Skip to main content
SpringerLink
Log in

BACE1 and cholinesterase inhibitory activities of Nelumbo nucifera embryos

  • Research Article
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

The aim of the present study was to evaluate the comparative anti-Alzheimer’s disease (AD) activities of different parts of Nelumbo nucifera (leaves, de-embryo seeds, embryos, rhizomes, and stamens) in order to determine the selectivity and efficient use of its individual components. Anti-AD activities of different parts of N. nucifera were evaluated via inhibitory activities on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) along with scavenging activity on peroxynitrite (ONOO−). Among the evaluated parts of N. nucifera, the embryo extract exhibited significant inhibitory potential against BACE1 and BChE as well as scavenging activity against ONOO−. Thus, the embryo extract was selected for detailed investigation on anti-AD activity using BACE1- and ChEs-inhibitory assays. Among the different solvent-soluble fractions, the dichloromethane (CH2Cl2), ethyl acetate (EtOAc), and n-butanol (n-BuOH) fractions showed promising ChEs and BACE1 inhibitory activities. Repeated column chromatography of the CH2Cl2, EtOAc and n-BuOH fractions yielded compounds 1–5, which were neferine (1), liensinine (2), vitexin (3), quercetin 3-O-glucoside (4) and northalifoline (5). Compound 2 exhibited potent inhibitory activities on BACE1, AChE, and BChE with respective IC50 values of 6.37 ± 0.13, 0.34 ± 0.02, and 9.96 ± 0.47 µM. Likewise, compound 1 showed potent inhibitory activities on BACE1, AChE, and BChE with IC50 values of 28.51 ± 4.04, 14.19 ± 1.46, and 37.18 ± 0.59 µM, respectively; the IC50 values of 3 were 19.25 ± 3.03, 16.62 ± 1.43, and 11.53 ± 2.21 µM, respectively. In conclusion, we identified potent ChEs- and BACE1-inhibitory activities of N. nucifera as well as its isolated constituents, which may be further explored to develop therapeutic and preventive agents for AD and oxidative stress related diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abbasi, E., M. Nassiri-Asl, M. Shafeei, and M. Sheikhi. 2012. Neuroprotective effects of vitexin, a flavonoid, on pentylenetetrazole-induced seizure in rats. Chemical Biology and Drug Design 80: 274–278.

    Article  CAS  PubMed  Google Scholar 

  • Aisen, P.S. 2002. The potential of anti-inflammatory drugs for the treatment of Alzheimer’s disease. The Lancet Neurology 1: 279–284.

    Article  CAS  PubMed  Google Scholar 

  • Butterfield, D.A., J. Drake, C. Pocernich, and A. Castegna. 2001. Evidence of oxidative damage in Alzheimer’s disease brain: Central role for amyloid β-peptide. Trends in Molecular Medicine 7: 548–554.

    Article  CAS  PubMed  Google Scholar 

  • Chen, Y., G. Fan, H. Wu, Y. Wu, and A. Mitchell. 2007. Separation, identification and rapid determination of liensine, isoliensinine and neferine from embryo of the seed of Nelumbo nucifera Gaertn. by liquid chromatography coupled to diode array detector and tandem mass spectrometry. Journal of Pharmaceutical and Biomedical Analysis 43: 99–104.

    Article  PubMed  Google Scholar 

  • Chen, S., L. Fang, H. Xi, L. Guan, J. Fang, Y. Liu, B. Wu, and S. Li. 2012. Simultaneous qualitative assessment and quantitative analysis of flavonoids in various tissues of lotus (Nelumbo nucifera) using high performance liquid chromatography coupled with triple quad mass spectrometry. Analytica Chimica Acta 724: 127–135.

    Article  CAS  PubMed  Google Scholar 

  • Choi, J.S., M.N. Islam, M.Y. Ali, E.J. Kim, Y.M. Kim, and H.A. Jung. 2014. Effects of C-glycosylation on anti-diabetic, anti-Alzheimer’s disease and anti-inflammatory potential of apigenin. Food and Chemical Toxicology 64: 27–33.

    Article  CAS  PubMed  Google Scholar 

  • Choo, C.Y., N.Y. Sulong, F. Man, and T.W. Wong. 2012. Vitexin and isovitexin from the leaves of Ficus deltoidea with in vivo α-glucosidase inhibition. Journal of Ethnopharmacology 142: 776–781.

    Article  CAS  PubMed  Google Scholar 

  • Dong, Z.X., X. Zhao, D.F. Gu, Y.Q. Shi, J. Zhang, X.X. Hu, M.Q. Hu, B.F. Yang, and B.X. Li. 2012. Comparative effects of liensinine and neferine on the human ether-a-go-go-related gene potassium channel and pharmacological activity analysis. Cellular Physiology and Biochemistry 29: 431–442.

    Article  CAS  PubMed  Google Scholar 

  • Ellman, G.L., K.D. Courtney, V. Andres Jr., and R.M. Featherstone. 1961. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemistry and Pharmacology 7: 88–95.

    Article  CAS  Google Scholar 

  • Fu, Y., Y. Zu, W. Liu, L. Zhang, M. Tong, T. Efferth, Y. Kong, C. Hou, and L. Chen. 2008. Determination of vitexin and isovitexin in pigeonpea using ultrasonic extraction followed by LC–MS. Journal of Separation Science 31: 268–275.

    Article  CAS  PubMed  Google Scholar 

  • Hashim, N.H.N., F. Abas, K. Shaari, H. Nordin, and N.H. Lajis. 2012. LC–DAD–ESIMS/MS characterization of antioxidant and anticholinesterase constituents present in the active fraction from Persicaria hydropiper. LWT-Food Science and Technology 46: 468–476.

    Article  Google Scholar 

  • Jung, H.A., Y.J. Jung, N.Y. Yoon, D.M. Jeong, H.J. Bae, D.W. Kim, D.H. Na, and J.S. Choi. 2008. Inhibitory effects of Nelumbo nucifera leaves on rat lens aldose reductase, advanced glycation endproducts formation, and oxidative stress. Food and Chemical Toxicology 46: 3818–3826.

    Article  CAS  PubMed  Google Scholar 

  • Jung, H.A., S.E. Jin, R.J. Choi, D.H. Kim, Y.S. Kim, J.H. Ryu, D.W. Kim, Y.K. Son, J.J. Park, and J.S. Choi. 2010a. Anti-amnesic activity of neferine with antioxidant and anti-inflammatory capacities, as well as inhibition of ChEs and BACE1. Life Sciences 87: 420–430.

    Article  CAS  PubMed  Google Scholar 

  • Jung, H.A., Y.J. Jung, S.K. Hyun, B.S. Min, D.W. Kim, J.H. Jung, and J.S. Choi. 2010b. Selective cholinesterase inhibitory activities of a new monoterpene diglycoside and other constituents from Nelumbo nucifera stamens. Biological and Pharmaceutical Bulletin 33: 267–272.

    Article  CAS  PubMed  Google Scholar 

  • Jung, H.A., S.E. Jin, B.R. Ahn, C.M. Lee, and J.S. Choi. 2013. Anti-inflammatory activity of edible brown alga Eisenia bicyclis and its constituents fucosterol and phlorotannins in LPS-stimulated RAW264.7 macrophages. Food and Chemical Toxicology 59: 199–206.

    Article  CAS  PubMed  Google Scholar 

  • Kooy, N.W., J.A. Royall, H. Ischiropoulos, and J.S. Beckman. 1994. Peroxynitrite-mediated oxidation of dihydrorhodamine 123. Free Radical Biology and Medicine 16: 149–156.

    Article  CAS  PubMed  Google Scholar 

  • Lee, Y.J., S.B. Han, S.Y. Nam, K.W. Oh, and J.T. Hong. 2010a. Inflammation and Alzheimer’s disease. Archives of Pharmacal Research 33: 1539–1556.

    Article  CAS  PubMed  Google Scholar 

  • Lee, J., N.H. Kim, J.W. Nam, Y.M. Lee, D.S. Jang, Y.S. Kim, S.H. Nam, E.K. Seo, M.S. Yang, and J.S. Kim. 2010b. Scopoletin from the flower buds of Magnolia fargesii inhibits protein glycation, aldose reductase, and cataractogenesis ex vivo. Archives of Pharmacal Research 33: 1317–1323.

    Article  CAS  PubMed  Google Scholar 

  • Lin, Z., H. Wang, Q. Fu, H. An, Y. Liang, B. Zhang, Y. Hashi, and S. Chen. 2013. Simultaneous separation, identification and activity evaluation of three butyrylcholinesterase inhibitors from Plumula nelumbinis using on-line HPLC-UV coupled with ESI–IT–TOF-MS and BChE biochemical detection. Talanta 110: 180–189.

    Article  CAS  PubMed  Google Scholar 

  • Liu, S., B. Wang, X.Z. Li, L.F. Qi, and Y.Z. Liang. 2009. Preparative separation and purification of liensinine, isoliensinine and neferine from seed embryo of Nelumbo nucifera GAERTN using high-speed counter-current chromatography. Journal of Separation Science 32: 2476–2481.

    Article  CAS  PubMed  Google Scholar 

  • Ma, C., J. Wang, H. Chu, X. Zhang, Z. Wang, H. Wang, and G. Li. 2014. Purification and characterization of aporphine alkaloids from leaves of Nelumbo nucifera Gaertn and their effects on glucose consumption in 3T3-L1 adipocytes. International Journal of Molecular Sciences 15: 3481–3494.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Maisuthisakul, P., M. Suttajit, and R. Pongsawatmanit. 2007. Assessment of phenolic content and radical scavenging capacity of some Thai indigenous plants. Food Chemistry 100: 1409–1418.

    Article  CAS  Google Scholar 

  • Mehta, N.R., E.P. Patel, P.V. Patani, and B. Shah. 2013. Nelumbo nucifera (Lotus): A review on ethnobotany, phytochemistry and pharmacology. Indian Journal of Pharmaceutical and Biological Research 1: 152–167.

    CAS  Google Scholar 

  • Nishimura, K., S. Horii, T. Tanahashi, Y. Sugimoto, and J. Yamada. 2013. Synthesis and pharmacological activity of alkaloids from embryo of lotus, Nelumbo nucifera. Chemical and Pharmaceutical Bulletin 61: 59–68.

    Article  CAS  PubMed  Google Scholar 

  • Nowak, S., and M. Wolbiś. 2002. Flavonoids from some species of genus Scopolia Jacq. Acta Poloniae Pharmaceutica 59: 275–280.

    CAS  PubMed  Google Scholar 

  • Oh, J.H., B.J. Choi, M.S. Chang, and S.K. Park. 2009. Nelumbo nucifera semen extract improves memory in rats with scopolamine-induced amnesia through the induction of choline acetyltransferase expression. Neuroscience Letters 461: 41–44.

    Article  CAS  PubMed  Google Scholar 

  • Ohno, M., E.A. Sametsky, L.H. Younkin, H. Oakley, S.G. Younkin, M. Citron, R. Vassar, and J.F. Disterhoft. 2004. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’s disease. Neuron 41: 27–33.

    Article  CAS  PubMed  Google Scholar 

  • Orhan, I., and M. Aslan. 2009. Appraisal of scopolamine-induced antiamnesic effect in mice and in vitro anti-acetylcholinesterase and antioxidant activities of some traditionally used lamiaceae plants. Journal of Ethnopharmacology 122: 327–332.

    Article  PubMed  Google Scholar 

  • Pákáski, M., and J. Kálmán. 2008. Interactions between the amyloid and cholinergic mechanisms in Alzheimer’s disease. Neurochemistry International 53: 103–111.

    Article  PubMed  Google Scholar 

  • Rao, A.A., G.R. Sridhar, and U.N. Das. 2007. Elevated butyrylcholinesterase and acetylcholinesterase may predict the development of type 2 diabetes mellitus and Alzheimer’s disease. Medical Hypotheses 69: 1272–1276.

    Article  CAS  PubMed  Google Scholar 

  • Sastre, M., J. Walter, and S.M. Gentleman. 2008. Interactions between APP secretases and inflammatory mediators. Journal of Neuroinflammation 5: 25.

    Article  PubMed Central  PubMed  Google Scholar 

  • Sridhar, K.R., and R. Bhat. 2007. Lotus—A potential nutraceutical source. Journal of Agricultural Technology 3: 143–155.

    Google Scholar 

  • Sugimoto, Y., S. Furutani, A. Itoh, T. Tanahashi, H. Nakajima, H. Oshiro, S. Sun, and J. Yamada. 2008. Effects of extracts and neferine from the embryo of Nelumbo nucifera seeds on the central nervous system. Phytomedicine 15: 1117–1124.

    Article  CAS  PubMed  Google Scholar 

  • Swerdlow, R.H. 2007. Pathogenesis of Alzheimer’s disease. Clinical Interventions in Aging 2: 347–359.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Vassar, R. 2002. β-Secretase (BACE1) as a drug target for Alzheimer’s disease. Advanced Drug Delivery Reviews 54: 1589–1602.

    Article  CAS  PubMed  Google Scholar 

  • Vassar, R. 2005. β-Secretase, APP and Aβ in Alzheimer’s disease. Subcellular Biochemistry 38: 79–103.

    CAS  PubMed  Google Scholar 

  • Wang, J.L., Y. Nong, G.L. Xia, W.X. Yao, and M.X. Jiang. 1993. Effects of linesinine on slow action potentials in myocardium and slow inward current in canine cardiac Purkinje fibers. Yao Xue Xue Bao 28: 812–816.

    CAS  PubMed  Google Scholar 

  • Woodruff-Pak, D.S., R.W. Vogel III, and G.L. Wenk. 2001. Galantamine: Effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning. Proceedings of the National Academy of Sciences of the United States of America 98: 2089–2094.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wu, S., C. Sun, X. Cao, H. Zhou, Z. Hong, and Y. Pan. 2004. Preparative counter-current chromatography isolation of liensinine and its analogues from embryo of the seed of Nelumbo nucifera GAERTN. using upright coil planet centrifuge with four multilayer coils connected in series. Journal of Chromatography A 1041: 153–162.

    Article  CAS  PubMed  Google Scholar 

  • Xie, Y., Y. Zhang, L.T. Zhang, S.X. Zeng, Z.B. Guo, and B.D. Zheng. 2013. Protective effects of alkaloid compounds from Nelumbinis Plumula on tert-butyl hydroperoxide-induced oxidative stress. Molecules 18: 10285–10300.

    Article  CAS  PubMed  Google Scholar 

  • Yan, R., M.J. Bienkowski, M.E. Shuck, H. Miao, M.C. Tory, A.M. Pauley, J.R. Brashier, N.C. Stratman, W.R. Mathews, A.E. Buhl, D.B. Carter, A.G. Tomasselli, L.A. Parodi, R.L. Heinrikson, and M.E. Gurney. 1999. Membrane-anchored aspartyl protease with Alzheimer’s disease β-secretase activity. Nature 402: 533–537.

    Article  CAS  PubMed  Google Scholar 

  • Yang, J., and K. Zhou. 2004. NMR spectroscopic analysis of neferine and isoliensinine. Magnetic Resonance in Chemistry 42: 994–997.

    Article  CAS  PubMed  Google Scholar 

  • Yang, W.M., K.J. Shim, M.J. Choi, S.Y. Park, B.J. Choi, M.S. Chang, and S.K. Park. 2008. Novel effects of Nelumbo nucifera rhizome extract on memory and neurogenesis in the dentate gyrus of the rat hippocampus. Neuroscience Letters 443: 104–107.

    Article  CAS  PubMed  Google Scholar 

  • Yang, Z.D., X. Zhang, J. Du, Z.J. Ma, F. Guo, S. Li, and X.J. Yao. 2012. An aporphine alkaloid from Nelumbo nucifera as an acetylcholinesterase inhibitor and the primary investigation for structure–activity correlations. Natural Product Research 26: 387–392.

    Article  CAS  PubMed  Google Scholar 

  • Yao, Y., X. Cheng, L. Wang, S. Wang, and G. Ren. 2011. A determination of potential α-glucosidase inhibitors from Azuki Beans (Vigna angularis). International Journal of Molecular Sciences 12: 6445–6451.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang, Y., B. Bao, B. Lu, Y. Ren, X. Tie, and Y. Zhang. 2005. Determination of flavone C-glucosides in antioxidant of bamboo leaves (AOB) fortified foods by reversed-phase high-performance liquid chromatography with ultraviolet diode array detection. Journal of Chromatography A 1065: 177–185.

    Article  CAS  PubMed  Google Scholar 

  • Zhu, X., H.G. Lee, G. Perry, and M.A. Smith. 2007. Alzheimer disease, the two-hit hypothesis: An update. Biochimica et Biophysica Acta 1772: 494–502.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a Research Grant of Pukyong National University (2015).

Author information

Authors and Affiliations

  1. Department of Food Science and Human Nutrition, Chonbuk National University, Jeonju, 561-756, Republic of Korea

    Hyun Ah Jung

  2. Department of Food Science and Nutrition, Pukyong National University, Busan, 608-737, Republic of Korea

    Subash Karki, Ji Hye Kim & Jae Sue Choi

Authors
  1. Hyun Ah Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Subash Karki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ji Hye Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jae Sue Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jae Sue Choi.

Additional information

Hyun Ah Jung and Subash Karki have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jung, H.A., Karki, S., Kim, J.H. et al. BACE1 and cholinesterase inhibitory activities of Nelumbo nucifera embryos. Arch. Pharm. Res. 38, 1178–1187 (2015). https://doi.org/10.1007/s12272-014-0492-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-014-0492-4

Keywords

Search

Navigation