Journal of Natural Medicines

, Volume 73, Issue 1, pp 318–330 | Cite as

Preventive agents for neurodegenerative diseases from resin of Dracaena cochinchinensis attenuate LPS-induced microglia over-activation

  • Yingzhan Tang
  • Guangyue Su
  • Ning Li
  • Wenjie Li
  • Gang Chen
  • Ru Chen
  • Di Zhou
  • Yue Hou


Our previous research revealed resin of Dracaena cochinchinensis as a candidate for therapy of neurodegenerative diseases. In the present study, the material basis of Chinese Dragon’s blood and the primary mechanism of the effective components are discussed. Multiple chromatography and spectra analysis were utilized to identify effective constituents. The production of NO was determined using nitrite assay in BV-2 microglial cells stimulated with lipopolysaccharide (LPS). Cell viability was tested using MTT assay. The mRNA level of inducible nitric oxide synthase (iNOS) was investigated by quantitative real-time PCR (qRT-PCR), and the production of IL-6 and TNF-α in the cell supernatants was tested by ELISA. The bioassay-directed separation of the effective extract of D. cochinchinensis afforded two new compounds, a stilbene-flavane dimer (2) and a quinoid flavonoid (11), in addition to 25 known compounds. The evaluation of their anti-neuroinflammatory activities showed that 5, 9, 12, 13, and 14 could exhibit significant anti-neuroinflammatory effects without cytotoxities at the tested concentration, compared to a positive control, minocycline (21.87 ± 2.36 µM). A primary mechanistic study revealed that the effective components could inhibit over-activation of microglial through decreasing the expressions of iNOS, proinflammatory cytokines IL-6 and TNF-α in LPS- induced BV2 microglial cells. Chalcone 9, homoisoflavane 5 and flavone 1214 are considered to be responsible for the anti-neuroinflammatory effects of Chinese Dragon’s blood. These could inhibit neuroinflammation by reducing the expressions of iNOS, IL-6 and TNF-α in over-activated microglial. Furthermore, the SAR is briefly discussed.


Resin of Dracaena cochinchinensis Neurodegenerative diseases Neuroinflammation Microglial cells Bioactive chemical compositions Primary mechanism 



The work was supported partially by National Natural Science Foundation of China (Grant no. 81473108, 81673323, U1403102, 81473330, U1603125), Natural Science Foundation of Liaoning Province, Liaoning, China (Grant no. 2015020732), Shenyang science and technology research project, Liaoning, China (Grant no. F15-199-1-26), Research Project for Key laboratory of Liaoning Educational Committee, Liaoning, China (Grant no. LZ2015067), The project of the State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (CMEMR2017-B03, CMEMR2018-B01), Program for Liaoning Excellent Talents in University (LR2015022) and the Fundamental Research Funds for the Central Universities (N162004003).

Compliance with ethical standards

Conflict of interest

The Author(s) declare(s) that they have no conflicts of interest.

Supplementary material

11418_2018_1266_MOESM1_ESM.docx (651 kb)
Supplementary material 1 (DOCX 650 kb)


  1. 1.
    Prince M, Prina M, Guerchet M (2013) Journey of caring: an analysis of long-term care for dementia. World Alzheimer Report 19 Sep 2013Google Scholar
  2. 2.
    Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, Kieburtz K, Marshall FJ, Ravina BM, Schifitto G, Siderowf A, Tanner CM (2007) Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 68:384–386CrossRefGoogle Scholar
  3. 3.
    Abbott A (2011) Dementia: a problem for our age. Nature 475:2–4CrossRefGoogle Scholar
  4. 4.
    Barrientos RM, Kitt MM, Watkins LR, Maier SF (2015) Neuroinflammation in the normal aging hippocampus. Neuroscience 309:84–99CrossRefGoogle Scholar
  5. 5.
    Kumar H, Lim HW, More SV, Kim BW, Koppula S, Kim IS, Choi DK (2012) The role of free radicals in the aging brain and Parkinson’s disease: convergence and parallelism. Int J Mol Sci 13:10478–10504CrossRefGoogle Scholar
  6. 6.
    Nakajima K, Kohsaka S (1998) Functional roles of microglia in the central nervous system. Hum Cell 11:141–155Google Scholar
  7. 7.
    Suzumura A, Takeuchi H, Zhang G, Kuno R, Mizuno T (2006) Roles of gliaderived cytokines on neuronal degeneration and regeneration. Ann N Y Acad Sci 1088:219–229CrossRefGoogle Scholar
  8. 8.
    Perry VH, Nicoll JA, Holmes C (2001) Microglia in neurodegenerative disease. Nat Rev Neurol 6:193–201CrossRefGoogle Scholar
  9. 9.
    Li N, Ma ZJ, Li MJ, Xing YC, Hou Y (2014) Natural potential therapeutic agents of neurodegenerative diseases from the traditional herbal medicine Chinese Dragon’s blood. J Ethnopharmacol 152:508–521CrossRefGoogle Scholar
  10. 10.
    Yi T, Chen HB, Zhao ZZ, Yu ZL, Jiang ZH (2011) Comparison of the chemical profiles and anti-platelet aggregation effects of two “Dragon’s Blood” drugs used in traditional Chinese medicine. J Ethnopharmacol 133:796–802CrossRefGoogle Scholar
  11. 11.
    Xin N, Li YJ, Li Y, Dai RJ, Meng WW, Chen Y, Schlappi M, Deng YL (2011) Dragon’s blood extract has antithrombotic properties, affecting platelet aggregation functions and anticoagulation activities. J Ethnopharmacol 135:510–514CrossRefGoogle Scholar
  12. 12.
    Miller MJS, MacNaughton WK, Zhang XJ, Thompson JH, Charbonnet RM, Bobrowski P, Lao J, Trentacosti AM, Sandoval M (2000) Treatment of gastric ulcers and diarrhea with the Amazonian herbal medicine sangre de grado. Am J Physiol Gastrointest Liver Physiol 279:192–200CrossRefGoogle Scholar
  13. 13.
    Risco E, Ghia F, Vila R, Iglesias J, Alvarez E, Canigueral S (2003) Immunomodulatory activity and chemical characterisation of sangre de drago (Dragon’s blood) from Croton lechleri. Planta Med 69:785–794CrossRefGoogle Scholar
  14. 14.
    Edward HGM, de Oliveira LFC, Quye A (2001) Raman spectroscopy of coloured resins used in antiquity: dragon’s blood and related substances. Spectrochim Acta Part A Mol Biomol Spectrosc 57:2831–2842CrossRefGoogle Scholar
  15. 15.
    Ubillas R, Jolad SD, Bruening RC (1999) SP-303, an antiviral oligomeric proanthocyanidin from the latex of Croton lechleri (Sangre de Drago). Phytomedicine 1:77–106CrossRefGoogle Scholar
  16. 16.
    Gupta D, Bleakley B, Gupta RK (2008) Dragon’s blood: botany, chemistry and therapeutic uses. J Ethnopharmacol 115:361–380CrossRefGoogle Scholar
  17. 17.
    Rossia D, Guerrinia A, Paganettoa G, Bernacchiaa G, Confortib F, Stattib G, Maiettia S, Poppia I, Tacchinia M, Sacchettia G (2013) Croton lechleri Müll Arg. (Euphorbiaceae) stem bark essential oil as possible mutagen-protective food ingredient against heterocyclic amines from cooked food. Food Chem 139:439–447CrossRefGoogle Scholar
  18. 18.
    Alonso-Castro AJ, Ortiz-Sanchez E, Domínguez F, López-Toledo G, Chávezd M, Ortiz-Tellob ADJ, García-Carrancáb A (2012) Antitumor effect of Croton lechleri Mull. Arg. (Euphorbiaceae). J Ethnopharmacol 140:438–442CrossRefGoogle Scholar
  19. 19.
    Montopoli M, Bertin R, Chen Z, Bolcato J, Caparrotta L, Froldi G (2012) Croton lechleri sap and isolated alkaloid taspine exhibit inhibition against human melanoma SK23 and colon cancer HT29 cell lines. J Ethnopharmacol 144:747–753CrossRefGoogle Scholar
  20. 20.
    Zheng QA, Li H, Zhang Y, Yang C (2004) Flavonoids from the resin of Dracaena cochinchinensis. Helv Chim Acta 87:1167–1171CrossRefGoogle Scholar
  21. 21.
    Chen P, Yang JS (2007) Flavonol galactoside caffeiate ester and homoisoflavones from Caesalpinia millettii HOOK. et ARN. Chem Pharm Bull 55:655–657CrossRefGoogle Scholar
  22. 22.
    Ichikawa K, Kitaoka M, Taki M, Takaishi S, Iijima Y, Boriboon M, Akiyama T (1993) Retrodihydrochalcones and homoisoflavones isolated from Thai medicinal plant Dracaena loureiri and their estrogen agonist activity. Planta Med 63:540–543CrossRefGoogle Scholar
  23. 23.
    Yang Y, Huang SX, Zhao YM, Zhao QS, Sun HD (2005) Flavonoids from Lycoris aurea. Nat Prod Res Dev 17:539–541Google Scholar
  24. 24.
    Ji S, Li Z, Song W, Wang Y, Liang W (2016) Bioactive constituents of Glycyrrhiza uralensis (Licorice): discovery of the effective components of a traditional herbal medicine. J Nat Prod 79:281–292CrossRefGoogle Scholar
  25. 25.
    Hao Q, Saito Y, Matsuo Y, Li HZ, Tanaka T (2015) Chalcane-stilbene conjugates and oligomeric flavonoids from Chinese Dragon’s blood produced from Dracaena cochinchinensis. Phytochemistry 119:76–82CrossRefGoogle Scholar
  26. 26.
    Jiang WJ, Daikonya A, Ohkawara M, Nemoto T, Noritake R (2017) Structure-activity relationship of the inhibitory effects of flavonoids on nitric oxide production in RAW264.7 cells. Bioorg Med Chem 25:779–788CrossRefGoogle Scholar
  27. 27.
    Masek A, Chrzescijanska E, Latos M, Zaborski M (2016) Influence of hydroxyl substitution on flavanone antioxidants properties. Food Chem 215:501–507CrossRefGoogle Scholar
  28. 28.
    Hauteville M, Rakotovao M, Duclos MC, Voirin B (1998) ChemInform abstract: synthesis of 5-hydroxy-6- and 8-methylflavones and their ultraviolet spectral differentiation. Phytochemistry 48:547–553CrossRefGoogle Scholar
  29. 29.
    Xiao TS, Wang Q, Jiang LL, Jiang JQ, Li YB (2013) Chemical constituents of Artemisia anomala. Chin Tradit Herb Drugs 44:515–518Google Scholar
  30. 30.
    Zheng SS, Wu T, Wang ZT (2011) Chemical constituents from the roots of Hedysarum polybotrys. Chin J Chin Mater Med 36:2350–2352Google Scholar
  31. 31.
    Huang YL, Chen CC (2011) Two tannins from Phyllanthus tenellus. J Nat Prod 61:523–524CrossRefGoogle Scholar
  32. 32.
    Chen PD, Liang JY (2006) Chemical constituents in Populus davidiana. Chin Tradit Herb Drugs 37:816–818Google Scholar
  33. 33.
    Yang WQ, Wang HC, Wang WJ, Wang Y, Zhang XQ, Ye W (2011) Chemical constituents from the fruits of Areca catechu. J Chin Med Mater 35:400–403Google Scholar
  34. 34.
    Frau J, Muñoz F, Glossman-Mitnik D (2016) A molecular electron density theory study of the chemical reactivity of cis- and trans-Resveratrol. Molecules 21:1650–1663CrossRefGoogle Scholar
  35. 35.
    Wang YN, Lin S, Chen MH, Jiang BY, Guo QL, Zhu CG, Wang SJ, Yang YC, Shi JG (2012) Chemical constituents from aqueous extract of Gastrodia elata. Chin J Chin Mater Med 37:1775–1781Google Scholar
  36. 36.
    Song QY, Fu YB, Liu J, Zheng D, Han L, Huang XS (2011) Chemical constituents from Angelica sinensis. Chin Tradit Herb Drugs 42:1900–1904Google Scholar
  37. 37.
    Viñas-Bravo O, Merino-Montiel P, Romero-López A, Montiel-Smith S, Meza-Reyes S (2015) Epimerization of C-22 in (25R)- and (25S)-sapogenins. Steroids 93:60–67CrossRefGoogle Scholar
  38. 38.
    Yang L, Feng F, Gao Y (2009) Chemical constituents from herb of Solanum lyratum. Chin J Chin Mater Med 34:1805–1808Google Scholar
  39. 39.
    Penkov S, Kaptan D, Erkut C, Sarov M, Mende F (2015) Integration of carbohydrate metabolism and redox state controls dauer larva formation in Caenorhabditis elegans. Nat Commun 20:8060CrossRefGoogle Scholar
  40. 40.
    Chau VM, Tien DN, Nguyen HD, Phan VK (2009) Unusual 22S-spirostane steroids from Dracaena cambodiana. et ARN. Nat Prod Commun 4:1197–1200Google Scholar
  41. 41.
    Hou Y, Li GX, Wang J, Pan YN, Jiao K, Du J, Chen R, Wang B, Li N (2017) Okanin, effective constituent of the flower tea Coreopsis tinctoria, attenuates LPS-induced microglial activation through inhibition of the TLR4/NF-κB signaling pathways. Sci Rep 7:45105CrossRefGoogle Scholar
  42. 42.
    Zhou D, Wei HY, Jiang Z, Li XZ, Jiao K, Jia XG, Hou Y, Li N (2017) Natural potential neuroinflammatory inhibitors from Alhagi sparsifolia Shap. Bioorg Med Chem Lett 27:973–978CrossRefGoogle Scholar
  43. 43.
    Zhou D, Zhang YH, Jiang Z, Hou Y, Jiao K, Yan CY, Li N (2017) Biotransformation of isofraxetin-6-O-β-d-glucopyranoside by Angelica sinensis (Oliv.) Diels callus. Bioorg Med Chem Lett 27:248–253CrossRefGoogle Scholar
  44. 44.
    Xing YC, Li N, Zhou D, Chen G, Jiao K, Wang WL, Si YY, Hou Y (2017) Sesquiterpene coumarins from Ferula sinkiangensis act as neuroinflammation inhibitors. Planta Med 83:135–142Google Scholar
  45. 45.
    Zhou D, Li N, Zhang YH, Yan CY, Jiao K, Sun Y, Ni H, Lin B, Hou Y (2016) Biotransformation of neuro-inflammation inhibitor Kellerin by Angelica sinensis (Oliv.) Diels callus. RSC Adv 6:97302–97312CrossRefGoogle Scholar
  46. 46.
    Li N, Wang Y, Li XZ, Zhang H, Zhou D, Wang WL, Li W, Zhang XR, Li XY, Hou Y, Meng DL (2016) Bioactive phenols as potential neuroinflammation inhibitors from the leaves of Xanthoceras sorbifolia Bunge. Bioorg Med Chem Lett 26:5018–5023CrossRefGoogle Scholar
  47. 47.
    Hou Y, Li N, Xie GB, Wang J, Yuan Q, Jia CC, Liu X, Li GX, Tang YZ, Wang B (2015) Pterostilbene exerts anti- neuro inflammatory effect on lipopolysaccharide-activated microglia via inhibition of MAPK signalling pathways. J Funct Foods 19:676–687CrossRefGoogle Scholar
  48. 48.
    Li N, Meng DL, Pan Y, Cui QL, Li GX, Ni H, Sun Y, Qing DG, Jia XG, Pan YN, Hou Y (2015) Anti-neuroinflammatory and NQO1 inducing activity of natural phytochemicals from Coreopsis tinctoria. J Funct Foods 17:837–846CrossRefGoogle Scholar
  49. 49.
    Li JY, Jiang Z, Li XZ, Hou Y, Liu F, Li N, Liu X, Yang LH, Chen G (2015) Natural therapeutic agents for neurodegenerative diseases from a traditional herbal medicine Pongamia pinnata (L.) Pierre. Bioorg Med Chem Lett 25:53–58CrossRefGoogle Scholar
  50. 50.
    Henn A, Lund S, Hedtjarn M, Schrattenholz A, Porzgen P, Leist M (2009) The suitability of BV2 cells as alternative model system for primary microglia cultures or for animal experiments examining brain inflammation. Altex 26:83–94CrossRefGoogle Scholar
  51. 51.
    Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, Volpe JJ, Vartanian T (2003) Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci USA 100:8514–8519CrossRefGoogle Scholar
  52. 52.
    Gao HM, Hong JS (2008) Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends Immunol 29:357–365CrossRefGoogle Scholar
  53. 53.
    Hou Y, Xie G, Miao F, Ding L, Mou Y, Wang L, Su G, Chen G, Yang J, Wu C (2014) Pterostilbene attenuates lipopolysaccharide-induced learning and memory impairment possibly via inhibiting microglia activation and protecting neuronal injury in mice. Prog Neuropsychopharmacol Biol Psychiatry 3(54):92–102CrossRefGoogle Scholar
  54. 54.
    Hou Y, Xie G, Liu X, Li G, Jia C, Xu J, Wang B (2016) Minocycline protects against lipopolysaccharide-induced cognitive impairment in mice. Psychopharmacology (Berl) 233(5):905–916CrossRefGoogle Scholar
  55. 55.
    Das A, Chai JC, Kim SH, Lee YS, Park KS, Jung KH, Chai YG (2015) Transcriptome sequencing of microglial cells stimulated with TLR3 and TLR4 ligands. BMC Genom 16:517CrossRefGoogle Scholar
  56. 56.
    Lyu SA, Lee SY, Lee SJ, Son SW, Kim MO, Kim GY, Kim YH, Yoon HJ, Kim H, Park DI, Ko WS (2006) Seungma-galgeun-tang attenuates proinflammatory activities through the inhibition of NF-kappaB signal pathway in the BV-2 microglial cells. J Ethnopharmacol 107(1):59–66CrossRefGoogle Scholar
  57. 57.
    Yu DK, Lee B, Kwon M, Yoon N, Shin T, Kim NG, Choi JS, Kim HR (2015) Phlorofucofuroeckol B suppresses inflammatory responses by down-regulating nuclear factor κB activation via Akt, ERK, and JNK in LPS-stimulated microglial cells. Int Immunopharmacol 28(2):1068–1075CrossRefGoogle Scholar
  58. 58.
    Nan L, Liu BW, Ren WZ, Liu JX, Li SN, Fu SP, Zeng YL, Xu SY, Yan X, Gao YJ, Liu DF, Wang W (2016) GLP-2 attenuates LPS-induced inflammation in BV-2 cells by inhibiting ERK1/2, JNK1/2 and NF-κB signaling pathways. Int J Mol Sci 17(2):190–200CrossRefGoogle Scholar
  59. 59.
    Huang B, He D, Chen G, Ran X, Guo W, Kan X, Wang W, Liu D, Fu S, Liu J (2018) alpha-Cyperone inhibits LPS-induced inflammation in BV-2 cells through activation of Akt/Nrf2/HO-1 and suppression of the NF-kappaB pathway. Food Funct 9(5):2735–2743CrossRefGoogle Scholar
  60. 60.
    Morales-Serna JA, Jiménez A, Estrada-Reyes R, Marquez C, Cárdenas J, Salmón M (2010) Homoisoflavanones from Agave tequilana weber. Molecules 15:3295–3301CrossRefGoogle Scholar
  61. 61.
    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE (2009) Gaussian 09, revision A02. Gaussian Inc, WallingfordGoogle Scholar
  62. 62.
    OʼBoyle NM, Tenderholt A, Langner KM (2009) Cclib: a library for package independent computational chemistry algorithms. J Comput Chem 29:839–845CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Pharmacognosy and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of Traditional Chinese Materia Medica 81#, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of EducationShenyang Pharmaceutical UniversityShenyangChina
  2. 2.School of Functional Food and WineShenyang Pharmaceutical UniversityShenyangChina
  3. 3.State Key Laboratory for Chemistry and Molecular Engineering of Medicinal ResourcesGuangxi Normal UniversityGuilinChina
  4. 4.Women and Children’s Hospital of ShenyangShenyangChina
  5. 5.College of Life and Health SciencesNortheastern UniversityShenyangChina

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