Roles of Nicotinic Receptors in Acetylcholinesterase Inhibitor-Induced Neuroprotection and Nicotinic Receptor Up-Regulation

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  • Takada-Takatori Yuki
    Department of Pharmacology, Faculty of Pharmaceutical Sciences, Doshisha Women's College
  • Kume Toshiaki
    Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University
  • Izumi Yasuhiko
    Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University
  • Ohgi Yuta
    Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University
  • Niidome Tetsuhiro
    Department of Neuroscience for Drug Discovery Research, Graduate School of Pharmaceutical Sciences, Kyoto University
  • Fujii Takeshi
    Department of Pharmacology, Faculty of Pharmaceutical Sciences, Doshisha Women's College
  • Sugimoto Hachiro
    Department of Neuroscience for Drug Discovery Research, Graduate School of Pharmaceutical Sciences, Kyoto University
  • Akaike Akinori
    Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University

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Protection of neurons from neuronal damage and cell death in neurodegenerative disease is a major challenge in neuroscience research. Donepezil, galantamine and tacrine are acetylcholinesterase inhibitors used for the treatment of Alzheimer's disease, and were believed to be symptomatic drugs whose therapeutic effects are achieved by slowing the hydrolysis of acetylcholine at synaptic termini. However, recent accumulated evidence strongly suggests that these acetylcholinesterase inhibitors also possess neuroprotective properties whose mechanism is independent of acetylcholinesterase inhibition. We have shown that acetylcholinesterase inhibitors protect neurons from glutamate-induced neurotoxicity in the primary culture of rat cortical neurons. It was also found that acetylcholinesterase inhibitor treatment induces up-regulation of nicotinic receptor expression levels, a property which may also have some bearing on their therapeutic effects. We next showed that α4 and α7-nicotinic receptors play important roles in acetylcholinesterase inhibitor-induced neuroprotection and nicotinic receptor up-regulation. Our results also demonstrate the important roles of the phosphatidylinositol 3-kinase pathway downstream of nicotinic receptors in protecting neurons from death and up-regulating nicotinic receptors. This review summarizes recent findings on the roles of the nicotinic receptor in acetylcholinesterase inhibitor-induced neuroprotection and nicotinic receptor up-regulation.

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