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Research ArticleNEUROPHARMACOLOGY

Nicotinic Acetylcholine Receptor-Mediated Neuroprotection by Donepezil Against Glutamate Neurotoxicity in Rat Cortical Neurons

Yuki Takada, Atsushi Yonezawa, Toshiaki Kume, Hiroshi Katsuki, Shuji Kaneko, Hachiro Sugimoto and Akinori Akaike
Journal of Pharmacology and Experimental Therapeutics August 2003, 306 (2) 772-777; DOI: https://doi.org/10.1124/jpet.103.050104
Yuki Takada
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Atsushi Yonezawa
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Toshiaki Kume
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Hiroshi Katsuki
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Shuji Kaneko
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Hachiro Sugimoto
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Akinori Akaike
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Abstract

Donepezil is a potent and selective acetylcholinesterase (AChE) inhibitor developed for the treatment of Alzheimer's disease. To elucidate whether donepezil shows neuroprotective action in addition to amelioration of cognitive deficits, we examined the effects of donepezil on glutamate-induced neurotoxicity using primary cultures of rat cortical neurons. A 10-min exposure of cultures to glutamate followed by a 1-h incubation with glutamate-free medium caused a marked loss of viability, as determined by Trypan blue exclusion. Glutamate neurotoxicity was prevented by 24-h pretreatment of donepezil in a concentration-dependent manner. Among AChE inhibitors examined, donepezil and certain AChE inhibitors such as tacrine and galanthamine showed potent neuroprotective action, although physostigmine did not affect glutamate neurotoxicity. Neuroprotective action of donepezil was antagonized by mecamylamine, a nicotinic acetylcholine receptor (nAChR) antagonist, but not by scopolamine, a muscarinic acetylcholine receptor antagonist. Furthermore, both dihydro-β-erythroidine, an α4β2-neuronal nAChR antagonist, and methyllycaconitine, an α7-nAChR antagonist, each also significantly antagonized the effect of donepezil. Next, we examined the effects of donepezil on glutamate-induced apoptosis. Exposure of 100 μM glutamate to cortical neurons for 24 h induced apoptotic neuronal death and nuclear fragmentation. Donepezil for 24 h before and 24 h during glutamate exposure prevented nuclear fragmentation and glutamate-induced apoptosis. These results suggest that donepezil not only protects cortical neurons against glutamate neurotoxicity via α4β2- and α7-nAChRs but also prevents apoptotic neuronal death.

Footnotes

  • This study was supported in part by a grant-in-aid for Scientific Research and a grant-in-aid on priority areas from the Ministry of Education, Science, Sports, and Culture (Japan). This study was also supported in part by a grant from the Smoking Research Foundation (Japan).

  • DOI: 10.1124/jpet.103.050104.

  • ABBREVIATIONS: AD, Alzheimer's disease; Aβ, amyloid-β protein; nAChR, nicotinic acetylcholine receptor; AChE, acetylcholinesterase; MEM, minimal essential medium; DHβE, dihydro-β-erythroidine; MLA, methyllycaconitine

    • Received February 12, 2003.
    • Accepted May 6, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 306 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 306, Issue 2
1 Aug 2003
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Research ArticleNEUROPHARMACOLOGY

Nicotinic Acetylcholine Receptor-Mediated Neuroprotection by Donepezil Against Glutamate Neurotoxicity in Rat Cortical Neurons

Yuki Takada, Atsushi Yonezawa, Toshiaki Kume, Hiroshi Katsuki, Shuji Kaneko, Hachiro Sugimoto and Akinori Akaike
Journal of Pharmacology and Experimental Therapeutics August 1, 2003, 306 (2) 772-777; DOI: https://doi.org/10.1124/jpet.103.050104

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Research ArticleNEUROPHARMACOLOGY

Nicotinic Acetylcholine Receptor-Mediated Neuroprotection by Donepezil Against Glutamate Neurotoxicity in Rat Cortical Neurons

Yuki Takada, Atsushi Yonezawa, Toshiaki Kume, Hiroshi Katsuki, Shuji Kaneko, Hachiro Sugimoto and Akinori Akaike
Journal of Pharmacology and Experimental Therapeutics August 1, 2003, 306 (2) 772-777; DOI: https://doi.org/10.1124/jpet.103.050104
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