAS  Google Scholar 

  • Hardingham, G. E., and Bading, H. (2002). Coupling of extrasynaptic NMDA receptors to a CREB shut-off pathway is developmentally regulated. Biochim. Biophys Acta. 1600:148–153.

    PubMed  CAS  Google Scholar 

  • Hayakawa, M., Miyashita, H., Sakamoto, I., Kitagawa, M., Tanaka, H., Yasuda, H., Karin, M., Kikugawa, K. (2003). Evidence that reactive oxygen species do not mediate NF-kappaB activation. EMBO J. 22:3356–3366.

    Article  PubMed  CAS  Google Scholar 

  • Heese, K., Fiebich, B. L., Bauer, J., and Otten, U. (1997). Nerve growth factor (NGF) expression in rat microglia is induced by adenosine A2a-receptors. Neurosci. Lett. 231:83–86.

    Article  PubMed  CAS  Google Scholar 

  • Hermann, G. E., Rogers, R. C., Bresnahan, J. C., and Beattie, M. S. (2001). Tumor necrosis factor-alpha induces cFOS and strongly potentiates glutamate-mediated cell death in the rat spinal cord. Neurobiol. Dis. 8:590–599.

    Article  PubMed  CAS  Google Scholar 

  • Hinoi, E., Balcar, V. J., Kuramoto, N., Nakamichi, N., and Yoneda, Y. (2002). Nuclear transcription factors in the hippocampus. Prog. Neurobiol. 68:145–165.

    Article  PubMed  CAS  Google Scholar 

  • Hu, B. R., Fux, C. M., Martone, M. E., Zivin, J. A., and Ellisman, M. H. (1999). Persistent phosphorylation of cyclic AMP responsive element-binding protein and activating transcription factor-2 transcription factors following transient cerebral ischemia in rat brain. Neuroscience 89:437–452.

    Article  PubMed  CAS  Google Scholar 

  • Huang, E. J., and Reichardt, L. F. (2001). Neurotrophins: Roles in neuronal development and function. Annu. Rev. Neurosci. 24:677–736.

    Article  PubMed  CAS  Google Scholar 

  • Hunot, S., and Hirsch, E. C. (2003). Neuroinflammatory processes in Parkinson's disease. Ann Neurol. 53(Suppl 3):S49–S58; discussion S58–S60.

    Article  PubMed  CAS  Google Scholar 

  • Jean, D., Harbison, M., McConkey, D. J., Ronai, Z., and Bar-Eli, M. (1998). CREB and its associated proteins act as survival factors for human melanoma cells. J. Biol. Chem. 273:24884–24890.

    Article  PubMed  CAS  Google Scholar 

  • Kaltschmidt, B., Baeuerle, P. A., and Kaltschmidt, C. (1993). Potential involvement of the transcription factor NF-kappa B in neurological disorders. Mol. Aspects Med. 14:171–190.

    Article  PubMed  CAS  Google Scholar 

  • Lee, B., Butcher, G. Q., Hoyt, K. R., Impey, S., and Obrietan, K. (2005a). Activity-dependent neuroprotection and cAMP response element-binding protein (CREB): Kinase coupling, stimulus intensity, and temporal regulation of CREB phosphorylation at serine 133. J. Neurosci. 25:1137–1148.

    Article  PubMed  CAS  Google Scholar 

  • Lee, C. S., Kim, Y. J., Ko, H. H., and Han, E. S. (2005b). Synergistic effects of hydrogen peroxide and ethanol on cell viability loss in PC12 cells by increase in mitochondrial permeability transition. Biochem. Pharmacol. 70:317–325.

    Article  PubMed  CAS  Google Scholar 

  • Lee, Y., Aono, M., Laskowitz, D., Warner, D. S., and Pearlstein, R. D. (2004). Apolipoprotein E protects against oxidative stress in mixed neuronal-glial cell cultures by reducing glutamate toxicity. Neurochem. Int. 44:107–118.

    Article  PubMed  CAS  Google Scholar 

  • Lonze, B. E., and Ginty, D. D. (2002). Function and regulation of CREB family transcription factors in the nervous system. Neuron. 35:605–623.

    Article  PubMed  CAS  Google Scholar 

  • Mabuchi, T., Kitagawa, K., Kuwabara, K., Takasawa, K., Ohtsuki, T., Xia, Z., Storm, D., Yanagihara, T., Hori, M., and Matsumoto, M., (2001). Phosphorylation of cAMP response element-binding protein in hippocampal neurons as a protective response after exposure to glutamate in vitro and ischemia in vivo. J. Neurosci. 21:9204–9213.

    PubMed  CAS  Google Scholar 

  • MacKenzie, S. J., and Houslay, M. D. (2000). Action of rolipram on specific PDE4 cAMP phosphodiesterase isoforms and on the phosphorylation of cAMP-response-element-binding protein (CREB) and p38 mitogen-activated protein (MAP) kinase in U937 monocytic cells. Biochem. J. 347:571–578.

    Article  PubMed  CAS  Google Scholar 

  • Mantamadiotis, T., Lemberger, T., Bleckmann, S. C., Kern, H., Kretz, O., Martin Villalba, A., Tronche, F., Kellendonk, C., Gau, D., Kapfhammer, J., Otto, C., Schmid, W., Schutz, G. (2002). Disruption of CREB function in brain leads to neurodegeneration. Nat. Genet. 31:47–54.

    Article  PubMed  CAS  Google Scholar 

  • Mattson, M. P., and Camandola, S. (2001). NF-kappaB in neuronal plasticity and neurodegenerative disorders. J. Clin. Invest. 107:247–254.

    Article  PubMed  CAS  Google Scholar 

  • Meffert, M. K., and Baltimore, D. (2005). Physiological functions for brain NF-kappaB. Trends Neurosci. 28:37–43.

    Article  PubMed  CAS  Google Scholar 

  • Meffert, M. K., Chang, J. M., Wiltgen, B. J., Fanselow, M. S., and Baltimore, D. (2003). NF-kappa B functions in synaptic signaling and behavior. Nat. Neurosci. 6:1072–1078.

    Article  PubMed  CAS  Google Scholar 

  • Nakagawa, S., Kim, J. E., Lee, R., Chen, J., Fujioka, T., Malberg, J., Tsuji, S., Duman, R. S., (2002). Localization of phosphorylated cAMP response element-binding protein in immature neurons of adult hippocampus. J. Neurosci. 22:9868–9876.

    PubMed  CAS  Google Scholar 

  • Nanji, A. A., Jokelainen, K., Fotouhinia, M., Rahemtulla, A., Thomas, P., Tipoe, G. L., Su, G. L., Dannenberg, A. J., (2001). Increased severity of alcoholic liver injury in female rats: Role of oxidative stress, endotoxin, and chemokines. Am. J. Physiol. Gastrointest Liver Physiol. 281:G1348–G1356.

    PubMed  CAS  Google Scholar 

  • Nawashiro, H., Martin, D., and Hallenbeck, J. M. (1997). Neuroprotective effects of TNF binding protein in focal cerebral ischemia. Brain Res. 778:265–271.

    Article  PubMed  CAS  Google Scholar 

  • Nestler, E. J. (2002). Common molecular and cellular substrates of addiction and memory. Neurobiol. Learn Mem. 78:637–647.

    Article  PubMed  CAS  Google Scholar 

  • Noraberg, J., Kristensen, B. W., and Zimmer, J. (1999). Markers for neuronal degeneration in organotypic slice cultures. Brain Res. Brain Res. Protoc. 3:278–290.

    Article  PubMed  CAS  Google Scholar 

  • O’Neill, L. A., and Kaltschmidt, C. (1997). NF-kappa B: A crucial transcription factor for glial and neuronal cell function. Trends Neurosci. 20:252–258.

    Article  PubMed  CAS  Google Scholar 

  • Pandey, S. C., Chartoff, E. H., Carlezon, W. A. Jr., Zou, J., Zhang, H., Kreibich, A. S., Blendy, J. A., Crews, F. T., (2005). CREB gene transcription factors: Role in molecular mechanisms of alcohol and drug addiction. Alcohol Clin. Exp. Res. 29:176–184.

    Article  PubMed  CAS  Google Scholar 

  • Pizzi, M., Goffi, F., Boroni, F., Benarese, M., Perkins, S. E., Liou, H. C., and Spano, P. (2002). Opposing roles for NF-kappa B/Rel factors p65 and c-Rel in the modulation of neuron survival elicited by glutamate and interleukin-1beta. J. Biol. Chem. 277:20717–20723.

    Article  PubMed  CAS  Google Scholar 

  • Riccio, A., Ahn, S., Davenport, C. M., Blendy, J. A., and Ginty, D. D. (1999). Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science 286:2358–2361.

    Article  PubMed  CAS  Google Scholar 

  • Schneider, A., Martin-Villalba, A., Weih, F., Vogel, J., Wirth, T., and Schwaninger, M. (1999). NF-kappaB is activated and promotes cell death in focal cerebral ischemia. Nat. Med. 5:554–559.

    Article  PubMed  CAS  Google Scholar 

  • Shieh, P. B., and Ghosh, A. (1999). Molecular mechanisms underlying activity-dependent regulation of BDNF expression. J. Neurobiol. 41:127–134.

    Article  PubMed  CAS  Google Scholar 

  • Shrivastava, A., and Aggarwal, B. B. (1999). Antioxidants differentially regulate activation of nuclear factor-kappa B, activator protein-1, c-jun amino-terminal kinases, and apoptosis induced by tumor necrosis factor: Evidence that JNK and NF-kappa B activation are not linked to apoptosis. Antioxid. Redox Signal 1:181–191.

    Article  PubMed  CAS  Google Scholar 

  • Silva, A. J., Kogan, J. H., Frankland, P. W., and Kida, S. (1998). CREB and memory. Annu. Rev. Neurosci. 21:127–148.

    Article  PubMed  CAS  Google Scholar 

  • Somers, J. P., DeLoia, J. A., and Zeleznik, A. J. (1999). Adenovirus-directed expression of a nonphosphorylatable mutant of CREB (cAMP response element-binding protein) adversely affects the survival, but not the differentiation, of rat granulosa cells. Mol. Endocrinol. 13:1364–1372.

    Article  PubMed  CAS  Google Scholar 

  • Venters, H. D., Dantzer, R., and Kelley, K. W. (2000). Tumor necrosis factor-alpha induces neuronal death by silencing survival signals generated by the type I insulin-like growth factor receptor. Ann. N.Y. Acad. Sci. 917:210–220.

    Article  PubMed  CAS  Google Scholar 

  • Venters, H. D., Tang, Q., Liu, Q., VanHoy, R. W., Dantzer, R., and Kelley, K. W. (1999). A new mechanism of neurodegeneration: A proinflammatory cytokine inhibits receptor signaling by a survival peptide. Proc. Natl. Acad. Sci. U S A. 96:9879–9884.

    Article  PubMed  CAS  Google Scholar 

  • Walton, M., Woodgate, A. M., Muravlev, A., Xu, R., During, M. J., and Dragunow, M. (1999). CREB phosphorylation promotes nerve cell survival. J Neurochem. 73:1836–1842.

    PubMed  CAS  Google Scholar 

  • Walton, M. R., and Dragunow, I. (2000). Is CREB a key to neuronal survival? Trends Neurosci. 23:48–53.

    Article  PubMed  CAS  Google Scholar 

  • Yamakawa, H., Ito, Y., Naganawa, T., Banno, Y., Nakashima, S., Yoshimura, S., Sawada, M., Nishimura, Y., Nozawa, Y., and Sakai, N., (2000). Activation of caspase-9 and -3 during H2O2-induced apoptosis of PC12 cells independent of ceramide formation. Neurol. Res. 22:556–564.

    PubMed  CAS  Google Scholar 

  • Zhang, P., Nelson, S., Summer, W. R., and Spitzer, J. A. (1997). Acute ethanol intoxication suppresses the pulmonary inflammatory response in rats challenged with intrapulmonary endotoxin. Alcohol Clin. Exp. Res. 21:773–778.

    Article  PubMed  CAS  Google Scholar 

  • Zou, J. Y., and Crews, F. T. (2005). TNF alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: Neuroprotection by NF kappa B inhibition. Brain Res. 1034:11–24.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. 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

    Jian Zou & Fulton Crews

Authors
  1. Jian Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fulton Crews
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fulton Crews.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zou, J., Crews, F. CREB and NF-κB Transcription Factors Regulate Sensitivity to Excitotoxic and Oxidative Stress Induced Neuronal Cell Death. Cell Mol Neurobiol 26, 383–403 (2006). https://doi.org/10.1007/s10571-006-9045-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-006-9045-9

KEY WORDS:

Search

Navigation