Alkaloids of Linderae Radix suppressed the lipopolysaccharide-induced expression of cytokines in cultured macrophage RAW 264.7 cells

Chou, David Jiyao;Lam, Kelly Yinching;Chen, Jianping;Yao, Ping;Dong, Tina Tingxia;Xiong, Aizhen;Chou, Guixin;Wang, Zhengtao;Tsim, Karl Wah-Keung

  • Received : 2014.04.14
  • Accepted : 2014.11.10
  • Published : 2014.11.30


Linderae Radix, the dry roots of Lindera aggregata (Sims) Kosterm, has long been used as traditional Chinese medicine for treatment of inflammatory diseases. The total alkaloids are believed to be the active components responsible for anti-inflammation of Linderae Radix. Here, the total alkaloids of Linderae Radix were extracted and isolated, including 12 isoquinoline alkaloids and 1 furan sesquiterpene. Within the alkaloids, norisoboldine, boldine, linderaline, isoboldine, reticuline, N-methyllaurotetanine, norjuziphine were found to be the major ingredients. In lipopolysaccharide-treated macrophage RAW 264.7 cells, application of Linderae Radix extract, or total alkaloids, suppressed the transcription of proinflammatory cytokines, interleukin-$1{\beta}$ and interleukin-6. Out of the 12 alkaloids, norisoboldine, boldine, and isoboldine were tested in lipopolysaccharide-treated macrophages, and norisoboldine was the strongest alkaloid in suppressing the cytokine expressions. The current studies suggested that the identification of alkaloids from Linderae Radix could provide a plausible explanation for herbal therapeutic functions.


traditional Chinese medicine;Linderae Radix;total alkaloids;isoquinoline alkaloids;proinflammatory cytokines


  1. Bresnihan B. Pathogenesis of joint damage in rheumatoid arthritis. J Rheumatol. 1999;26:717-719.
  2. Chiou CM, Kang JJ, Lee SS. Litebamine N-homologues: preparation and anti-acetylcholinesterase activity. J Nat Prod. 1998;61:46-50.
  3. Chou, GX, Nakamura, N, Ma, CM, Wang, ZT, Hattori, M. Isoquinoline alkaloids from Lindera aggregata. Chin J Nat Med. 2005;3:272-275.
  4. Du CY, Choi RC, Zheng KY, Dong TT, Lau DT, Tsim KW. Yu Ping Feng San, an Ancient Chinese Herbal Decoction Containing Astragali Radix, Atractylodis Macrocephalae Rhizoma and Saposhnikoviae Radix, Regulates the Release of Cytokines in Murine Macrophages. PLoS One. 2013;8:e78622.
  5. El-Kawi MA, Slatkin DJ, Schiff PL Jr, Dasgupta S, Chattopadhyay SK, Ray AB. Additional alkaloids of Pachygone ovata. J Nat Prod. 1984;47:459-464.
  6. Feldmann M, Maini SR. Role of cytokines in rheumatoid arthritis: an education in pathophysiology and therapeutics. Immunol Rev. 2008;223:7-19.
  7. Marok R, Winyard PG, Coumbe A, Kus ML, Gaffney K, Blades S, Mapp PI, Morris CJ, Blake DR, Kaltschmidt C, Baeuerle PA. Activation of the transcription factor nuclear factor-kappaB in human inflamed synovial tissue. Arthritis Rheum. 1996;39:583-591.
  8. Ferrero-Miliani L, Nielsen OH, Andersen PS, Girardin SE. Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1beta generation. Clin Exp Immunol. 2007;147:227-235.
  9. Grainger AJ, Rowbotham EL. Rheumatoid arthritis. Semin Musculoskelet Radiol. 2013;17:69-73.
  10. Guinaudenu H, Leboeuf M, Cave A. Aporphine alkaloids. II. J Nat Prod. 1979;42:325-343.
  11. Milian L, Estelles R, Abarca B, Ballesteros R, Sanz MJ, Blazquez MA. Reactive oxygen species (ROS) generation inhibited by aporphine and phenanthrene alkaloids semisynthesized from natural boldine. Chem Pharm Bull. 2004;52:696-699.
  12. Li Q, Chou G, Dou C, Wang Z, Huang F. Studies on the analgesic and anti-inflammatory action of Radix Linderae extract. Zhong Yao Cai. 1997;20:629-631.
  13. Luo Y, Liu M, Dai Y, Yao X, Xia Y, Chou G, & Wang Z. Norisoboldine inhibits the production of pro-inflammatory cytokines in lipopolysaccharide-stimulated RAW 264.7 cells by down-regulating the activation of MAPKs but not NF-$\kappa$B. Inflammation. 2010;33:389-397.
  14. Luo Y, Liu M, Xia Y, Dai Y, Chou G, Wang Z. Therapeutic effect of norisoboldine, an alkaloid isolated from Radix Linderae, on collagen-induced arthritis in mice. Phytomedicine. 2010;17:726-731.
  15. Luo Y, Liu M, Yao X, Xia Y, Dai Y, Chou G, & Wang Z. Total alkaloids from Radix Linderae prevent the production of inflammatory mediators in lipopolysaccharide-stimulated RAW 264.7 cells by suppressing NF-$\kappa$B and MAPKs activation. Cytokine. 2009;46:104-110.
  16. Tak PP, Bresnihan B. The pathogenesis and prevention of joint damage in rheumatoid arthritis: advances from synovial biopsy and tissue analysis. Arthritis Rheum. 2000;43:2619-2633.<2619::AID-ANR1>3.0.CO;2-V
  17. Mix KS, Mengshol JA, Benbow U, Vincenti MP, Sporn MB, Brinckerhoff CE. A synthetic triterpenoid selectively inhibits the induction of matrix metalloproteinases 1 and 13 by inflammatory cytokines. Arthritis Rheum. 2001;44:1096-1104.<1096::AID-ANR190>3.0.CO;2-6
  18. Rachmatiah T, Mukhtar MR, Nafiah MA, Hanafi M, Kosela S, Morita H, Litaudon M, Awang K, Omar H, Hadi AH. (+)-N-(2-hydroxypropyl) lindcarpine: a new cytotoxic aporphine isolated from Actinodaphne pruinosa Nees. Molecules. 2009;14:2850-2856.
  19. Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010;376:1094-1108.
  20. Xiao Y, Li Z Y, Li L. Chemical constituents (II) from Litsea euosma W. W. Smith. Yunnan Chemical Technology. 2006;33:22-23.
  21. Xiao Y, Yang XD, Zhou HJ, Zhao JF, Yang JH, Li L. Isoquinoline alkaloids from Litsea euosma. Journal of Yunnan University. 2004;26:192-193.
  22. Winer J, Jung CK, Shackel I, Williams PM. Development and validation of real-time quantitative reverse transcriptasepolymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro. Anal Biochem. 1999;270:41-49.
  23. Yu R, Ye Q, Chen B, Zhang GL. Chemical study on Mitrephora Natural Product Research and Development. 2003;15:212-215.
  24. Zhu CL, Yang PM. Isolation and structure identification of chemical constituents from the root of Litsea cubeba. Chinese Journal of Pharmaceuticals. 2007;38:558-560.


Supported by : Hong Kong Chinese Materia Medica Standards, GRF