Donepezil rescues the medial septum cholinergic neurons via nicotinic ACh receptor stimulation in olfactory bulbectomized mice

DOI: 10.4236/aad.2013.24021   PDF   HTML     4,903 Downloads   7,955 Views   Citations


Olfactory bulbectomy (OBX) causes cognitive dysfunction by degeneration of cholinergic neurons in the medial septum. Here, we define an involvement of nicotinic acetylcholine receptor (nAChR) in neuroprotective effect of donepezil in the septum neurons of OBX mice. Neuroprotective effects on the medial septal cholinergic neurons were assessed after chronic donepezil administration in OBX mice. We also measured Akt and ERK phosphorylation to define the neuroprotective mechanism of donepezil. We found that treatment with donepezil (1 - 3 mg/kg) for 15 consecutive days completely rescued cholinergic neurons in the OBX mice with concomitant improved memory. Reduction of both protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) phosphorylation were restored by chronic donepezil administration (1 - 3 mg/kg) in OBX mouse medial septum. Both phosphorylated Akt and ERK immunoreactivities were localized in cell bodies of choline acetyltransferase (ChAT)-positive cholinergic cells in the medial septum. Enhancement of Akt and ERK phosphorylation seen following donepezil administration was totally blocked by pre-administration of mecamylamine (10 μM), a nicotinic acetylcholine receptor antagonist. Donepezil increases phosphorylation of Akt and ERK via nAChR stimulation in the medial septum cholinergic neurons. The Akt and ERK stimulation by donepezil is associated with its ability of neuroprotection in the medial septum and memory improvement.

Share and Cite:

Yamamoto, Y. and Fukunaga, K. (2013) Donepezil rescues the medial septum cholinergic neurons via nicotinic ACh receptor stimulation in olfactory bulbectomized mice. Advances in Alzheimer's Disease, 2, 161-170. doi: 10.4236/aad.2013.24021.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Sieck, M.H. (1972) The role of the olfactory system in avoidance learning and activity. Physiology and Behavior, 8, 705-710.
[2] Serby, M., Corwin, J., Conrad, P. and Rotrosen, J. (1985) Olfactory dysfunction in Alzheimer’s disease and Parkinson’s disease. The American Journal of Psychiatry, 142, 781-782.
[3] Koss, E. (1986) Olfactory dysfunction in Alzheimer’s disease. Developmental Neuropsychology, 2, 89-99.
[4] Esiri, M.M. and Wilcock, G.K. (1984) The olfactory bulbs in Alzheimer’s disease. Journal of Neurology, Neurosurgery and Psychiatry, 47, 56-60.
[5] Doty, R.L. (1991) Olfactory capacities in aging and Alzheimer’s disease: Psychophysical and anatomic considerations. Annals of the New York Academy of Sciences, 640, 20-27.
[6] Ferreira, G., Meurisse, M., Tillet, Y. and Lévy, F. (2001) Distribution and colocalization of choline acetyltransferase and p75 neurotrophin receptors in the sheep basal forebrain implications for the use of a specific cholinergic immunotoxin. Neuroscience, 104, 419-439.
[7] Han, F., Shioda, N., Moriguchi, S., Qin, Z.H. and Fukunaga, K. (2008) The vanadium (IV) compound rescues septohippocampal cholinergic neurons from neurodegeneration in olfactory bulbectomized mice. Neuroscience, 151, 671-679.
[8] Nakajima, A., Yamakuni, T., Haraguchi, M., Omae, N., Song, S.Y., Kato, C., Nakagawasai, O., Tadano, T., Yokosuka, A. and Mimaki, Y. (2007) Nobiletin, a citrus flavonoid that improves memory impairment, rescues bulbectomy-induced cholinergic neurodegeneration in mice. Journal of Pharmacological Science, 105, 122-126.
[9] Han, F., Shioda, N., Moriguchi, S., Yamamoto, Y., Raie, A.Y., Yamaguchi, Y., Hino, M. and Fukunaga, K. (2008) Spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET- 1446/ST101) treatment rescues olfactory bulbectomy-induced memory impairment by activating Ca2+/calmodulin kinase II and protein kinase C in mouse hippocampus. Journal of Pharmacology and Experimental Therapeutics, 326, 127-134.
[10] Yamamoto, Y., Shioda, N., Han, F., Moriguchi, S. and Fukunaga, K. (2013) The novel cognitive enhancer ST101 enhances acetylcholine release in mouse dorsal hippocampus through T-type voltagegated calcium channel stimulation. Journal of Pharmacological Sciences, 121, 212-226.
[11] Aleksandrova, I.Y., Kuvichkin, V.V., Kashparov, I.A., Medvinskaya, N.I., Nesterova, I.V., Lunin, S.M., Samokhin, A.N., Bobkova, N.V. (2004) Increased level of beta- amyloid in the brain of bulbectomized mice. Biochemistry, 69, 176-180.
[12] Winblad, B., Kilander, L., Eriksson, S., Minthon, L., Bats-man, S., Wetterholm, A.L., Jansson-Blixt, C. and Haglund, A. (2006) Donepezil in patients with severe Alzheimer’s disease: Double-blind, parallel-group, placebo-controlled study. Lancet, 367, 1057-1065.
[13] Seltzer, B. (2005) Donepezil: A review. Expert Opinion on Drug Metabolism and Toxicology, 1, 527-536.
[14] Naik, R.S., Hartmann, J., Kiewert, C., Duysen, E.G., Lockridge, O. and Klein, J. (2009) Effects of rivastigmine and donepezil on brain acetylcholine levels in acetylcho- linesterase-deficient mice. Journal of Pharmacy and Pharmaceutical Science, 12, 79-85.
[15] Takada, Y., Yonezawa, A., Kume, T., Katsuki, H., Kaneko, S., Sugimoto, H. and Akaike, A. (2003) Nicotinic acetylcholine receptor-mediated neuroprotection by donepezil against glutamate neurotoxicity in rat cortical neurons. Journal of Pharmacology and Experimental Therapeutics, 306, 772-777.
[16] Akasofu, S., Kosasa, T., Kimura, M. and Kubota, A. (2003) Protective effect of donepezil in a primary culture of rat cortical neurons exposed to oxygen-glucose deprivation. European Journal of Pharmacology, 472, 57-63.
[17] Shen, H., Kihara, T., Hongo, H., Wu, X., Kem, W.R., Shimohama, S., Akaike, A., Niidome, T. and Sugimoto, H. (2010) Neuroprotection by donepezil against glutamate excitotoxicity involves stimulation of alpha7 nicotinic receptors and internalization of NMDA receptors. British Journal of Pharmacology, 161, 127-139.
[18] Yuan, H., Wang, W.P., Feng, N., Wang, L. and Wang, X.L. (2011) Donepezil attenuated oxygen-glucose deprivation insult by blocking Kv2.1 potassium channels. European Journal of Pharmacology, 657, 76-83.
[19] Saxena, G., Singh, S.P., Agrawal, R. and Nath, C. (2008) Effect of donepezil and tacrine on oxidative stress in intracerebral streptozotocin-induced model of dementia in mice. European Journal of Pharmacology, 581, 283-289.
[20] Min, D., Mao, X., Wu, K., Cao, Y., Guo, F., Zhu, S., Xie, N., Wang, L., Chen, T., Shaw, C. and Cai, J. (2012) Donepezil attenuates hippocampal neuronal damage and cognitive deficits after global cerebral ischemia in gerbils. Neuroscience Letters, 10, 29-33.
[21] Hashimoto, M., Kazui, H., Matsumoto, K., Nakano, Y., Yasuda, M. and Mori, E. (2005) Does donepezil treatment slow the progression of hippocampal atrophy in patients with Alzheimer’s disease? The American Journal of Psychiatry, 162, 676-682.
[22] Takada-Takatori, Y., Kume, T., Sugimoto, M., Katsuki, H., Sugimoto, H. and Akaike, A. (2006) Acetylcholinesterase inhibitors used in treatment of Alzheimer’s disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. Neuropharmacology, 51, 474-486.
[23] Oda, T., Kume, T., Katsuki, H., Niidome, T., Sugimoto, H. and Akaike, A. (2007) Donepezil potentiates nerve growth factor-induced neurite outgrowth in PC12 cells. Journal of Pharmacological Science, 104, 349-354.
[24] Noh, M.Y., Koh, S.H., Kim, Y., Kim, H.Y., Cho, G.W. and Kim, S.H. (2009) Neuroprotective effects of donepezil through inhibition of GSK-3 activity in amyloid-beta- induced neuronal cell death. Journal of Neurochemistry, 108, 1116-1125.
[25] Toborek, M., Son, K.W., Pudelko, A., King-Pospisil, K., Wylegala, E. and Malecki, A. (2007) ERK 1/2 signaling pathway is involved in nicotine-mediated neuroprotection in spinal cord neurons. Journal of Cellular Biochemistry, 100, 279-292.
[26] Hozumi, S., Nakagawasai, O., Tan-No, K., Niijima, F., Yamadera, F., Murata, A., Arai, Y., Yasuhara, H. and Tadano, T. (2003) Characteristics of changes in cholinergic function and impairment of learning and memory-related behavior induced by olfactory bulbectomy. Behavioral Brain Research, 138, 9-15.
[27] Ennaceur, A. and Aggleton, J.P. (1997) The effects of neurotoxic lesions of the perirhinal cortex combined to fornix transection on object recognition memory in the rat. Behavioral Brain Research, 88, 181-193.
[28] Tyagi, E., Agrawal, R., Nath, C. and Shukla, R. (2010) Cholinergic protection via alpha7 nicotinic acetylcholine receptors and PI3K-Akt pathway in LPS-induced neuroinflammation. Neurochemistry International, 56, 135-142.
[29] Azam, L., Winzer-Serhan, U. and Leslie, F.M. (2003) Co-expression of 7 and 2 nicotinic acetylcholine receptor subunit mRNAs within rat brain cholinergic neurons. Neuroscience, 119, 965-977.
[30] Thinschmidt, J.S., Frazier, C.J., King, M.A., Meyer, E.M. and Papke, R.L. (2005) Medial septal/diagonal band cells express multiple functional nicotinic receptor subtypes that are correlated with firing frequency. Neuroscience Letters, 389, 163-168.
[31] Moriguchi, S., Yamamoto, Y., Ikuno, T. and Fukunaga, K. (2011) Sigma-1 receptor stimulation by dehydroepian-drosterone ameliorates cognitive impairment through activation of CaM kinase II, protein kinase C and extracellular signal-regulated kinase in olfactory bulbectomized mice. Journal of Neurochemistry, 117, 879-891.
[32] Ogura, H., Kosasa, T., Kuriya, Y. and Yamanishi, Y. (2000) Donepezil, a centrally acting acetylcholinesterase inhibitor, alleviates learning deficits in hypocholinergic models in rats. Methods and Findings in Experimental and Clinical Pharmacology, 22, 89-95.
[33] Dong, H., Csernansky, C.A., Martin, M.V., Bertchume, A., Vallera, D. and Csernansky, J.G. (2005) Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer’s disease. Psychopharmacology, 181, 145-152.
[34] Van Dam, D., Abramowski, D., Staufenbiel, M. and De Deyn, P.P. (2005) Symptomatic effect of donepezil, rivastigmine, galantamine and memantine on cognitive deficits in the APP23 model. Psychopharmacology, 180, 177-190.
[35] Kimura, M., Akasofu, S., Ogura, H. and Sawada, K. (2005) Protective effect of donepezil against Abeta(1-40) neurotoxicity in rat septal neurons. Brain Research, 1047, 72-84.
[36] Akasofu, S., Kimura, M., Kosasa, T., Sawada, K. and Ogura, H. (2008) Study of neuroprotection of donepezil, a therapy for Alzheimer’s disease. Chemico-Biological Interactions, 175, 222-226.
[37] Akaike, A., Takada-Takatori, Y., Kume, T. and Izumi, Y. (2010) Mechanisms of neuroprotective effects of nicotine and acetylcholinesterase inhibitors: Role of alpha4 and alpha7 receptors in neuroprotection. Journal of Molecular Neuroscience, 40, 211-226.
[38] Takada-Takatori, Y., Kume, T., Ohgi, Y., Izumi, Y., Niidome, T., Fujii, T., Sugimoto, H. and Akaike, A. (2008) Mechanism of neuroprotection by donepezil pretreatment in rat cortical neurons chronically treated with donepezil. Journal of Neuroscience Research, 86, 3575-3583.
[39] Arias, E., Gallego-Sandín, S., Villarroya, M., García, A.G. and López, M.G. (2005) Unequal neuroprotection afforded by the acetylcholinesterase inhibitors galantamine, donepezil, and rivastigmine in SH-SY5Y neuroblastoma cells role of nicotinic receptors. Journal of Pharmacology and Experimental Therapeutics, 315, 1346-1353.
[40] Du, K. and Montminy, M. (1998) CREB is a regulatory target for the protein kinase Akt/PKB. Journal of Biological Chemistry, 273, 32377-32379.
[41] Weeber, E.J. and Sweatt, J.D. (2002) Molecular neurobiology of human cognition. Neuron, 33, 845-848.
[42] Leyhe, T., Stransky, E., Eschweiler, G.W., Buchkremer, G. and Laske, C. (2008) Increase of BDNF serum concentration during donepezil treatment of patients with early Alzheimer’s disease. Journal of Alzheimer’s Disease, 16, 649-656.
[43] Lindstrom, J. (1996) Neuronal nicotinic acetylcholine receptors. Ion Channels, 4, 377-450.
[44] Roger, S.W., Gahring, L.C., Collins, A.C. and Marks, M. (1998) Age-related changes in neuronal nicotinic acetylcholine receptor subunit a4 expression are modified by long-term nicotine administration. The Journal of Neuroscience, 18, 4825-4832.
[45] Liu, Q., Huang, Y., Xue, F., Simard, A., DeChon, J., Li, G., Zhang, J., Lucero, L., Wang, M., Sierks, M., Hu, G., Chang, Y., Lukas, R.J. and Wu, J. (2009) A novel nicotinic actylcholine receptor subtype in basal forebrain cholinergic neurons with high sensitivity to amyloid peptides. The Journal of Neuroscience, 29, 918-929.
[46] Pugazhenthi, S., Nesterova, A., Sable, C., Heidenreich, K.A., Boxer, L.M., Heasley, L.E. and Reusch, J.E. (2000) Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. Journal of Biological Chemistry, 275, 10761-10766.
[47] Hao, Y., Creson, T., Zhang, L., Li, P., Du, F., Yuan, P., Gould, T.D., Manji, H.K. and Chen, G. (2004) Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. Journal of Neuroscience, 24, 6590-6599.
[48] Greer, P.L. and Greenberg, M.E. (2008) From synapse to nucleus: Calcium-dependent gene transcription in the control of synapse development and function. Neuron, 59, 846-860.
[49] Autio, H., Matlik, K., Rantamaki, T., Lindemann, L., Hoener, M.C., Chao, M., Arumae, U. and Castrén, E. (2011) Acetylcholinesterase inhibitors rapidly activate Trk neurotrophin receptors in the mouse hippocampus. Neuropharmacology, 61, 1291-1296.

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.