DOI QR코드

DOI QR Code

New Four-herb Formula Ameliorates Memory Impairments via Neuroprotective Effects on Hippocampal Cells

한약재 4종 복합추출물의 해마신경세포 보호를 통한 기억력 개선

  • Received : 2015.11.16
  • Accepted : 2016.03.15
  • Published : 2016.04.30

Abstract

The current study was conducted to evaluate beneficial effects of a new formula (CWC-9) using four traditional Oriental medicinal herbs, Cynanchum wilfordii, Rehmannia glutinosa, Polygala tenuifolia, and Acorus gramineus, on hippocampal cells and memory function. To examine the neuroprotective effects of a new four-herb extract, cell viability, cytotoxicity, and reactive oxygen species (ROS) assays were performed in HT22 cells and behavioral tests (Morris water maze and passive avoidance retention), Western blot, and immunohistochemistry were performed in a mouse model of focal cerebral ischemia. In HT22 hippocampal cells, pretreatment with CWC-9 resulted in significantly reduced glutamate-induced cell death with suppression of ROS accumulation caused by glutamate. In a mouse model of focal cerebral ischemia, we observed significant improvement of spatial and short-term memory function by treatment with CWC-9. Phosphorylated p38 mitogen-activated protein kinases (MAPK) in hippocampus of ischemic mice were decreased by treatment with CWC-9, but phosphorylated phosphatidylinositol-3 kinase (PI3K) and cAMP response element binding protein (CREB) were significantly enhanced. By immunohistochemical analysis, we confirmed higher expression of phosphorylation of CREB in the hippocampal neurons of CWC-9 treated mice. These results suggest that new multi-herb formula CWC-9 mainly exerted beneficial effects on cognitive function through regulation of neuro-protective signaling pathways associated with CREB.

Keywords

Focal cerebral ischemia;hippocampal neurons;memory;neuroprotection

References

  1. Anderson, C. N. and Tolkovsky, A. M. 1999. A role for MAPK/ERK in sympathetic neuron survival: protection against a p53-dependent, JNK-independent induction of apoptosis by cytosine arabinoside. J. Neurosci. 19, 664-673. https://doi.org/10.1523/JNEUROSCI.19-02-00664.1999
  2. Bonni, A., Brunet, A., West, A. E., Datta, S. R., Takasu, M. A. and Greenberg, M. E. 1999. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286, 1358-1362. https://doi.org/10.1126/science.286.5443.1358
  3. Cechetti, F., Worm, P. V., Elsner, V. R., Bertoldi, K., Sanches, E., Ben, J., Siqueira, I. R. and Netto, C. A. 2012. Forced treadmill exercise prevents oxidative stress and memory deficits following chronic cerebral hypoperfusion in the rat. Neurobiol. Learn. Mem. 97, 90-96. https://doi.org/10.1016/j.nlm.2011.09.008
  4. Collino, M., Aragno, M., Mastrocola, R., Gallicchio, M., Rosa, A. C., Dianzani, C., Danni, O., Thiemermann, C. and Fantozzi, R. 2006. Modulation of the oxidative stress and inflammatory response by PPAR-gamma agonists in the hippocampus of rats exposed to cerebral ischemia/reperfusion. Eur. J. Pharmacol. 530, 70-80. https://doi.org/10.1016/j.ejphar.2005.11.049
  5. Coyle, J. T. and Puttfarcken, P. 1993. Oxidative stress, glutamate, and neurodegenerative disorders. Science 262, 689-695. https://doi.org/10.1126/science.7901908
  6. Debette, S. 2013. Vascular risk factors and cognitive disorders. Rev. Neurol. (Paris) 169, 757-764. https://doi.org/10.1016/j.neurol.2013.07.022
  7. Dineley, K. T., Westerman, M., Bui, D., Bell, K., Ashe, K. H. and Sweatt, J. D. 2001. Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors: In vitro and in vivo mechanisms related to Alzheimer′s disease. J. Neurosci. 21, 4125-4133. https://doi.org/10.1523/JNEUROSCI.21-12-04125.2001
  8. Fukui, M., Choi, H. J. and Zhu, B. T. 2010. Mechanism for the protective effect of resveratrol against oxidative stress-induced neuronal death. Free Radic. Biol. Med. 49, 800-813. https://doi.org/10.1016/j.freeradbiomed.2010.06.002
  9. Ghosh, A., Sarkar, S., Mandal, A. K. and Das, N. 2013. Neuroprotective role of nanoencapsulated quercetin in combating ischemia-reperfusion induced neuronal damage in young and aged rats. PLoS One 8, e57735. https://doi.org/10.1371/journal.pone.0057735
  10. Gim, S. A. and Koh, P. O. 2014. Ferulic acid prevents the injury-induced decrease of gamma-enolase expression in brain tissue and HT22 cells. Lab. Animal Res. 30, 8-13. https://doi.org/10.5625/lar.2014.30.1.8
  11. Hwang, B. Y., Kim, Y. H., Ro, J. S., Lee, K. S. and Lee, J. J. 1999. Acetophenones from the roots of Cynanchum wilfordii H(EMSLEY). Arch. Pharm. Res. 22, 72-74. https://doi.org/10.1007/BF02976439
  12. Itua, I. and Naderali, E. K. 2010. Review: omega-3 and memory function: to eat or not to eat. Am. J. Alzheimers Dis. Other. Demen. 25, 479-482. https://doi.org/10.1177/1533317510376943
  13. Jamarkattel-Pandit, N., Pandit, N. R., Kim, M. Y., Park, S. H., Kim, K. S., Choi, H., Kim, H. and Bu, Y. 2010. Neuroprotective effect of defatted sesame seeds extract against in vitro and in vivo ischemic neuronal damage. Planta Med. 76, 20-26. https://doi.org/10.1055/s-0029-1185903
  14. Kitagawa, K. 2007. CREB and cAMP response elementmediated gene expression in the ischemic brain. FEBS J. 274, 3210-3217. https://doi.org/10.1111/j.1742-4658.2007.05890.x
  15. Lasa, M., Abraham, S. M., Boucheron, C., Saklatvala, J. and Clark, A. R. 2002. Dexamethasone causes sustained expression of mitogen-activated protein kinase (MAPK) phosphatase 1 and phosphatase-mediated inhibition of MAPK p38. Mol. Cell. Biol. 22, 7802-7811. https://doi.org/10.1128/MCB.22.22.7802-7811.2002
  16. Lee, K. Y., Jeong, E. J., Huh, J., Cho, N., Kim, T. B., Jeon, B. J., Kim, S. H., Kim, H. P. and Sung, S. H. 2012. Cognition-enhancing and neuroprotective activities of the standardized extract of Betula platyphylla bark and its major diarylheptanoids. Phytomedicine 19, 1315-1320. https://doi.org/10.1016/j.phymed.2012.09.012
  17. Lee, M. K., Yeo, H., Kim, J., Markelonis, G. J., Oh, T. H. and Kim, Y. C. 2000. Cynandione A from Cynanchum wilfordii protects cultured cortical neurons from toxicity induced by H2O2, L-glutamate, and kainate. J. Neurosci. Res. 59, 259-264. https://doi.org/10.1002/(SICI)1097-4547(20000115)59:2<259::AID-JNR12>3.0.CO;2-3
  18. Lo, E. H., Dalkara, T. and Moskowitz, M. A. 2003. Mechanisms, challenges and opportunities in stroke. Nat. Rev. Neurosci. 4, 399-415.
  19. Maher, P. and Davis, J. B. 1996. The role of monoamine metabolism in oxidative glutamate toxicity. J. Neurosci. 16, 6394-6401. https://doi.org/10.1523/JNEUROSCI.16-20-06394.1996
  20. May, B. H., Lu, C., Bennett, L., Hugel, H. M. and Xue, C. C. 2012. Evaluating the traditional Chinese literature for herbal formulae and individual herbs used for age-related dementia and memory impairment. Biogerontology 13, 299-312. https://doi.org/10.1007/s10522-012-9375-6
  21. Qin, R., Li, X., Li, G., Tao, L., Li, Y., Sun, J., Kang, X. and Chen, J. 2011. Protection by tetrahydroxystilbene glucoside against neurotoxicity induced by MPP+: the involvement of PI3K/Akt pathway activation. Toxicol Lett. 202, 1-7. https://doi.org/10.1016/j.toxlet.2011.01.001
  22. Stanciu, M., Wang, Y., Kentor, R., Burke, N., Watkins, S., Kress, G., Reynolds, I., Klann, E., Angiolieri, M. R., Johnson, J. W. and DeFranco, D. B. 2000. Persistent activation of ERK contributes to glutamate-induced oxidative toxicity in a neuronal cell line and primary cortical neuron cultures. J. Biol. Chem. 275, 12200-12206. https://doi.org/10.1074/jbc.275.16.12200
  23. Tan, S., Sagara, Y., Liu, Y., Maher, P. and Schubert, D. 1998. The regulation of reactive oxygen species production during programmed cell death. J. Cell Biol. 141, 1423-1432. https://doi.org/10.1083/jcb.141.6.1423
  24. Tan, S., Schubert, D. and Maher, P. 2001. Oxytosis: A novel form of programmed cell death. Curr. Top. Med. Chem. 1, 497-506. https://doi.org/10.2174/1568026013394741
  25. Taylor, C. P., Weber, M. L., Gaughan, C. L., Lehning, E. J. and LoPachin, R. M. 1999. Oxygen/glucose deprivation in hippocampal slices: altered intraneuronal elemental composition predicts structural and functional damage. J. Neurosci. 19, 619-629. https://doi.org/10.1523/JNEUROSCI.19-02-00619.1999
  26. Xu, J., Xilouri, M., Bruban, J., Shioi, J., Shao, Z., Papazoglou, I., Vekrellis, K. and Robakis, N. K. 2011. Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling. Neurobiol. Aging 32, 2326.
  27. Yamamoto-Sasaki, M., Ozawa, H., Saito, T., Rosler, M. and Riederer, P. 1999. Impaired phosphorylation of cyclic AMP response element binding protein in the hippocampus of dementia of the Alzheimer type. Brain Res. 824, 300-303. https://doi.org/10.1016/S0006-8993(99)01220-2
  28. Yue, R., Yuan, X., Liu, X., Zhang, J., Jiang, P., He, C., Shan, L., Yu, Y. and Zhang, W. 2012. Cynandione A mitigates ischemic injuries in rats with cerebral ischemia. J. Neurochem. 121, 451-464. https://doi.org/10.1111/j.1471-4159.2012.07682.x