Acetylcholinesterase 억제 및 신경세포 보호 활성을 갖는 다시마목 해조 추출물 NX42의 마우스 학습능력 향상 효과

Improvement of Learning Behavior of Mice by an Antiacetylcholinesterase and Neuroprotective Agent NX42, a Laminariales-Alga Extract

  • Lee, Bong-Ho (Laboratory of Aging and Degenerative Diseases, Hanbat National University) ;
  • Stein, Steven M. (Department of Medicine, University of Washington)
  • 발행 : 2004.12.31

초록

다당류 및 플로로탄닌 등을 주성분으로 하는 갈조추출물 NX42가 인지능력 향상에 미치는 영향을 평가하기 위한 in vitro 및 동물실험을 수행하였다. 그 결과 NX42는 acetylcholinesterase에 대하여 온화하지만 용량의존적인 억제효과($IC_{50}=600-700\;{\mu}g/mL$)를 나타내었다. NX42로부터 추출된 플로로탄닌 분획은 현저히 높은 용량 의존적 억제 효과($IC_{50}=54\;{\mu}g/mL$)를 나타내었다. 반면, 플로로탄닌이 제거된 분획과 푸코이단은 억제효과가 없었다. NX42 및 플로로탄닌 분획은 과산화수소에 의해 유발된 산화스트레스 조건 하에서의 SK-N-SH 세포의 파괴를 유의성 있게 억제한 반면, 플로로탄닌이 제거된 분획과 푸코이단은 보호효과를 나타내지 않았다. 스트레스 조건 하에 있는 마우스의 학습능력에 미치는 효과를 평가한 결과, NX42를 섭취한 마우스의 경우에는 섭취하지 않은 경우에 비하여 유의성 있게 개선된 학습능력을 나타내었으며, 이는 in vitro 실험 결과를 바탕으로 볼 때, NX42에 함유된 플로로탄닌의 acetylcholinesterase 억제 활성 및 신경보호활성에 의한 것으로 해석된다.

Brown-alga-derived natural agent NX42, mainly composed of algal polysaccharides and phlorotannins, showed mild but dose-dependent inhibition of acetylcholinesterase with $IC_{50}=600-700\;{\mu}g/mL$. Phlorotannin-rich fraction of NX42 showed substantial increase of the activity by more than one order of magnitude ($IC_{50}=54\;{\mu}g/mL$) and significant protection of SK-N-SH cells from oxidative stress by $H_2O_2$. Learning trials of mice for 5 consecutive days revealed electric-shock treatment during learning period significantly retarded learning process, whereas NX42-treated mice showed significant resistance against leaning deficiency possibly mainly due to anticholinesterase and neuroprotective activities of phlorotannin.

키워드

참고문헌

  1. Wenk GL. The nucleus basalis magnocellularis cholinergic system: one hundred years of progress. Neurobiol. Learn. Mem. 67: 85-95 (1997) https://doi.org/10.1006/nlme.1996.3757
  2. Power AE, Vazdarjanova A, McGaugh JL. Muscarinic cholinergic influences in memory consolidation. Neurobiol. Learn. Mem. 80: 178-193 (2003) https://doi.org/10.1016/S1074-7427(03)00086-8
  3. Rasmusson DD. The role of acetylcholine in cortical synaptic plasticity. Behav. Brain Res. 115: 205-218 (2000) https://doi.org/10.1016/S0166-4328(00)00259-X
  4. Fagen ZM, Mansvelder HD, Keath JR, McGehee DS. Short- and long-term modulation of synaptic inputs to brain reward areas by nicotine. Ann. N.Y. Acad. Sci. 1003: 185-195 (2003) https://doi.org/10.1196/annals.1300.011
  5. Disterhoft JF, Matthew OM. Modulation of cholinergic transmission enhances excitability of hippocampal pyramidal neurons and ameliorates learning impairments in aging animals. Neurobiol. Learn. Mem. 80: 223-233 (2003) https://doi.org/10.1016/j.nlm.2003.08.004
  6. Yasuji K, Takatoshi H, Dai W, Ira P, Shigetada N. Impairment of reward-related learning by cholinergic cell ablation in the striatum. Proc. Natl. Acad. Sci. USA. 100: 7965-7970 (2003) https://doi.org/10.1073/pnas.1032899100
  7. Tsukada H, Nishiyama S, Fukumoto D, Ohba H, Sato K, Kakiuchi T. Effects of acute acetylcholinesterase inhibition on the cerebral cholinergic neuronal system and cognitive function: functional imaging of the conscious monkey brain using animal PET in combination with microdialysis. Synapse 52: 1-10 (2004) https://doi.org/10.1002/syn.10310
  8. Delagarza VW. New drugs for Alzheimer's disease. Am. Fam. Phys. 58: 1175-1182 (1998)
  9. Roman GC, Rogers SJ. Donepezil: a clinical review of current and emerging indications. Expert Opin. Pharmacother. 5: 161-180 (2004) https://doi.org/10.1517/14656566.5.1.161
  10. Dubois B, Albert ML. MCI or prodromal Alzheimer's disease? Lancet Neurol. 3: 246-248 (2004) https://doi.org/10.1016/S1474-4422(04)00710-0
  11. Tracy HM. Disorders of memory: mild cognitive impairment. Neuro Invest. 102: 4-18 (2003)
  12. Kwon EK, Oh SW, Lee CH, Han D. Screening of HMG-CoA reductase inhibitoryactivity in several natural products (abstract no P7-32). In: 70th Nutrigenomics Symposium: Recent trends in food science and technology. June 26-28, Gyeongju TEMF Hotel,Gyeongju, Korea. The Korean Society of Food Science and Technology (2003)
  13. Kang JW. Illustrated Encyclopedia of Fauna and Flora of Korea. Vol. 8. Sam Hwa Publishing Co., Seoul, Korea (1968)
  14. Taira K, Tanaka H, Arakawa M, Nagahama N, Uza M, Shirakawa S. Sleep health and lifestyle of elderly people in Ogimi, a village of longevity. Psych. Clinic. Neurosci. 56: 243-244 (2002) https://doi.org/10.1046/j.1440-1819.2002.01014.x
  15. Morita K, Nakano T. Seaweed accelerates the excretion of dioxin stored in rats. J. Agric. Food Chem. 50: 910-917 (2002) https://doi.org/10.1021/jf0111920
  16. Uhm CS, Kim KB, Lim JH, Pee DH, Kim YH, Kim H, Eun BL, Tockgo YC. Effective treatment with fucoidan for perinatal hypoxic-ischemic encephalopathy in rats. Neurosci. Lett. 353: 21- 24 (2003) https://doi.org/10.1016/j.neulet.2003.09.013
  17. Ruehl ML, Orozco JA, Stoker MB, McDonagh PF, Coull BM, Ritter LS. Protective effects of inhibiting both blood and vascular selectins after stroke and reperfusion. Neurol. Res. 24: 226-232 (2002) https://doi.org/10.1179/016164102101199738
  18. Glombitza KW, Gerstberger G. Phlorotannins with dibenzodioxin structural elements from the brown alga Eisenia arborea. Phytochemistry 24: 543-551 (1985) https://doi.org/10.1016/S0031-9422(00)80764-5
  19. Fukuyama Y, Kodama M, Miura I, Kinzyo Z, Kido M, Mori H, Nakayama Y, Takahashi M. Structure of an anti-plasmin inhibitor, eckol, isolated from the brown alga Ecklonia kurome OKAMURA and inhibitory activities of its derivatives on plasmin inhibitors. Chem. Pharm. Bull. 37: 349-353 (1989) https://doi.org/10.1248/cpb.37.349
  20. Nakamura T, Nagayama K, Uchida K, Tanaka R. Antioxidant activity of phlorotannins isolated from the brown alga Eisenia bicyclis. Fish. Sci. 62: 923-926 (1996) https://doi.org/10.2331/fishsci.62.923
  21. Shibata T, Fujimoto K, Nagayama K, Yamaguchi K, Nakamura T. Inhibitory activity of brown algal phlorotannins against hyaluronidase. Int. J. Food Sci. Technol. 37: 703-709 (2002) https://doi.org/10.1046/j.1365-2621.2002.00603.x
  22. Shibata T, Nagayama K, Tanaka R, Yamaguchi K, Nakamura T. Inhibitory effects of brown algal phlorotannins on secretory phospholipase $A_2s$ , lipoxygenases, and cycloxygenases. J. Appl. Phy-col.15:61-66(2003) https://doi.org/10.1023/A:1022972221002
  23. Ellmans GL, Courtney KD, Andress VJ, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol. 7: 88-95 (1961) https://doi.org/10.1016/0006-2952(61)90145-9
  24. Jang CG, Lee SY, Yoo JH, Yan JJ, Song DK, Loh HH, Ho IK. Impaired water maze learning performance in m-opioid receptor knockout mice. Mol. Brain Res. 117: 68-72 (2003) https://doi.org/10.1016/S0169-328X(03)00291-2
  25. Mori K, Muto Y, Kokuzawa J, Yoshioka T, Yoshimura S, Iwama T, Okano Y, Sakai N. Neuronal protein NP25 interacts with Factin. Neurosci. Res. 48: 439-446 (2004) https://doi.org/10.1016/j.neures.2003.12.012
  26. Sharma SK, Carlson EC. Ebadi, neuroprotective actions of selegiline in inhibiting 1-methyl-4-phenylpyridinium ion (MPP+)- induced apoptosis in SK-N-SH neurons. J. Neurocytol. 32: 329- 343 (2003) https://doi.org/10.1023/B:NEUR.0000011327.23739.1b
  27. Ba F, Pang PK, Davidge ST, Benishin CG. The neuroprotective effects of estrogen in SK-N-SH neuroblastoma cell cultures. Neurochem. Intl. 44: 401-411 (2004) https://doi.org/10.1016/j.neuint.2003.08.004
  28. Ba F, Pang PK, Benishin CG. The establishment of a reliable cytotoxic system with SK-N-SH neuroblastoma cell culture. J. Neurosci. Meth. 123: 11-22 (2003) https://doi.org/10.1016/S0165-0270(02)00324-2
  29. Power AE. Slow-wave sleep, acetylcholine, and memory consolidation. Proc. Natl. Acad. Sci. USA. 101: 1795-1796 (2004) https://doi.org/10.1073/pnas.0400237101
  30. Sanford LD, Yang L, Tang X. Influence of contextual fear on sleep in mice: a strain comparison. Sleep 26: 527-540 (2003) https://doi.org/10.1093/sleep/26.5.527