Donepezil is the common standard symptomatic treatment for mild-to-moderate Alzheimer’s disease (AD) patients, but it showed only moderate efficacy and also emergence tolerance. To conquer this shortcoming, combinations of several drugs are widely used. Statins, competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, are commonly prescribed drugs for the treatment of hypercholesterolemia. Growing evidence demonstrated that this class of medicines exerts neuroprotective effects in neurological disorders, including AD. We have examined whether co-administration of lovastatin with donepezil provides a synergistic cognition-improving effect in an animal model of AD. In rats with the bilaterally lesioned nucl. basalis magnocellularis (NBM), lovastatin (20 mg/kg) and donepezil (10 mg/kg), when administered separately, noticeably improved working and reference memory tests in the radial maze, compared to the NBM lesioned group with no treatment but not with lower doses. Combined administration of subtherapeutic doses of lovastatin (1.0 mg/kg) and donepezil (0.1 mg/kg), which exerted no discernible effects on performance when given alone, significantly improved working and reference memory, indicating a synergistic cognitionimproving effect. This result suggests that a low dose of lovastatin potentiates the effect of an inactivedose of donepezil on cognitive impairment, and that the synergistic effect may be mediated through increases in the choline acetyltransferase activity and ACh level to compensate the cholinergic deficit in the rat model of Alzheimer’s disease.
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References
M. Dumont and M. F. Beal, “Neuroprotective strategies involving ROS in Alzheimer disease,” Free Radic. Biol. Med., 51, No. 5, 1014-1026 (2011).
J. McGaughy, M. W. Decker, and M. Sarter, “Enhancement of sustained attention performance by the nicotinic acetylcholine receptor agonist ABT-418 in intact but not basal forebrain-lesioned rats,” Psychopharmacology (Berl.), 144, No. 2, 175-182 (1999).
M. Khanmohamadi, D. D. Farhud, and M. Malmir, “Genetic of Alzheimer’s disease: A narrative review article,” Iran J. Public. Health, 44, No. 7, 892-901(2015).
M. Zahedi, M. R. Hojjati, H. Fathpour, et al., “Effect of Rheum ribes hydro-alcoholic extract on memory impairments in rat model of Alzheimer’s disease,” Iran. J. Pharm. Res., 14, No. 4, 1197-1206 (2015).
S. Easton, A. Sankaranarayanan, A. Tanghe, et al., “Effects of sub-chronic donepezil on brain Aβ and cognition in a mouse model of Alzheimer’s disease,” Psychopharmacology (Berl.), 230, No. 2, 279-289 (2013).
N. A. Kapai, J. V. Bukanova, E. I. Solntseva, and V. G. Skrebitsky, “Donepezil in a narrow concentration range augments control and impaired by beta-amyloid peptide hippocampal LTP in NMDA-independent manner,” Cell. Mol. Neurobiol., 32, No. 2, 219-226 (2012).
M. J. Grothe, C. Schuster, F. Bauer, et al., “Atrophy of the cholinergic basal forebrain in dementia with Lewy bodies and Alzheimer’s disease dementia,” J. Neurol., 261, No. 10, 1939–1948 (2014).
D. Cutuli, F. Foti, L. Mandolesi, et al., “Cognitive performance of cholinergically depleted rats following chronic donepezil administration,” J. Alzheimers Dis., 17, No. 1, 161-176 (2009).
M. A. Raghanti, G. Simic, S. Watson, et al., “Comparative analysis of the nucleus basalis of Meynert among primates,” Neuroscience, 184, 1-15 (2011).
A. Contestabile, E. Ciani, and A. Contestabile, “The place of choline acetyltransferase activity measurement in the “cholinergic hypothesis” of neurodegenerative diseases,” Neurochem. Res., 33, No. 2, 318-327(2008).
M. Paleja, T. A. Girard, K. A. Herdman, and B. K. Christensen, “Two distinct neural networks functionally connected to the human hippocampus during pattern separation tasks,” Brain Cognit., 92, 101-111 (2014).
W. Peng, J. Yang, B. Yang, et al., “Impact of statins on cognitive deficits in adult male rodents after traumatic brain injury: a systematic review,” Biomed. Res. Int., 13 (2014), doi: https://doi.org/10.1155/2014/261409.
A. M. Dolga, I. M. Nijholt, A. Ostroveanu, et al., “Lovastatin induces neuroprotection through tumor necrosis factor receptor 2 signaling pathway,” J. Alzheimers Dis., 13, No. 2, 111-122(2008).
A. Mendoza-Oliva, P. Ferrera, J. Fragoso-Medina, and C. Airas, “Lovastatin differentially affects neuronal cholesterol and amyloid-β production in vivo and in vitro,” CNS. Neurosci. Ther., 21, No. 8, 631-641 (2015).
A. M. Dolga, I. Granic , I. M. Nijholt, et al., “Pretreatment with lovastatin prevents N-methyl-D-aspartate-induced neurodegeneration in the magnocellular nucleus basalis and behavioral dysfunction,” J. Alzheimers Dis., 17, No. 2, 327-336 (2009).
R. Li, D. E. Xu, and T. Ma, “Lovastatin suppresses the aberrant tau phosphorylation from FTDP-17 mutation and okadaic acid-induction in rat primary neurons,” Neuroscience, 294, 14-20 (2009).
G. Chen, S. Zhang, J. Shi, et al., “Simvastatin reduces secondary brain injury caused by cortical contusion in rats: possible involvement of TLR4/ NF-кβ pathway,” Exper. Neurol., 216, No. 2, 398-406 (2009).
N.B. Chauhan and R. Gatto, “Restoration of cognitive deficits after statin feeding in TBI,” Restor. Neurol. Neurosci., 29, No. 1, 23-34 (2011).
J.-Q. Yan, Y.-J. Ma, J.-Ch. Sun, et al., “Neuroprotective effect of lovastatin by inhibiting NMDA receptor1 in 6-hydroxydopamine treated PC12 cells,” Int. J. Clin. Exp. Med., 7, No. 10, 3313-3319 (2014).
S. F. Chen, T. H. Hung, C. C. Chen, et al., “Lovastatin improves histological and functional outcomes and reduces inflammation after experimental traumatic brain injury,” Life Sci.,81, No. 4, 288-298 (2007).
S. Ashkavandi, A. A. Moazedi, S. Semnanian, et al., “Effects of GM1 ganglioside on the recovery of spatial learning after a lesion of the nucleus basalis magnocellularis in an experimental model of Alzheimer’s disease in adult male rats, ” Amer. J. Med. Medic. Sci., 5, No.1, 42-47 (2015).
Z. Rabiei, M. Rafieian-Kopaei, E. Heidarian, et al., “Effects of Zizyphus jujube extract on memory and learning impairment induced by bilateral electric lesions of the nucleus basalis of Meynert in rat,” Neurochem. Res., 39, No. 2, 353–360 (2014).
C. P. Davis, L. M. Franklin, G. S. Johnson, and L. M. Schrott, “Prenatal oxycodone exposure impairs spatial learning and/or memory in rats,” Behav. Brain Res., 212, No. 1, 27-34 (2010).
J. Gratwicke, J. Kahan, L. Zrinzo, et al., “The nucleus basalis of Meynert: a new target for deep brain stimulation in dementia?,” Neurosci. Biobehav. Rev., 37, No. 10 Pt 2, 2676-2688 (2013).
Y. Yamaguchi, M. Higashi, T. Matsuno, and S. Kawashima, “Ameliorative effects of azaindolizinone derivative ZSET845 on scopolamine-induced deficits in passive avoidance and radial arm maze learning in the rat,” Jpn. J. Pharmacol., 87, No. 3, 240–244 (2001).
M. D. Lindner, J. B. Hogan, D. B. Hodges Jr., et al., “Donepezil primarily attenuates scopolamine-induced deficits in psychomotor function, with moderate effects on simple conditioning and attention, and small effects on working memory and spatial mapping,” Psychopharmacology (Berl.), 188, No. 4, 629-640 (2006).
K. S. Kroker, G. Rast, R. Giovannini, et al., “Inhibition of acetylcholinesterase and phosphodiesterase-9A has differential effects on hippocampal early and late LTP,” Neuropharmacology, 62, Nos. 5–6, 1964-1974(2012).
Q. Wang, J. Yan, X. Chen, et al., “Statins: multiple neuroprotective mechanisms in neurodegenerative diseases,” Exp. Neurol., 230, No. 1, 27-34 (2011).
P. J. Van der Most, A. M. Dolga, I. M. Nijholt, et al., “Statins: mechanism of neuroprotection,” Prog. Neurobiol., 88, No. 1, 64-75 (2009).
R. A. Mans, N. Chowdhury, D. Cao, et al., “Simvastatin enhances hippocampal long-potentiation in C57BL/6 mice,” Neuroscience, 166, No. 2, 435-444 (2010).
N. F. Ho, S. D. Han, and G. S. Dawe, “Effect of voluntary running on adult hippocampal neurogenesis in cholinergic lesioned mice,” BMC Neuroscience, 10:57 (2009), doi: https://doi.org/10.1186/1471-2202-10-5.
Z. Zhao, S. Zhao, N. Xu, et al., “Lovastatin improves neurological outcome after neucleus basalis magnocellularis lesion in rats,”Neuroscience, 167, No. 3, 954-963 (2010).
A. Coccamo, A. Fisher, and F. M. LaFerla, “M1 agonists as a potential disease-modifying therapy for Alzheimer’s disease,” Curr. Alzheimer Res.,6, No. 2, 112-117(2009).
G. Yamin, “NMDA receptor-dependent signaling pathways that underlie amyloid beta protein disruption of LTP in the hippocampus,” J. Neurosci. Res., 87, No. 8, 1729-1736 (2009).
T. Freret, V. Bouet, A. Quiedeville , et al., “Synergistic effect of acetylcholinesterase inhibition (donepezil) and 5-HT(4) receptor activation (RS67333) on object recognition in mice,” Behav. Brain Res., 230, No.1, 304-308 (2012).
H. Tsunekawa, Y. Noda, A. Mouri, et al., “Synergistic effects of selegiline and donepezil on cognitive impairment induced by amyloid beta (25-35),” Behav. Brain Res., 190, No. 2, 224-32 (2008).
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Eskandary, A., Moazedi, A.A., Najaph zade varzi, H. et al. Combined Effects of Donepezil and Lovastatin on Cognition Deficit Induced by Bilateral Lesion of the Nucl. Basalis Magnocellularis in a Rat Model of Alzheimer’s Disease. Neurophysiology 50, 99–107 (2018). https://doi.org/10.1007/s11062-018-9723-5
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DOI: https://doi.org/10.1007/s11062-018-9723-5