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The Effects of Donepezil, an Acetylcholinesterase Inhibitor, on Impaired Learning and Memory in Rodents

  • Received : 2017.09.25
  • Accepted : 2017.11.07
  • Published : 2018.05.01

Abstract

A previous study in humans demonstrated the sustained inhibitory effects of donepezil on acetylcholinesterase (AChE) activity; however, the effective concentration of donepezil in humans and animals is unclear. This study aimed to characterize the effective concentration of donepezil on AChE inhibition and impaired learning and memory in rodents. A pharmacokinetic study of donepezil showed a mean peak plasma concentration of donepezil after oral treatment (3 and 10 mg/kg) of approximately $1.2{\pm}0.4h$ and $1.4{\pm}0.5h$, respectively; absolute bioavailability was calculated as 3.6%. Further, AChE activity was inhibited by increasing plasma concentrations of donepezil, and a maximum inhibition of $31.5{\pm}5.7%$ was observed after donepezil treatment in hairless rats. Plasma AChE activity was negatively correlated with plasma donepezil concentration. The pharmacological effects of donepezil are dependent upon its concentration and AChE activity; therefore, we assessed the effects of donepezil on learning and memory using a Y-maze in mice. Donepezil treatment (3 mg/kg) significantly prevented the progression of scopolamine-induced memory impairment in mice. As the concentration of donepezil in the brain increased, the recovery of spontaneous alternations also improved; maximal improvement was observed at $46.5{\pm}3.5ng/g$ in the brain. In conclusion, our findings suggest that the AChE inhibitory activity and pharmacological effects of donepezil can be predicted by the concentration of donepezil. Further, $46.5{\pm}3.5ng/g$ donepezil is an efficacious target concentration in the brain for treating learning and memory impairment in rodents.

Keywords

Acknowledgement

Supported by : Korea Health Industry Development Institute (KHIDI)

References

  1. Bhateria, M., Ramakrishna, R., Pakala, D. B. and Bhatta, R. S. (2015) Development of an LC-MS/MS method for simultaneous determination of memantine and donepezil in rat plasma and its application to pharmacokinetic study. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1001, 131-139. https://doi.org/10.1016/j.jchromb.2015.07.042
  2. Colovic, M. B., Krstic, D. Z., Lazarevic-Pasti, T. D., Bondzic, A. M. and Vasic, V. M. (2013) Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr. Neuropharmacol. 11, 315-335. https://doi.org/10.2174/1570159X11311030006
  3. Davis, R. E., Doyle, P. D., Carroll, R. T., Emmerling, M. R. and Jaen, J. (1995) Cholinergic therapies for Alzheimer's disease. Palliative or disease altering? Arzneimittelforschung 45, 425-431.
  4. Dela Pena, I. J. I., Kim, H. J., Botanas, C. J., de la Pena, J. B., Van Le, T. H., Nguyen, M. D., Park, J. H. and Cheong, J. H. (2017) The psychopharmacological activities of Vietnamese ginseng in mice: characterization of its psychomotor, sedative-hypnotic, antistress, anxiolytic, and cognitive effects. J. Ginseng Res. 41, 201-208. https://doi.org/10.1016/j.jgr.2016.03.005
  5. Farlow, M., Veloso, F., Moline, M., Yardley, J., Brand-Schieber, E., Bibbiani, F., Zou, H., Hsu, T. and Satlin, A. (2011) Safety and tolerability of donepezil 23 mg in moderate to severe Alzheimer's disease. BMC Neurol. 11, 57. https://doi.org/10.1186/1471-2377-11-57
  6. Geerts, H., Guillaumat, P. O., Grantham, C., Bode, W., Anciaux, K. and Sachak, S. (2005) Brain levels and acetylcholinesterase inhibition with galantamine and donepezil in rats, mice, and rabbits. Brain Res. 1033, 186-193. https://doi.org/10.1016/j.brainres.2004.11.042
  7. Goh, C. W., Aw, C. C., Lee, J. H., Chen, C. P. and Browne, E. R. (2011) Pharmacokinetic and pharmacodynamic properties of cholinesterase inhibitors donepezil, tacrine, and galantamine in aged and young Lister hooded rats. Drug Metab. Dispos. 39, 402-411. https://doi.org/10.1124/dmd.110.035964
  8. Haug, K. H., Bogen, I. L., Osmundsen, H., Walaas, I. and Fonnum, F. (2005) Effects on cholinergic markers in rat brain and blood after short and prolonged administration of donepezil. Neurochem. Res. 30, 1511-1520. https://doi.org/10.1007/s11064-005-8828-6
  9. Ito, Y., Harada, T., Fushimi, K., Kagawa, Y., Oka, H., Nakazawa, H., Homma, R., Kato, Y. and Yamada, S. (2010) Pharmacokinetic and pharmacodynamic analysis of acetylcholinesterase inhibition by distigmine bromide in rats. Drug Metab. Pharmacokinet. 25, 254- 261. https://doi.org/10.2133/dmpk.25.254
  10. Kim, M. H., Maeng, H. J., Yu, K. H., Lee, K. R., Tsuruo, T., Kim, D. D., Shim, C. K. and Chung, S. J. (2010) Evidence of carrier-mediated transport in the penetration of donepezil into the rat brain. J. Pharm. Sci. 99, 1548-1566. https://doi.org/10.1002/jps.21895
  11. Kosasa, T., Kuriya, Y., Matsui, K. and Yamanishi, Y. (2000) Inhibitory effect of orally administered donepezil hydrochloride (E2020), a novel treatment for Alzheimer's disease, on cholinesterase activity in rats. Eur. J. Pharmacol. 389, 173-179. https://doi.org/10.1016/S0014-2999(99)00876-6
  12. Matsui, K., Mishima, M., Nagai, Y., Yuzuriha, T. and Yoshimura, T. (1999) Absorption, distribution, metabolism, and excretion of donepezil (Aricept) after a single oral administration to Rat. Drug Metab. Dispos. 27, 1406-1414.
  13. Moon, M., Song, H., Hong, H. J., Nam, D. W., Cha, M. Y., Oh, M. S., Yu, J., Ryu, H. and Mook-Jung, I. (2013) Vitamin D-binding protein interacts with A${\beta}$ and suppresses A${\beta}$-mediated pathology. Cell Death Differ. 20, 630-638. https://doi.org/10.1038/cdd.2012.161
  14. Mugwagwa, A. T., Gadaga, L. L., Pote, W., Tagwireyi, D. (2015) Antiamnesic effects of a hydroethanolic extract of Crinum macowanii on scopolamine-induced memory impairment in mice. J. Neurodegener. Dis. 2015, 242505.
  15. Olton, D. S. and Papas, B. C. (1979) Spatial memory and hippocampal function. Neuropsychologia 17, 669-682. https://doi.org/10.1016/0028-3932(79)90042-3
  16. Prince, M., Bryce, R., Albanese, E., Wimo, A., Ribeiro, W. and Ferri, C. P. (2013) The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 9, 63-75.e2. https://doi.org/10.1016/j.jalz.2012.11.007
  17. Rogers, S. L., Doody, R. S., Mohs, R. C. and Friedhoff, L. T. (1998) Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch. Intern. Med. 158, 1021-1031. https://doi.org/10.1001/archinte.158.9.1021
  18. Saluja, S., Kasha, P. C., Paturi, J., Anderson, C., Morris, R. and Banga, A. K. (2013) A novel electronic skin patch for delivery and pharmacokinetic evaluation of donepezil following transdermal iontophoresis. Int. J. Pharm. 453, 395-399. https://doi.org/10.1016/j.ijpharm.2013.05.029
  19. Sarter, M., Bodewitz, G. and Stephens, D. N. (1988) Attenuation of scopolamine-induced impairment of spontaneous alteration behaviour by antagonist but not inverse agonist and agonist ${\beta}$-carbolines. Psychopharmacology (Berl.) 94, 491-495. https://doi.org/10.1007/BF00212843
  20. Seltzer, B. (2007) Donepezil: an update. Expert Opin. Pharmacother. 8, 1011-1023. https://doi.org/10.1517/14656566.8.7.1011
  21. Small, G. W., Rabins, P. V., Barry, P. P., Buckholtz, N. S., DeKosky, S. T., Ferris, S. H., Finkel, S. I., Gwyther, L. P., Khachaturian, Z. S., Lebowitz, B. D., McRae, T. D., Morris, J. C., Oakley, F., Schneider, L. S., Streim, J. E., Sunderland, T., Teri, L. A. and Tune, L. E. (1997) Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society. JAMA 278, 1363-1371. https://doi.org/10.1001/jama.1997.03550160083043
  22. Sozio, P., Cerasa, L. S., Marinelli, L. and Di Stefano, A. (2012) Transdermal donepezil on the treatment of Alzheimer's disease. Neuropsychiatr. Dis. Treat. 8, 361-368.
  23. Sramek, J. J. and Cutler, N. R. (2000) RBC cholinesterase inhibition: a useful surrogate marker for cholinesterase inhibitor activity in Alzheimer disease therapy? Alzheimer Dis. Assoc. Disord. 14, 216- 227. https://doi.org/10.1097/00002093-200010000-00006
  24. Traina, M. E. and Serpietri, L. A. (1984) Changes in the levels and forms of rat plasma cholinesterases during chronic diisopropylphosphorofluoridate intoxication. Biochem. Pharmacol. 33, 645-653. https://doi.org/10.1016/0006-2952(84)90321-6
  25. Wietrzych, M., Meziane, H., Sutter, A., Ghyselinck, N., Chapman, P. F., Chambon, P. and Krezel, W. (2005) Working memory deficits in retinoid X receptor gamma-deficient mice. Learn. Mem. 12, 318-326. https://doi.org/10.1101/lm.89805
  26. Yang, J. H., Han, S. J., Ryu, J. H., Jang, I. S. and Kim, D. H. (2009) Ginsenoside Rh2 ameliorates scopolamine-induced learning deficit in mice. Biol. Pharm. Bull. 32, 1710-1715. https://doi.org/10.1248/bpb.32.1710

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