Chemical constituents from the fruits of Citrus unshiu and their inhibitory effects on acetylcholinesterase

Authors

  • Jiwon Baek School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea
  • Hye Lim Lee College of Korean Medicine, Gachon University, Seongnam 461-701, Republic of Korea
  • Ki Sung Kang College of Korean Medicine, Gachon University, Seongnam 461-701, Republic of Korea
  • Ki Hyun Kim School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea http://orcid.org/0000-0002-5285-9138

DOI:

https://doi.org/10.20450/mjcce.2017.1139

Keywords:

chromatography, spectroscopy, isolation, natural product, acetylcholinesterase

Abstract

Acetylcholinesterase (AChE) inhibition has been considered a promising temporary treatment for Alzheimer’s disease. The present study was conducted to isolate chemical constituents from the fruit of Citrus unshiu Markovich (Rutaceae) and evaluate their inhibitory effects on AChE. Phytochemical investigation of C. unshiu fruit led to the isolation of methyl nomilinate (1), limocitrunshin (2), nobiletin (3), kaempferol 3-O-rutinoside (4), limocitrin 3-glucoside (5), kaempferol 3-(2G-rhamnosylrutinoside) (6), didymin (7), (2S)-narirutin 4'-O-glucoside (8) and naringenin 7-O-rutinoside (9). The structures were identified with 1H and 13C NMR spectroscopic data and ESI-MS, then comparison of their spectroscopic and physical data with those previously reported, as well as by measurement of their specific rotations. A limonoid, methyl nomilinate (1), inhibited AChE activity by more than 50% at a concentration of 30 μg/ml. The findings in this study provide the first experimental evidence that a limonoid compound 1 from C. unshiu fruit acts as a natural AChE inhibitor.

References

G. McKhann, D. Drachman, M. Folstein, R. Katzman, D. Price, E. M. Stadlan, Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease, Neurology 34(7), 939944 (1984).

DOI: 10.1212/WNL.34.7.939.

D. J. Selkoe, P. J. Lansbury Jr., Basic Neurochemistry: Molecular, Cellular and Medical Aspects. sixth ed., Lippincott-Raven, Philadelphia, 1999.

A. Enz, R. Amstutz, H. Boddeke, G. Gmelin, J. Malanowski, Brain selective inhibition of acetylcholinesterase: A novel approach to therapy for Alzheimer's disease, Prog. Brain Res. 98, 431438 (1993).

DOI: 10.1016/S0079-6123(08)62429-2.

R. S. Shah, H. G. Lee, Z. Xiongwei, G. Perry, M. A. Smith, R. J. Castellani, Current approaches in the treat-ment of Alzheimer’s disease, Biomed. Pharmacother. 62, 199207 (2008).

DOI: 10.1016/j.biopha.2008.02.005.

K. Ingkaninan, P. Temkitthawon, K. Cheunchom, T. Yuyaem, W. Thongnoi, Screening for acetylcholinesterase inhibitory activity in plants used in Thai traditional rejuvenating and neurotonic remedies, J. Ethnopharmacol. 89, 261264 (2003).

DOI: 10.1016/j.jep.2003.08.008.

E. Scarpini, P. Scheltens, H. Feldman, Treatment of Alzheimer’s disease: current status and new perspectives, Lancet Neurol. 2(9), 539 547 (2003).

DOI: 10.1016/S1474-4422(03)00502-7.

H. J. Eom, D. Lee, S. Lee, H. J. Noh, J. W. Hyun, P. H. Yi, K. S. Kang, K. H. Kim, Flavonoids and a limonoid from the fruits of Citrus unshiu and their biological ac-tivity, J. Agric. Food Chem. 64(38), 71717178 (2016). DOI: 10.1021/acs.jafc.6b03465.

C. I. Cheigh, E. Y. Chung, M. S. Chung, Enhanced ex-traction of flavonones hesperidin and narirutin from Cit-rus unshiu peel using subcritical water, J. Food Eng. 110, 472477 (2012).

DOI: 10.1016/j.jfoodeng.2011.12.019.

S. Lee, J. Ra, J. Y. Song, C. Gwak, H. J. Kwon, S. V. Yim, S. P. Hong, J. Kim, K. H. Lee, J. J. Cho, Y. S. Park, C. S. Park, H. J. Ahn, Extracts from Citrus unshiu promote immune-mediated inhibition of tumor growth in a murin renal cell carcinoma model, J. Ethnopharmacol. 133, 973979 (2011).

DOI: 10.1016/j.jep.2010.07.018.

M. Y. Choi, C. Chai, J. H. Park, J. Lim, J. Lee, S. W. Kwon, Effect storage period and heat treatment on phe-nolic compound composition in dried Citrus peels (Chenpi) and discrimination of chenpi with different stor-age periods through targeted metabolomics study using HPLC-DAD analysis, J. Pharm. Biomed. Anal. 54(4), 638 645 (2011).

DOI: 10.1016/j.jpba.2010.09.036.

T. Inoue, S. Tsubaki, K. Ogawa, K. Onishi, J. Azuma, Isolation of hesperidin from peels of thinned Citrus unshiu fruits by microwave-assisted extraction, Food Chem. 123, 542547 (2010).

DOI: 10.1016/j.foodchem.2010.04.051.

Y. Q. Ma, X. Q. Ye, Z. X, Fang, J. C. Chen, G. H. Xu, D. H. Liu, Phenolic compounds and antioxidant activity of extracts from ultrasonic treatment of satsuma mandarin (Citrus unshiu Marc.) peels, J. Agric. Food Chem. 56, 56825690 (2008).

DOI: 10.1021/jf072474o.

H. J. Noh, D. Hwang, E. S. Lee, J. W. Hyun, P. H. Yi, G. S. Kim, S. E. Lee, C. Pang, Y. J. Park, K. H. Chung, G. D. Kim, K. H. Kim, Anti-inflammatory activity of a new cyclic peptide, citrusin XI, isolated from the fruits of Citrus unshiu, J. Ethnopharmacol. 163, 106112 (2015).

DOI: 10.1016/j.jep.2015.01.024.

J. P. Dzoyem, A. T. Tsamo, R. Melong, P. Mkounga, A. E. Nkengfack, L. J. McGaw, J. N. Eloff, Cytotoxicity, nitric oxide and acetylcholinesterase inhibitory activity of three limonoids isolated from Trichilia welwitschii (Meliaceae), Biol. Res. 48, 57 (2015).

DOI: 10.1186/s40659-015-0049-0.

R. D. Bennett, S. Hasegawa, Z. Herman, Glucosides of acidic limonoids in citrus, Phytochemistry 28(10), 27772781 (1989).

DOI: 10.1016/S0031-9422(00)98087-7.

K. Machida, K. Osawa, On the flavonoid constituents from the peels of Citrus hassaku Hort. ex Tanaka, Chem. Pharm. Bull. 37(4), 10921094 (1989).

DOI: 10.1248/cpb.37.1092.

K. Kazuma, N. Noda, M. Suzuki, Malonylated flavonol glycosides from the petals of Clitoria ternatea, Phytochemistry 62(2), 229237 (2003).

DOI: 10.1016/S0031-9422(02)00486-7.

B. Bennini, A. J. Chulia, M. Kaouadji, F. Thomasson, Flavonoid glycosides from Erica cinera, Phytochemistry 31(7), 24832486 (1992).

DOI: 10.1016/0031-9422(92)83305-I.

R. Liu, L. Kong, A. Li, A. Sun, Preparative isolation and purification of saponin and flavone glycoside compounds from Clinopodium chinense (Benth) O. Kuntze by high speed countercurrent chromatography, J. Liq. Chromatogr. Relat. Technol. 30(4), 521532 (2007).

DOI: 10.1080/10826070601093846.

H. Kumamoto, Y. Matsubara, Y. Iizuka, K. Okamoto, K. Yokoi, Structures and hypotensive effect of flavonoid glycosides in unshiu peel. II, J. Jpn. Oil Chem. Soc. 35(5), 379381 (1986).

DOI: 10.5650/jos1956.35.379.

Y. Matsubara, H. Kumamoto, Y. Iizuka, T. Murakami, K. Okamoto, H. Miyake, K. Yokoi, Structure and hypo-tensive effect of flavonoid glycosides in Citrus unshiu peelings, Agric. Biol. Chem. 49(4), 909914 (1985).

DOI: 10.1271/bbb1961.49.909.

G. Zhan, J. Zhou, R. Liu, T. Liu, G. Guo, J. Wang, M. Xiang, Y. Xue, Z. Luo, Y. Zhang, G. Yao, Galanthamine, Plicamine, and Secoplicamine Alkaloids from Zephyranthes candida and Their Anti-acetylcholinesterase and Anti-inflammatory Activities, J. Nat. Prod. 79(4), 760766 (2016).

DOI: 10.1021/acs.jnatprod.5b00681.

M. Samochocki, A. Höffle, A. Fehrenbacher, R. Jostock, J. Ludwig, C. Christner, M. Radina, M. Zerlin, C. Ullmer, E. F. R. Pereira, H. Lübbert, E. X. Albuquerque, A. Maelicke, Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors, J. Pharmacol. Exp. Ther. 305(3), 10241036 (2003).

DOI: 10.1124/jpet.102.045773.

N. Li, Y. Liu, W. Li, L. Zhou, Q. Li, X. Wang, P. He, A UPLC/MS-based metabolomics investigation of the pro-tective effect of ginsenosides Rg1 and Rg2 in mice with Alzheimer's disease, J. Ginseng Res. 40(1), 917 (2016). DOI: 10.1016/j.jgr.2015.04.006.

T. Xu, X. Shen, H. Yu, L. Sun, W. Lin, C. Zhang, Water-soluble ginseng oligosaccharides protect against sco-polamine-induced cognitive impairment by functioning as an antineuroinflammatory agent, J. Ginseng Res. 40(3), 211219 (2016).

DOI: 10.1016/j.jgr.2015.07.007.

J. R. Bae, B. D. Lee, Function and dysfunction of leucine-rich repeat kinase 2 (LRRK2): Parkinson's disease and beyond. BMB Rep. 48(5), 243248 (2015).

DOI: 10.5483/BMBRep.2015.48.5.032.

J. Y. Sim, M. A. Kim, M. J. Kim, W. J. Chun, Y. S. Kwon, Acetylcholinesterase inhibitors from the stem of Zea mays, Nat. Prod. Sci. 20(1), 1316 (2014).

A. Roy, S. Saraf, Limonoids: Overviews of significant bioactive triterpenes distributed in plants kingdom, Biol. Pharm. Bull. 29(2), 191201 (2006).

DOI: 10.1248/bpb.29.191.

S. B. Liu, W. L. Mei, H. Q. Chen, Z. K. Guo, H. F. Dai, Z. N. Wang, Mexicanolide-type limonoids from the roots of Trichilia sinensis, Molecules 21(9), 1152 (2016).

DOI: 10.3390/molecules21091152.

N. Guthrie, K. Morley, S. Hasegawa, G. D. Manners, T. Vandenberg, Inhibition of human breast cancer cells by citrus limonoids. ACS Symp. Ser. 758, 164–174 (2000). DOI: 10.1021/bk-2000-0758.ch012.

J. Kim, G. K. Jayaprakasha, A. Vikram, B. S. Patil, Me-thyl nomilinate from citrus can modulate cell cycle regu-lators to induce cytotoxicity in human colon cancer (SW480) cells in vitro. Toxicol. In Vitro 26(7), 1216–1223 (2012).

DOI: 10.1016/j.tiv.2012.06.005.

Downloads

Published

2017-06-17

How to Cite

Baek, J., Lee, H. L., Kang, K. S., & Kim, K. H. (2017). Chemical constituents from the fruits of Citrus unshiu and their inhibitory effects on acetylcholinesterase. Macedonian Journal of Chemistry and Chemical Engineering, 36(1), 15–22. https://doi.org/10.20450/mjcce.2017.1139

Issue

Vol. 36 No. 1 (2017)

Section

Natural Products