Skip to main content

Advertisement

SpringerLink
Log in

Mechanisms of Neuroprotective Effects of Nicotine and Acetylcholinesterase Inhibitors: Role of α4 and α7 Receptors in Neuroprotection

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Neurotoxicity induced by glutamate and other excitatory amino acids has been implicated in various neurodegenerative disorders including hypoxic ischemic events, trauma, and Alzheimer’s and Parkinson’s diseases. We examined the roles of nicotinic acetylcholine receptors (nAChRs) in survival of CNS neurons during excitotoxic events. Nicotine as well as other nicotinic receptor agonists protected cortical neurons against glutamate neurotoxicity via α4 and α7 nAChRs at least partly by inhibiting the process of apoptosis in near-pure neuronal cultures obtained from the cerebral cortex of fetal rats. Donepezil, galanatamine and tacrine, therapeutic acetylcholinesterase (AChE) inhibitors currently being used for treatment of Alzheimer’s disease also protected neuronal cells from glutamate neurotoxicity. Protective effects of nicotine and the AChE inhibitors were antagonized by nAChR antagonists. Moreover, nicotine and those AChE inhibitors induced up-regulation of nAChRs. Inhibitors for a non-receptor-type tyrosine kinase, Fyn, and janus-activated kinase 2, suppressed the neuroprotective effect of donepezil and galantamine. Furthermore, a phosphatidylinositol 3-kinase (PI3K) inhibitor also suppressed the neuroprotective effect of the AChE inhibitors. The phosphorylation of Akt, an effector of PI3K, and the expression level of Bcl-2, an anti-apoptotic protein, increased with donepezil and galantamine treatments. These results suggest that nicotine as well as AChE inhibitors, donepezil and galantamine, prevent glutamate neurotoxicity through α4 and α7 nAChRs and the PI3K-Akt pathway.

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

Figure 1
Figure 2

Similar content being viewed by others

References

  • Akaike, A. (2006). Preclinical evidence of neuroprotection by cholinesterase inhibitors. Alzheimer Disease and Associated Disorders, 20, S8–S11.

    Article  CAS  PubMed  Google Scholar 

  • Akaike, A., Tamura, Y., Yokota, T., Shimohama, S., & Kimura, J. (1994). Nicotine-induced protection of cultured cortical neurons against N-methyl-D-aspartate receptor-mediated glutamate cytotoxicity. Brain Research, 644, 181–187.

    Article  CAS  PubMed  Google Scholar 

  • Akasofu, S., Kosasa, T., Kimura, M., & Kubota, A. (2003). Protective effect of donepezil in a primary culture of rat cortical neurons exposed to oxygen glucose deprivation. European Journal of Pharmacology, 472, 57–63.

    Article  CAS  PubMed  Google Scholar 

  • Barnes, C. A., Meltzer, J., Houston, F., Orr, G., McGann, K., & Wenk, G. L. (2000). Chronic treatment of old rats with donepezil or galantamine: effects on memory, hippocampal plasticity and nicotinic receptors. Neuroscience, 99, 17–23.

    Article  CAS  PubMed  Google Scholar 

  • Collerton, D. (1986). Cholinergic function and intellectual decline in Alzheimer's disease. Neuroscience, 19, 1–28.

    Article  CAS  PubMed  Google Scholar 

  • Dajas-Bailador, F., & Wonnacott, S. (2004). Nicotinic acetylcholine receptors and the regulation of neuronal signaling. Trends in Pharmacological Sciences, 25, 317–324.

    Article  CAS  PubMed  Google Scholar 

  • Darsow, T., Booker, T. K., Piña-Crespo, J. C., & Heinemann, S. F. (2005). Exocytic trafficking is required for nicotine-induced up-regulation of alpha 4 beta 2 nicotinic acetylcholine receptors. Journal of Biological Chemistry, 280, 18311–18320.

    Article  CAS  PubMed  Google Scholar 

  • Dawson, V. L., Dawson, T. M., London, E. D., Bredt, D. S., & Snyder, S. H. (1991). Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proceedings of the National Academy of Sciences of the United States of America, 88, 6368–6371.

    Article  CAS  PubMed  Google Scholar 

  • Hynd, M. R., Scott, H. L., & Dodd, P. R. (2004). Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer’s disease. Neurochemistry International, 45, 583–395.

    Article  CAS  PubMed  Google Scholar 

  • Kaneko, S., Maeda, T., Kume, T., Kochiyama, H., Akaike, A., Shimohama, S., et al. (1997). Nicotine protects cultured cortical neurons against glutamate-induced cytotoxicity via α7 neuronal receptors and neuronal CNS receptors. Brain Research, 765, 135–140.

    Article  CAS  PubMed  Google Scholar 

  • Kihara, T., Shimohama, S., Sawada, H., Kimura, J., Kume, T., Maeda, T., et al. (1997). Nicotinic receptor stimulation protects neurons against β-amyloid toxicity. Annals of Neurology, 42, 159–163.

    Article  CAS  PubMed  Google Scholar 

  • Kihara, T., Shimohama, S., Sawada, H., Honda, H., Nakamizo, T., Shibasaki, H., et al. (2001). α7 Nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to block a β-amyoid-induced neurotoxcity. Journal of Biological Chemistry, 276, 13541–13546.

    CAS  PubMed  Google Scholar 

  • Kume, T., Asai, N., Nishikawa, H., Mano, N., Terauchi, T., Taguchi, R., et al. (2002). Isolation of a diterpenoid substance with potent neuroprotective activity from fetal calf serum. Proceedings of the National Academy of Sciences of the United States of America, 99, 3288–3293.

    Article  CAS  PubMed  Google Scholar 

  • Kuryatov, A., Luo, J., Cooper, J., & Lindstrom, J. (2005). Nicotine acts as a pharmacological chaperone to up-regulate human alpha4beta2 acetylcholine receptors. Molecular Pharmacology, 68, 1839–1851.

    CAS  PubMed  Google Scholar 

  • Levin, E. D., McClernon, F. J., & Rezvani, A. H. (2006). Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacol. (Berl), 184, 529–534.

    Google Scholar 

  • Maelicke, A., Samochocki, M., Jostock, R., Fehrenbacher, A., Ludwig, J., Albuquerque, E. X., et al. (2001). Allosteric sensitization of nicotinic receptors by galantamine, a new treatment strategy for Alzheimer's disease. Biological Psychiatry, 49, 279–288.

    Article  CAS  PubMed  Google Scholar 

  • Marks, M. J., Pauly, J. R., Gross, S. D., Deneris, E. S., Hermans-Borgmeyer, I., Heinemann, S. F., et al. (1992). Nicotine binding and nicotinic receptor subunit RNA after chronic nicotine treatment. Journal of Neuroscience, 12, 2765–2784.

    CAS  PubMed  Google Scholar 

  • Martinez, M., Frank, A., Diez-Tejedor, E., & Hernanz, A. (1993). Amino acid concentrations in cerebrospinal fluid and serum in Alzheimer's disease and vascular dementia. Journal of Neural Transmission. Parkinson's Disease and Dementia, 6, 1–9.

    Article  CAS  Google Scholar 

  • Matsuzaki, H., Tamatani, M., Mitsuda, N., Namikawa, K., Kiyama, H., Miyake, S., et al. (1999). Activation of Akt kinase inhibits apoptosis and changes in Bcl-2 and Bax expression induced by nitric oxide in primary hippocampal neurons. Journal of Neurochemistry, 73, 2037–2046.

    CAS  PubMed  Google Scholar 

  • Meldrum, B., & Garthwaite, J. (1990). Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends in Pharmacological Sciences, 11, 379–387.

    Article  CAS  PubMed  Google Scholar 

  • Nordberg, A. (2006). Mechanisms behind the neuroprotective actions of cholinesterase inhibitors in Alzheimer disease. Alzheimer Disease and Associated Disorders, 20, S12–S18.

    Article  CAS  PubMed  Google Scholar 

  • Nordberg, A., Amberla, K., Shigeta, M., Lundqvist, H., Viitanen, M., Hellström-Lindahl, E., et al. (1998). Long-term tacrine treatment in three mild Alzheimer patients: Effects on nicotinic receptors, cerebral blood flow, glucose metabolism, EEG, and cognitive abilities. Alzheimer Disease and Associated Disorders, 12, 228–237.

    Article  CAS  PubMed  Google Scholar 

  • Rosa, A. O., Egea, J., Gandía, L., López, M. G., & García, A. G. (2006). Neuroprotection by nicotine in hippocampal slices subjected to oxygen-glucose deprivation: involvement of the alpha7 nAChR subtype. Journal of Molecular Neuroscience, 30, 61–62.

    Article  CAS  PubMed  Google Scholar 

  • Reid, R. T., & Sabbagh, M. N. (2003). Effects of donepezil treatment on rat nicotinic acetylcholine receptor levels in vivo and in vitro. Journal of Alzheimer's Disease, 5, 429–436.

    CAS  PubMed  Google Scholar 

  • Sallette, J., Pons, S., Devillers-Thiery, A., Soudant, M., Prado de Carvalho, L., Changeux, J. P., et al. (2005). Nicotine upregulates its own receptors through enhanced intracellular maturation. Neuron, 46, 595–607.

    Article  CAS  PubMed  Google Scholar 

  • Shimohama, S., Akaike, A., & Kimura, J. (1996). Nicotine-induced protection against glutamate cytotoxicity-nicotinic cholinergic receptor-mediated inhibition of nitric oxide formation. Annals of the New York Academy of Sciences, 777, 356–361.

    Article  CAS  PubMed  Google Scholar 

  • Takada-Takatori, Y., Yonezawa, A., Kume, T., Katsuki, H., Kaneko, S., Sugimoto, H., et al. (2003). Nicotinic acetylcholine receptor-mediated neuroprotection by donepezil against glutamate neurotoxicity in rat cortical neurons. Journal of Pharmacology and Experimental Therapeutics, 306, 772–777.

    Article  CAS  Google Scholar 

  • Takada-Takatori, Y., Kume, T., Sugimoto, M., Katsuki, H., Niidome, T., Sugimoto, H., et al. (2006a). Neuroprotective effects of galanthamine and tacrine against glutamate neurotoxicity. European Journal of Pharmacology, 549, 19–26.

    Article  CAS  PubMed  Google Scholar 

  • Takada-Takatori, Y., Kume, T., Sugimoto, M., Katsuki, H., Sugimoto, H., & Akaike, A. (2006b). Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. Neuropharmacoloy, 51, 474–486.

    Article  CAS  Google Scholar 

  • Takada-Takatori, Y., Kume, T., Ohgi, Y., Izumi, Y., Niidome, T., Fujii, T., et al. (2008a). Mechanism of neuroprotection by donepezil pretreatment in rat cortical neurons chronically treated with donepezil. Journal of Neuroscience Research, 86, 3575–3583.

    Article  CAS  PubMed  Google Scholar 

  • Takada-Takatori, Y., Kume, T., Ohgi, Y., Fujii, T., Niidome, T., Sugimoto, H., et al. (2008b). Mechanisms of alpha7-nicotinic receptor up-regulation and sensitization to donepezil induced by chronic donepezil treatment. European Journal of Pharmacology, 20, 150–156.

    Article  CAS  Google Scholar 

  • Takada-Takatori, Y., Kume, T., Izumi, Y., Ohgi, Y., Niidome, T., Fujii, T., et al. (2009). Roles of nicotinic receptors in acetylcholinesterase inhibitor-induced neuroprotection and nicotinic receptor up-regulation. Biological and Pharmaceutical Bulletin, 32, 318–324.

    Article  CAS  PubMed  Google Scholar 

  • Tamura, Y., Sato, Y., Akaike, A., & Shiomi, H. (1992). Mechanisms of cholecystokinin-induced protection of cultured cortical neurons against N-methyl-D-aspartate receptor-mediated glutamate cytotoxicity. Brain Research, 592, 317–325.

    Article  CAS  PubMed  Google Scholar 

  • Whitehouse, P. J., Price, D. L., Struble, R. G., Clark, A. W., Coyle, J. T., & Delon, M. R. (1982). Alzheimer's disease and senile dementia: Loss of neurons in the basal forebrain. Science, 215, 1237–1239.

    Article  CAS  PubMed  Google Scholar 

  • Zhou, J., Fu, Y., & Tang, X. C. (2001). Huperzine A and donepezil protect rat phenochromocytoma cells against oxygen-glucose deprivation. Neuroscience Letters, 406, 53–56.

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported in part by Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, and Technology of Japan to Akinori Akaike, Yuki Takda-Takatori, and Toshiaki Kume. This study was also supported in part by a grant from the Smoking Research Foundation, Japan.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan

    Akinori Akaike, Toshiaki Kume & Yasuhiko Izumi

  2. Department of Pharmacology, Faculty of Pharmaceutical Sciences, Doshisha Women’s College, Kyoto, Japan

    Yuki Takada-Takatori

Authors
  1. Akinori Akaike
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuki Takada-Takatori
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshiaki Kume
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasuhiko Izumi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akinori Akaike.

Additional information

Proceedings of the XIII International Symposium on Cholinergic Mechanisms

Rights and permissions

Reprints and permissions

About this article

Cite this article

Akaike, A., Takada-Takatori, Y., Kume, T. et al. Mechanisms of Neuroprotective Effects of Nicotine and Acetylcholinesterase Inhibitors: Role of α4 and α7 Receptors in Neuroprotection. J Mol Neurosci 40, 211–216 (2010). https://doi.org/10.1007/s12031-009-9236-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-009-9236-1

Keywords

Search

Navigation