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Neuroprotective Effects of Spinosin on Recovery of Learning and Memory in a Mouse Model of Alzheimer's Disease

  • Xu, Fanxing (Jiangsu Kangyuan Pharmaceutical Co., Ltd.) ;
  • He, Bosai (Faculty of Functional Food and Wine, Shenyang Pharmaceutical University) ;
  • Xiao, Feng (Faculty of Functional Food and Wine, Shenyang Pharmaceutical University) ;
  • Yan, Tingxu (School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University) ;
  • Bi, Kaishun (School of Pharmacy, Shenyang Pharmaceutical University) ;
  • Jia, Ying (Faculty of Functional Food and Wine, Shenyang Pharmaceutical University) ;
  • Wang, Zhenzhong (Jiangsu Kangyuan Pharmaceutical Co., Ltd.)
  • 투고 : 2018.03.19
  • 심사 : 2018.05.08
  • 발행 : 2019.01.01

초록

Previous studies have shown that spinosin was implicated in the modulation of sedation and hypnosis, while its effects on learning and memory deficits were rarely reported. The aim of this study is to investigate the effects of spinosin on the improvement of cognitive impairment in model mice with Alzheimer's disease (AD) induced by $A{\beta}_{1-42}$ and determine the underlying mechanism. Spontaneous locomotion assessment and Morris water maze test were performed to investigate the impact of spinosin on behavioral activities, and the pathological changes were assayed by biochemical analyses and histological assay. After 7 days of intracerebroventricular (ICV) administration of spinosin ($100{\mu}g/kg/day$), the cognitive impairment of mice induced by $A{\beta}_{1-42}$ was significantly attenuated. Moreover, spinosin treatment effectively decreased the level of malondialdehyde (MDA) and $A{\beta}_{1-42}$ accumulation in hippocampus. $A{\beta}_{1-42}$ induced alterations in the expression of brain derived neurotrophic factor (BDNF) and B-cell lymphoma-2 (Bcl-2), as well as inflammatory response in brain were also reversed by spinosin treatment. These results indicated that the ameliorating effect of spinosin on cognitive impairment might be mediated through the regulation of oxidative stress, inflammatory process, apoptotic program and neurotrophic factor expression,suggesting that spinosin might be beneficial to treat learning and memory deficits in patients with AD via multi-targets.

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참고문헌

  1. Ahmad, M., Saleem, S., Ahmad, A. S., Yousuf, S., Ansari, M. A., Khan, M. B., Ishrat, T., Chaturvedi, R. K., Agrawal, A. K. and Islam, F. (2005) Ginkgo biloba affords dose-dependent protection against 6-hydroxydopamine-induced Parkinsonism in rats: neurobehavioural, neurochemical and immunohistochemical evidences. J. Neurochem. 93, 94-104. https://doi.org/10.1111/j.1471-4159.2005.03000.x
  2. Almeida, R. D., Manadas, B. J., Melo, C. V., Gomes, J. R., Mendes, C. S., Graos, M. M., Carvalho, R. F., Carvalho, A. P. and Duarte, C. B. (2005) Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways. Cell Death Differ. 12, 1329-1343. https://doi.org/10.1038/sj.cdd.4401662
  3. Butterfield, D. A. and Stadtman, E. R. (1997) Protein oxidation processes in aging brain. Adv. Cell Aging Gerontol. 2, 161-191. https://doi.org/10.1016/S1566-3124(08)60057-7
  4. Chu, Y. F., Chang, W. H., Black, R. M., Liu, J. R., Sompol, P. and Chen, Y. (2012) Crude caffeine reduces memory impairment and amyloid ${\beta}_{1-42}$ levels in an Alzheimer's mouse model. Food Chem. 135, 2095-2102. https://doi.org/10.1016/j.foodchem.2012.04.148
  5. Cummings, J. L., Morstorf, T. and Zhong, K. (2014) Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res. Ther. 6, 37. https://doi.org/10.1186/alzrt269
  6. De Strooper, B. and Karran, E. (2016) The cellular phase of Alzheimer's disease. Cell 164, 603-615. https://doi.org/10.1016/j.cell.2015.12.056
  7. Drummond, S. P. A. and Brown, G. G. (2001) The effects of total sleep deprivation on cerebral responses to cognitive performance. Neuropsychopharmacology 25, S68-S73. https://doi.org/10.1016/S0893-133X(01)00325-6
  8. Graves, L. A., Heller, E. A., Pack, A. I. and Abel, T. (2003) Sleep deprivation selectively impairs memory consolidation for contextual fear conditioning. Learn. Mem. 10, 168-176. https://doi.org/10.1101/lm.48803
  9. Gao, H. M., Zhou, H. and Hong, J. S. (2012) NADPH oxidases: novel therapeutic targets for neurodegenerative diseases. Trends Pharmacol. Sci. 33, 295-303. https://doi.org/10.1016/j.tips.2012.03.008
  10. Gomez-Ramirez, J. and Wu, J. (2014) Network-based biomarkers in Alzheimer's disease: review and future directions. Front. Aging Neurosci. 6, 12. https://doi.org/10.3389/fnagi.2014.00012
  11. Hardy, J. and Selkoe, D. J. (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353-356. https://doi.org/10.1126/science.1072994
  12. Ianiski, F. R., Alves, C. B., Souza, A. C. G., Pinton, S., Roman, S. S., Rhoden, C. R. B., Alves, M. P. and Luchese, C. (2012) Protective effect of meloxicam-loaded nanocapsules against amyloid-${\beta}$ peptide-induced damage in mice. Behav. Brain Res. 230, 100-107. https://doi.org/10.1016/j.bbr.2012.01.055
  13. Jiang, J. G., Huang, X. J., Chen, J. and Lin, Q. S. (2007) Comparison of the sedative and hypnotic effects of flavonoids, saponins, and polysaccharides extracted from Semen Ziziphus jujube. Nat. Prod. Res. 21, 310-320. https://doi.org/10.1080/14786410701192827
  14. Jung, I. H., Lee, H. E., Park, S. J., Ahn, Y. J., Kwon, G., Woo, H., Lee, S. Y., Kim, J. S., Jo, Y. W., Jang, D. S., Kang, S. S. and Ryu, J. H. (2014) Ameliorating effect of spinosin, a C-glycoside flavonoid, on scopolamine-induced memory impairment in mice. Pharmacol. Biochem. Behav. 120, 88-94. https://doi.org/10.1016/j.pbb.2014.02.015
  15. Ko, S. Y., Lee, H. E., Park, S. J., Jeon, S. J., Kim, B., Gao, Q., Jang, D. S. and Ryu, J. H. (2015) Spinosin, a C-glucosylflavone, from Zizyphus jujuba var. spinosa ameliorates $Abeta_{1-42}$ oligomer-induced memory impairment in mice. Biomol. Ther. (Seoul) 23, 156-164. https://doi.org/10.4062/biomolther.2014.110
  16. Kowalska, A. (2004) The beta-amyloid cascade hypothesis: a sequence of events leading to neurodegeneration in Alzheimer's disease. Neurol. Neurochir. Pol. 38, 405-412.
  17. Lee, Y., Jeon, S. J., Lee, H. E., Jung, I. H., Jo, Y. W., Lee, S., Cheong, J. H., Jang, D. S. and Ryu, J. H. (2016) Spinosin, a C-glycoside flavonoid, enhances cognitive performance and adult hippocampal neurogenesis in mice. Pharmacol. Biochem. Behav. 145, 9-16. https://doi.org/10.1016/j.pbb.2016.03.007
  18. Mao, X., Liao, Z., Guo, L., Xu, X., Wu, B., Xu, M., Zhao, X., Bi, K. and Jia, Y. (2015) Schisandrin C ameliorates learning and memory deficits by $Abeta_{1-42}$-induced oxidative stress and neurotoxicity in mice. Phytother. Res. 29, 1373-1380. https://doi.org/10.1002/ptr.5390
  19. Morris, R. (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Meth. 11, 47-60. https://doi.org/10.1016/0165-0270(84)90007-4
  20. Nagele, R. G., Wegiel, J., Venkataraman, V., Wang, K. C. and Wegiel, J. (2004) Contribution of glial cells to the development of amyloid plaques in Alzheimer's disease. Neurobiol. Aging 25, 663-674. https://doi.org/10.1016/j.neurobiolaging.2004.01.007
  21. Numakawa, T., Suzuki, S., Kumamaru, E., Adachi, N., Richards, M. and Kunugi, H. (2010) BDNF function and intracellular signaling in neurons. Histol. Histopathol. 25, 237-258.
  22. Palop, J. J. and Mucke, L. (2010) Amyloid-beta induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nat. Neurosci. 13, 812-818. https://doi.org/10.1038/nn.2583
  23. Pauwels, K., Williams, T. L., Morris, K. L., Jonckheere, W., Vandersteen, A., Kelly, G., Schymkowitz, J. S., Rousseau, F., Pastore, A., Serpell, L. C. and Broersen, K. (2012) Structural basis for increased toxicity of pathological $a{\beta}42$: $a{\beta}40$ ratios in Alzheimer disease. J. Biol. Chem. 287, 5650-5660. https://doi.org/10.1074/jbc.M111.264473
  24. Shin, K. H., Lee, C. K., Woo, W. S. and Kang, S. S. 1978. Sedative action of spinosin. Arch. Pharm. Res. 1, 7-11. https://doi.org/10.1007/BF02856299
  25. Singh, V. K. and Guthikonda, P. (1997) Circulating cytokines in Alzheimer's disease. J. Psychiatr. Res. 31, 657-660. https://doi.org/10.1016/S0022-3956(97)00023-X
  26. Tuppo, E. E. and Arias, H. R. (2005) The role of inflammation in Alzheimer's disease. Int. J. Biochem. Cell Biol. 37, 289-305. https://doi.org/10.1016/j.biocel.2004.07.009
  27. Wang, L. E., Bai, Y. J., Shi, X. R., Cui, X. Y., Cui, S. Y., Zhang, F., Zhang, Q. Y., Zhao, Y. Y. and Zhang, Y. H. (2008) Spinosin, a C-glycoside flavonoid from semen Zizhiphi Spinozae, potentiated pentobarbital-induced sleep via the serotonergic system. Pharmacol. Biochem. Behav. 90, 399-403. https://doi.org/10.1016/j.pbb.2008.03.022
  28. Wang, L. E., Cui, X. Y., Cui, S. Y., Cao, J. X., Zhang, J., Zhang, Y. H., Zhang, Q. Y., Bai, Y. J. and Zhao, Y. Y. (2010) Potentiating effect of spinosin, a C-glycoside flavonoid of Semen Ziziphi spinosae, on pentobarbital-induced sleep may be related to postsynaptic 5-HT1A receptors. Phytomedicine 17, 404-409. https://doi.org/10.1016/j.phymed.2010.01.014
  29. Wu, L., Tong, T., Wan, S., Yan, T., Ren, F., Bi, K. and Jia, Y. (2017) Protective effects of puerarin against $A{\beta}1$-42-induced learning and memoryimpairments in mice. Planta Med. 83, 224-231. https://doi.org/10.1055/s-0042-111521
  30. Yoon, S. S. and Jo, S. A. (2012) Mechanisms of Amyloid-${\beta}$ peptide clearance: potential therapeutic targets for Alzheimer's disease. Biomol. Ther. (Seoul) 20, 245-255. https://doi.org/10.4062/biomolther.2012.20.3.245
  31. You, Z. L., Xia, Q., Liang, F. R., Tang, Y. J., Xu, C. L., Huang, J., Zhao, L., Zhang, W. Z. and He, J. J. (2010) Effects on the expression of GABAA receptor subunits by jujuboside A treatment in rat hippocampal neurons. J. Ethnopharmacol. 128, 419-423. https://doi.org/10.1016/j.jep.2010.01.034
  32. Zhang, J., Zhen, Y. F., Pu-Bu-Ci-Ren, Song, L. G., Kong, W. N., Shao, T. M., Li, X. and Chai, X. Q. (2013) Salidroside attenuates beta amyloid-induced cognitive deficits via modulating oxidative stress and inflammatory mediators in rat hippocampus. Behav. Brain. Res. 244, 70-81. https://doi.org/10.1016/j.bbr.2013.01.037
  33. Ziech, D., Franco, R., Georgakilas, A. G., Georgakila, S., Malamou-Mitsi, V., Schoneveld, O., Pappa, A. and Panayiotidis, M. I. (2010) The role of reactive oxygen species and oxidative stress in environmental carcinogenesis and biomarker development. Chem. Biol. Interact. 188, 334-339. https://doi.org/10.1016/j.cbi.2010.07.010

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