배양한 대뇌피질세포에서 유발한 신경손상에 대한 콜린에스테라제 억제제의 영향

Effects of Cholinesterase Inhibitors on Neuronal Injuries in Primary Cultured Rat Cortical Cells

  • 발행 : 2002.06.01

초록

Alzheimer's disease (AD) involves neuronal degeneration with impaired cholinergic transmission, particularly in areas of the brain associated with learning and memory. Several cholinesterase inhibitors are widely prescribed to ameliorate the cognitive deficits in AD patients. In an attempt to examine if tacrine and donepezil, two well-known cholinesterase inhibitors, exhibit additional pharmacological actions in primary cultured rat cortical cells, we investigated the effects on neuronal injuries induced by glutamate or N-methyl-D-aspartate (NMDA), $\beta$-amyloid fragment ( $A_{{beta}25-35)}$), and various oxidative insults. Both tacrine and donepezil did not significantly inhibit the excitotoxic neuronal damage induced by glutamate. However, tacrine inhibited the toxicity induced by NMDA in a concentration-dependent fashion. In addition, tacrine significantly inhibited the $A_{{beta}25-35)}$-induced neuronal injury at the concentration of 50 $\mu$M. In contrast, donepezil did not reduce the NMDA- nor $A_{{beta}25-35)}$-induced neuronal injury. Tacrine and donepezil had no effects on oxidative neuronal injuries in cultures nor on lipid peroxidation in vitro. These results suggest that, in addition to its anticholinesterase activity, the neuroprotective effects by tacrine against the NMDA- and $A_{{beta}25-35)$-induced toxicity may be beneficial for the treatment of AD. In contrast, the potent and selective inhibition of central acetylcholinesterase appears to be the major action mechanism of donepezil.

키워드

참고문헌

  1. American Psychiatric Association. DSM-IV: Diagnostic and Statistical Manual of Mental Disorder. 4th ed, Washington D. C., p. 171 (1994)
  2. Parnetti, L., Senin, U., and Mecocci, P. : Cognitive enhancement therapy for Alzheimer's disease. The way forward. Drugs 53, 752 (1997)
  3. Hardy, J. and Allsop, D. : Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol. Sci. 12, 383 (1991) https://doi.org/10.1016/0165-6147(91)90609-V
  4. Selkoe, D. J. : The cell-biology of beta-amyloid precursor protein and presenilin in Alzheimer's disease. Trends Cell Biol. 8, 447 (1998) https://doi.org/10.1016/S0962-8924(98)01363-4
  5. Harkany, T., Hortobagyi, T., Sasvari, M., Konya, C, Penke, B., Luiten, P. G. M., and Nyakas, C. : Neuroprotective approaches in experimental models of $\beta$-amyloid neurotoxicity: relevance to Alzheimer's disease. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 23, 963 (1999)
  6. Choi, D. W. : Excitotoxic cell death. J. Neurobiol. 23, 1261 (1992) https://doi.org/10.1002/neu.480230915
  7. Behl, C. : Alzheimer's disease and oxidative stress: Implications for novel therapeutic approaches. Prog. Neurobiol. 57, 301 (1999)
  8. Coyle, J. T. and Puttfarken, P. : Oxidative stress, glutamate and neurodegenerative disorders. Science 262, 689 (1993)
  9. Giacobini, E. : Cholinesterase inhibitors for Alzheimer's diseas e therapy: from tacrine to future applications. Neurochem. Int. 32, 413 (1998)
  10. Ved, H. S., Koenig, M. L., Dave, J. R., and Doctor, B. P. : Huperzine A, a potential therapeutic agent for dementia, reduces neuronal cell death caused by glutamate. NeuroReport 8, 963 (1997)
  11. Wang, X.-D., Chen, X.-Q., Yang, H.-H., and Hu, G.-Y. : Comparison of the effects of cholinesterase inhibitors on [$^{3}H$]MK-801 binding in rat cerebral cortex. Neurosci. Lett. 272, 21 (1999). https://doi.org/10.1016/S0304-3940(99)00567-4
  12. Xiao, X. Q., Yang, J. W., and Tang, X. C. : Huperzine A protects rat pheochromocytoma cells against hydrogen peroxideinduced injury. Neurosci. Lett. 275, 73 (1999) https://doi.org/10.1016/S0304-3940(99)00695-3
  13. Xiao, X. Q., Wang, R., Han, Y. F, and Tang, X. C. : Protective effects of huperzine A on $\beta$-amyloid (25-35) induced oxidative injury in rat pheochromocytoma cells. Neurosci. Lett. 286, 155 (2000) https://doi.org/10.1016/S0304-3940(00)01088-0
  14. 조정숙, 양재하, 박창국, 이희순, 김영호: 뇌졸중 치료 생약 추출물의 흥분성 신경독성 억제효과. 약학회지 44, 29 (2000)
  15. Cho, J., Joo, N.E., Kong, J.-Y., Jeong, D.-Y., Lee, K. D., and Kang, B.-S.: Inhibition of excitotoxic neuronal death by methanol extract of Acori graminei rhizoma in cultured rat cortical neurons. J. Ethnopharmacol. 73, 31 (2000) https://doi.org/10.1016/S0378-8741(00)00262-2
  16. Cho, J., Kong, J.-Y., Jeong, D.-Y., Lee, K. D., Lee, D. U., and Kang, B.-S.: NMDA receptor-mediated neuroprotection by essential oils from rhizomes of Acorus gramineus. Life Sci. 68, 1567 (2001) https://doi.org/10.1016/S0024-3205(01)00944-4
  17. Cho, J., Kim, Y. H., Kong, J.-Y., Yang, C. H., and Park, C. G. : Protection of cultured rat cortical neurons from excitotoxicity by asarone, a major essential oil component in the rhizomes of Acorus gramineus. Life Sci. in press
  18. Hansen, M. B., Nielsen, S. E., and Berg, K. : Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J. Immunol. Methods 119, 203 (1989)
  19. Ng, T. B., Liu, F, and Wang, Z. T. : Antioxidative activity of natural products from plants. Life Sci. 66, 709 (2000) https://doi.org/10.1016/S0024-3205(99)00642-6
  20. Svensson, A.-L. and Nordberg, A. : Tacrine and donepezil attenuate the neurotoxic effect of $A_{\beta_(25-35)$ in rat PC12 cells. NeuroReport 9, 1519 (1998)
  21. Retz, W, Gsell, W, Munch, G., Rosier, M., and Riederer, P. : Free radicals in Alzheimer's disease. J. Neural Transm. Suppl. 54, 221 (1998)
  22. Sauer, D. and Fagg, G. E. : Excitatory amino acids, excitotoxicity and neurodegenerative disorders, In: Krogsgaard-Larsen P, Hansen JJ (Eds), Excitatory amino acid receptors. Ellis Horwood, New York, p. 13 (1992)
  23. Watkins, P. B., Zimmerman, H. J., Knapp, M. J, Gracon, S. I., and Lewis, K. W.: Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease. JAMA 271, 992 (1994)
  24. Rogers, S. L., Friedhoff, L. T. and the Donepezil Study Group: The efficacy and safety of donepezil in patients with Alzheimer's disease: Results of a US Multicentre, Randomized, Double-blind, Placebo-controlled Trial. Dementia 7, 293 (1996)
  25. Doody, R. S. : Clinical benefits of a new piperidine-class AChE inhibitor. Eur. Neuro-Psychopharmacol. 9, S69 (1999)
  26. Zhou, J., Fu, Y., and Tang, X. C. : Huperzine A and donepezil protect rat pheochromocytoma cells against oxygen-glucose deprivation. Neurosci. Lett. 306, 53 (2001) https://doi.org/10.1016/S0304-3940(01)01855-9