Mechanisms of alpha7-nicotinic receptor up-regulation and sensitization to donepezil induced by chronic donepezil treatment.
alpha7-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 muM, 4 days) (1) induces the up-regulation of alpha7-nicotinic receptors, (2) enhances the nicotine-induced increase in [Ca(2+)](i) and (3) enhances the sensitivity to the neuroprotective effect of donepezil. Here we demonstrate the involvement of alpha7-nicotinic receptors in these three effects. Concomitant treatment with nicotinic receptor antagonist inhibited the up-regulation of alpha7-nicotinic receptor, enhancement of the increase in [Ca(2+)](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 alpha7-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.
Takada-Takatori
Yuki
Y
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Doshisha Women's College, Kyoto 610-0395, Japan.
Kume
Toshiaki
T
Ohgi
Yuta
Y
Fujii
Takeshi
T
Niidome
Tetsuhiro
T
Sugimoto
Hachiro
H
Akaike
Akinori
A
D000818:Animals; D002478:Cells, Cultured; D000077265:Donepezil; D005419:Flavonoids / Q000494:pharmacology; D007189:Indans / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000032:analysis / Q000187:drug effects*; D015398:Signal Transduction; D015854:Up-Regulation; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579165:Chrna7 protein, rat; D005419:Flavonoids; D007189:Indans; D018696:Neuroprotective Agents; D018733:Nicotinic Antagonists; D010880:Piperidines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000077265:Donepezil; D019869:Phosphatidylinositol 3-Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one