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Mechanism of neuroprotection by donepezil pretreatment in rat cortical neurons chronically treated with donepezil.
J Neurosci Res. 2008 Dec; 86(16):3575-83.JN

Abstract

Previously, we showed that in rat cortical neurons, chronic donepezil treatment (10 microM, 4 days) up-regulates nicotinic receptors (nAChR) and makes neurons more sensitive to the neuroprotective effect of donepezil. Here we examined the mechanism of donepezil-induced neuroprotection in neurons chronically treated with donepezil. The mechanism of neuroprotection was examined under different conditions of exposure to glutamate, acute and moderate, that induce cell death associated with necrotic and apoptotic cell death, respectively. Concomitant treatment with antagonists of nAChRs but not muscarinic receptors inhibited donepezil pretreatment-induced neuroprotection against acute glutamate treatment-induced death. Donepezil pretreatment prevented acute glutamate- and ionomycin-induced neurotoxicity, but not S-nitrosocysteine-induced neurotoxicity, suggesting that donepezil protects neurons via nAChR at levels before nitric oxide synthase activation against acute glutamate neurotoxicity. Concomitant treatment with antagonists of nAChR or phosphatidylinositol 3-kinase (PI3K) signaling inhibitors significantly inhibited neuroprotection against moderate glutamate neurotoxicity and decreased the phosphorylation level of Akt. Neuroprotection was also inhibited by treatment with inhibitor of mitogen-activated protein kinase (MAPK) kinase. These results suggest that donepezil protects neurons against moderate glutamate neurotoxicity via nAChR-PI3K-Akt and MAPK signaling pathways. This study provides novel insight into the mechanism of donepezil-induced neuroprotection that involves nAChR up-regulation.

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Authors+Show Affiliations

Takada-Takatori Y
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Doshisha Women's College, Kyoto, Japan.
Kume T
No affiliation info available
Ohgi Y
No affiliation info available
Izumi Y
No affiliation info available
Niidome T
No affiliation info available
Fujii T
No affiliation info available
Sugimoto H
No affiliation info available
Akaike A
No affiliation info available

MeSH

AnimalsApoptosisCells, CulturedCerebral CortexCholinesterase InhibitorsCytoprotectionDonepezilEnzyme InhibitorsGlutamic AcidIndansIonomycinIonophoresMAP Kinase Signaling SystemNecrosisNerve DegenerationNeuronsNeuroprotective AgentsNicotinic AntagonistsPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsPiperidinesProto-Oncogene Proteins c-aktRatsRats, WistarReceptors, NicotinicSignal Transduction

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18655200

Citation

Takada-Takatori, Yuki, et al. "Mechanism of Neuroprotection By Donepezil Pretreatment in Rat Cortical Neurons Chronically Treated With Donepezil." Journal of Neuroscience Research, vol. 86, no. 16, 2008, pp. 3575-83.
Takada-Takatori Y, Kume T, Ohgi Y, et al. Mechanism of neuroprotection by donepezil pretreatment in rat cortical neurons chronically treated with donepezil. J Neurosci Res. 2008;86(16):3575-83.
Takada-Takatori, Y., Kume, T., Ohgi, Y., Izumi, Y., Niidome, T., Fujii, T., Sugimoto, H., & Akaike, A. (2008). Mechanism of neuroprotection by donepezil pretreatment in rat cortical neurons chronically treated with donepezil. Journal of Neuroscience Research, 86(16), 3575-83. https://doi.org/10.1002/jnr.21798
Takada-Takatori Y, et al. Mechanism of Neuroprotection By Donepezil Pretreatment in Rat Cortical Neurons Chronically Treated With Donepezil. J Neurosci Res. 2008;86(16):3575-83. PubMed PMID: 18655200.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanism of neuroprotection by donepezil pretreatment in rat cortical neurons chronically treated with donepezil. AU - Takada-Takatori,Yuki, AU - Kume,Toshiaki, AU - Ohgi,Yuta, AU - Izumi,Yasuhiko, AU - Niidome,Tetsuhiro, AU - Fujii,Takeshi, AU - Sugimoto,Hachiro, AU - Akaike,Akinori, PY - 2008/7/26/pubmed PY - 2009/2/20/medline PY - 2008/7/26/entrez SP - 3575 EP - 83 JF - Journal of neuroscience research JO - J Neurosci Res VL - 86 IS - 16 N2 - Previously, we showed that in rat cortical neurons, chronic donepezil treatment (10 microM, 4 days) up-regulates nicotinic receptors (nAChR) and makes neurons more sensitive to the neuroprotective effect of donepezil. Here we examined the mechanism of donepezil-induced neuroprotection in neurons chronically treated with donepezil. The mechanism of neuroprotection was examined under different conditions of exposure to glutamate, acute and moderate, that induce cell death associated with necrotic and apoptotic cell death, respectively. Concomitant treatment with antagonists of nAChRs but not muscarinic receptors inhibited donepezil pretreatment-induced neuroprotection against acute glutamate treatment-induced death. Donepezil pretreatment prevented acute glutamate- and ionomycin-induced neurotoxicity, but not S-nitrosocysteine-induced neurotoxicity, suggesting that donepezil protects neurons via nAChR at levels before nitric oxide synthase activation against acute glutamate neurotoxicity. Concomitant treatment with antagonists of nAChR or phosphatidylinositol 3-kinase (PI3K) signaling inhibitors significantly inhibited neuroprotection against moderate glutamate neurotoxicity and decreased the phosphorylation level of Akt. Neuroprotection was also inhibited by treatment with inhibitor of mitogen-activated protein kinase (MAPK) kinase. These results suggest that donepezil protects neurons against moderate glutamate neurotoxicity via nAChR-PI3K-Akt and MAPK signaling pathways. This study provides novel insight into the mechanism of donepezil-induced neuroprotection that involves nAChR up-regulation. SN - 1097-4547 UR - https://www.unboundmedicine.com/medline/citation/18655200/Mechanism_of_neuroprotection_by_donepezil_pretreatment_in_rat_cortical_neurons_chronically_treated_with_donepezil_ L2 - https://doi.org/10.1002/jnr.21798 DB - PRIME DP - Unbound Medicine ER -