TY - JOUR
T1 - Mechanisms of α7-nicotinic receptor up-regulation and sensitization to donepezil induced by chronic donepezil treatment
AU - Takada-Takatori, Yuki
AU - Kume, Toshiaki
AU - Ohgi, Yuta
AU - Fujii, Takeshi
AU - Niidome, Tetsuhiro
AU - Sugimoto, Hachiro
AU - Akaike, Akinori
N1 - Funding Information:
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 to Akinori Akaike and Yuki Takada-Takatori. This study was also supported in part by a grant from the Smoking Research Foundation, Japan to Akinori Akaike.
PY - 2008/8/20
Y1 - 2008/8/20
N2 - α7-nicotinic acetylcholine receptors are one of the most abundant subtypes of nicotinic receptors in the brain and have been shown to be involved in the neuroprotective effect of donepezil. Recently, we showed that in primary culture of rat cortical neurons, chronic donepezil treatment (10 μM, 4 days) (1) induces the up-regulation of α7-nicotinic receptors, (2) enhances the nicotine-induced increase in [Ca2+]i and (3) enhances the sensitivity to the neuroprotective effect of donepezil. Here we demonstrate the involvement of α7-nicotinic receptors in these three effects. Concomitant treatment with nicotinic receptor antagonist inhibited the up-regulation of α7-nicotinic receptor, enhancement of the increase in [Ca2+]i induced by nicotine, and enhancement of sensitivity to the neuroprotective effect of donepezil. Next, using inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase signaling pathways, we demonstrate the involvement of these pathways in the up-regulation of α7-nicotinic receptors and in making the neurons more sensitive to the neuroprotective effects of donepezil. Concomitant chronic donepezil treatment with inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways inhibited nicotinic receptor up-regulation and enhancement of the response to nicotine, and enhanced the sensitivity to donepezil. This study increases understanding of the less-studied mechanism of chronic donepezil treatment-induced nicotinic receptor up-regulation and increased sensitivity to donepezil.
AB - α7-nicotinic acetylcholine receptors are one of the most abundant subtypes of nicotinic receptors in the brain and have been shown to be involved in the neuroprotective effect of donepezil. Recently, we showed that in primary culture of rat cortical neurons, chronic donepezil treatment (10 μM, 4 days) (1) induces the up-regulation of α7-nicotinic receptors, (2) enhances the nicotine-induced increase in [Ca2+]i and (3) enhances the sensitivity to the neuroprotective effect of donepezil. Here we demonstrate the involvement of α7-nicotinic receptors in these three effects. Concomitant treatment with nicotinic receptor antagonist inhibited the up-regulation of α7-nicotinic receptor, enhancement of the increase in [Ca2+]i induced by nicotine, and enhancement of sensitivity to the neuroprotective effect of donepezil. Next, using inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase signaling pathways, we demonstrate the involvement of these pathways in the up-regulation of α7-nicotinic receptors and in making the neurons more sensitive to the neuroprotective effects of donepezil. Concomitant chronic donepezil treatment with inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways inhibited nicotinic receptor up-regulation and enhancement of the response to nicotine, and enhanced the sensitivity to donepezil. This study increases understanding of the less-studied mechanism of chronic donepezil treatment-induced nicotinic receptor up-regulation and increased sensitivity to donepezil.
KW - Alzheimer's disease
KW - Mitogen-activated protein kinase
KW - Neuroprotection
KW - Nicotinic receptor
KW - Phosphatidylinositol 3-kinase
KW - Up-regulation
UR - http://www.scopus.com/inward/record.url?scp=48049111171&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2008.06.027
DO - 10.1016/j.ejphar.2008.06.027
M3 - 学術論文
C2 - 18585378
AN - SCOPUS:48049111171
SN - 0014-2999
VL - 590
SP - 150
EP - 156
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -