Biomolecules & Therapeutics

  • 제20권1호
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  • Pages.96-103
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  • 2012
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  • 1976-9148(pISSN)
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  • 2005-4483(eISSN)
한국응용약물학회 (The Korean Society of Applied Pharmacology)
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The Methanol Extract of Azadirachta indica A. Juss Leaf Protects Mice Against Lethal Endotoxemia and Sepsis

  • Kim, Woong-Hyun (Department of Infection Biology, Zoonosis Research Center, Wonkwang University School of Medicine) ;
  • Song, Hyun-Ok (Department of Infection Biology, Zoonosis Research Center, Wonkwang University School of Medicine) ;
  • Jin, Chun-Mei (Department of Infection Biology, Zoonosis Research Center, Wonkwang University School of Medicine) ;
  • Hur, Jong-Moon (Institute of Oriental Medicine Scientifi cation, Globalherb Co., Ltd.) ;
  • Lee, Hwa-Sung (Institute of Oriental Medicine Scientifi cation, Globalherb Co., Ltd.) ;
  • Jin, Han-Yong (Department of Infection Biology, Zoonosis Research Center, Wonkwang University School of Medicine) ;
  • Kim, Sung-Yeon (Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University) ;
  • Park, Hyun (Department of Infection Biology, Zoonosis Research Center, Wonkwang University School of Medicine)
  • 투고 : 2011.05.19
  • 심사 : 2011.11.07
  • 발행 : 2012.01.31
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초록

In the present study, the inhibitory effect of neem leaf extract (NLE) on lipopolysaccaride (LPS)-induced nitric oxide (NO) and tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) production was examined both in vitro and in vivo. In vitro study revealed that NLE treatment ($100{\mu}g/ml$) inhibits LPS (100 ng/ml)-induced NO production by 96% and TNF-${\alpha}$ production by 32%. The reduction in NO production is probably conferred by the complete suppression of inducible nitric oxide synthase (iNOS) expression. Interestingly, in vivo NLE significantly improved the survival rate of mice in an experimental sepsis model. Administration of NLE (100 mg/kg) 24 h before LPS treatment (20 mg/kg) improved the survival rate of mice by 60%. The inhibition of plasma NO and TNF-${\alpha}$ production by NLE is likely to account for the improved survival of mice. Our results suggest that NLE may present a promising avenue in the development of therapeutic agents for the treatment of inflammatory diseases.

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참고문헌

  1. Almas, K. (1999) The antimicrobial effects of extracts of Azadirachta indica (Neem) and Salvadora persica (Arak) chewing sticks. Indian. J. Dent. Res. 10, 3-6.
  2. Annane, D., Bellissant, E. and Cavaillon, J. M. (2005) Septic shock. Lancet. 365, 63-78. https://doi.org/10.1016/S0140-6736(04)17667-8
  3. Ayala, A., Song, G. Y., Chung, C. S., Redmond, K. M. and Chaudry, I. H. (2000) Immune depression in polymicrobial sepsis: the role of necrotic (injured) tissue and endotoxin. Crit. Care Med. 28, 2949-2955. https://doi.org/10.1097/00003246-200008000-00044
  4. Badam, L., Joshi, S. P. and Bedekar, S. S. (1999) 'In vitro' antiviral activity of neem (Azadirachta indica. A. Juss) leaf extract against group B coxsackieviruses. J. Commun. Dis. 31, 79-90.
  5. Bernard, G. R., Vincent, J. L., Laterre, P. F., LaRosa, S. P., Dhainaut, J. F., Lopez-Rodriguez, A., Steingrub, J. S., Garber, G. E., Helterbrand, J. D., Ely, E. W. and Fisher, C. J. Jr; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group (2001). Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl. J. Med. 344, 699-709. https://doi.org/10.1056/NEJM200103083441001
  6. Carlson, D. L., Willis, M S., White, D. J., Horton, J. W. and Giroir, B. P. (2005) Tumor necrosis factor-alpha-induced caspase activation mediates endotoxin-related cardiac dysfunction. Crit. Care Med. 33, 1021-1028 https://doi.org/10.1097/01.CCM.0000163398.79679.66
  7. Chen, Y. C., Liang, Y. C., Lin-Shiau, S. Y., Ho, C. T. and Lin, J. K. (1999) Inhibition of TPA-induced protein kinase C and transcription activator protein-1 binding activities by theafl avin-3,3'-digallate from black tea in NIH3T3 cells. J. Agric. Food Chem. 47, 1416-1421. https://doi.org/10.1021/jf981099k
  8. Hu, Y., Xie, G. H., Chen, Q. X. and Fang, X. M. (2011) Small molecules in treatment of sepsis. Curr. Drug Targets. 12, 256-262. https://doi.org/10.2174/138945011794182737
  9. Ii, M., Matsunaga, N., Hazeki, K., Nakamura, K., Takashima, K., Seya, T., Hazeki, O., Kitazaki, T. and Iizawa, Y. (2006) A novel cyclohexene derivative, ethyl (6R)-6-[N-(2-Chloro-4-fl uorophenyl)sulfamoyl] cyclohex-1-ene-1-carboxylate (TAK-242), selectively inhibits tolllike receptor 4-mediated cytokine production through suppression of intracellular signaling. Mol. Pharmacol. 69, 88-95.
  10. Kim, B. H., Roh, E., Lee, H. Y., Lee, I. J., Ahn, B., Jung, S. H., Leem H., Hanm S. B. and Kimm Y. (2008) Benzoxathiole derivative blocks lipopolysaccharide-induced nuclear factor-kappaB activation and nuclear factor-kappaB-regulated gene transcription through inactivating inhibitory kappaB kinase beta. Mol. Pharmacol. 73, 1309-1318. https://doi.org/10.1124/mol.107.041251
  11. Kim, H. J., Tsoyi, K., Heo, J. M., Kang, Y. J., Park, M. K., Lee, Y. S., Lee, J. H., Seo, H. G., Yun-Choi, H. S. and Chang, K. C. (2007) Regulation of lipopolysaccharide-induced inducible nitric-oxide synthase expression through the nuclear factor-kappaB pathway and interferon-beta/tyrosine kinase 2/Janus tyrosine kinase 2-signal transducer and activator of transcription-1 signaling cascades by 2-naphthylethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (THI 53), a new synthetic isoquinoline alkaloid. J. Pharmacol. Exp. Ther. 320, 782-789.
  12. MacMicking, J. D., Nathan, C., Hom, G., Chartrain, N., Fletcher, D. S., Trumbauer, M., Stevens, K., Xie, Q. W., Sokol, K., Hutchinson, N., et al. (1995) Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell. 81, 641-650. https://doi.org/10.1016/0092-8674(95)90085-3
  13. Mayeux, P. R. (1997) Pathobiology of lipopolysaccharide. J. Toxicol. Environ. Health. 51, 415-435. https://doi.org/10.1080/00984109708984034
  14. Mora, A., Payá, M., Ríos, J. L. and Alcaraz, M. J. (1990) Structureactivity relationships of polymethoxyflavones and other flavonoids as inhibitors of non-enzymic lipid peroxidation. Biochem. Pharmacol. 40, 793-797. https://doi.org/10.1016/0006-2952(90)90317-E
  15. Mora, P., Masip, I., Cortés, N., Marquina, R., Merino, R., Merino, J., Carbonell, T., Mingarro, I., Messeguer, A. and Pérez-Payá, E. (2005) Identification from a positional scanning peptoid library of in vivo active compounds that neutralize bacterial endotoxins. J. Med. Chem. 48, 1265-1268. https://doi.org/10.1021/jm040834i
  16. Nguyen, T. B., Adisechan, A. K., Suresh Kumar, E. V., Balakrishna, R., Kimbrell, M. R., Miller, K. A., Datta, A. and David, S. A. (2007) Protection from endotoxic shock by EVK-203, a novel alkylpolyamine sequestrant of lipopolysaccharide. Bioorg. Med. Chem. 15, 5694-5709. https://doi.org/10.1016/j.bmc.2007.06.015
  17. Okpanyi, S. N. and Ezeukwu, G. C. (1981) Anti-inflammatory and antipyretic activities of Azadirachta indica. Planta. Med. 41, 34-39. https://doi.org/10.1055/s-2007-971670
  18. Rao, A. D., Devi, K. N. and Thyagaraju, K. (1998) Isolation of antioxidant principle from Azadirachta seed kernels: determination of its role on plant lipoxygenases. J. Enzyme. Inhib. 14, 85-96. https://doi.org/10.3109/14756369809036547
  19. Rasko, D. A., Moreira, C. G., Li de, R., Reading, N. C., Ritchie, J. M., Waldor, M. K., Williams, N., Taussig, R., Wei, S., Roth, M., Hughes, D. T., Huntley, J. F., Fina, M. W., Falck, J. R. and Sperandio, V. (2008) Targeting QseC signaling and virulence for antibiotic development. Science. 321, 1078-1080. https://doi.org/10.1126/science.1160354
  20. Shen, S. C., Lee, W. R., Lin, H. Y., Huang, H. C., Ko, C. H., Yang, L. L. and Chen, Y. C. (2002) In vitro and in vivo inhibitory activities of rutin, wogonin, and quercetin on lipopolysaccharide-induced nitric oxide and prostaglandin E(2) production. Eur. J. Pharmacol. 446, 187-194. https://doi.org/10.1016/S0014-2999(02)01792-2
  21. Sil, D., Shrestha, A., Kimbrell, M. R., Nguyen, T. B., Adisechan, A. K., Balakrishna, R., Abbo, B. G., Malladi, S., Miller, K. A., Short, S., Cromer, J. R., Arora, S., Datta, A. and David, S. A. (2007) Bound to shock: protection from lethal endotoxemic shock by a novel, nontoxic, alkylpolyamine lipopolysaccharide sequestrant. Antimicrob. Agents. Chemother. 51, 2811-2819. https://doi.org/10.1128/AAC.00200-07
  22. Sireci, G., La Manna, M. P., Di Liberto, D., Lo Dico, M., Taniguchi, M., Dieli, F. and Salerno, A. (2008) Prophylaxis of lipopolysaccharideinduced shock by alpha-galactosylceramide. J. Leukoc. Biol. 84, 550-560. https://doi.org/10.1189/jlb.0707499
  23. Takahashi, K., Morikawa, A., Kato, Y., Sugiyama, T., Koide, N., Mu, M. M., Yoshida, T. and Yokochi, T. (2001) Flavonoids protect mice from two types of lethal shock induced by endotoxin. FEMS. Immunol. Med. Microbiol. 31, 29-33, 2001. https://doi.org/10.1111/j.1574-695X.2001.tb01582.x
  24. Thiemermann, C. (1997) Nitric oxide and septic shock. Gen. Pharmacol. 29, 159-166. https://doi.org/10.1016/S0306-3623(96)00410-7
  25. Titheradge, M. A. (1999) Nitric oxide in septic shock. Biochim. Biophys. Acta. 1411, 437-455. https://doi.org/10.1016/S0005-2728(99)00031-6
  26. Toussaint, S., and Gerlach, H. (2009) Activated protein C for sepsis. N. Engl. J. Med. 361, 2646-2652. https://doi.org/10.1056/NEJMct0808063
  27. Tracey, K. J. and Cerami, A. (1994) Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu. Rev. Med. 45, 491-503. https://doi.org/10.1146/annurev.med.45.1.491
  28. Van Amersfoort, ES., Van Berkel, T. J. and Kuiper, J. (2003) Receptors, mediators, and mechanisms involved in bacterial sepsis and septic shock. Clin. Microbiol. Rev. 16, 379-414. https://doi.org/10.1128/CMR.16.3.379-414.2003
  29. van Leeuwen, H. J., Van Der Tol, M., Van Strijp, J. A., Verhoef, J. and van Kessel, K. P. (2005) The role of tumour necrosis factor in the kinetics of lipopolysaccharide-mediated neutrophil priming in whole blood. Clin. Exp. Immunol. 140, 65-72. https://doi.org/10.1111/j.1365-2249.2005.02748.x
  30. Victor, V. M., Minanom M., Guayerbasm N., Del Riom M., Medinam S. and De la Fuente. M. (1998) Effects of endotoxic shock in several functions of murine peritoneal macrophages. Mol. Cell Biochem. 189, 25-31. https://doi.org/10.1023/A:1006891926301
  31. Wei, X. Q., Charles, I. G., Smith, A., Ure, J., Feng, G. J., Huang, F. P., Xu, D., Muller, W., Moncada, S. and Liew, F. Y. (1995) Altered immune responses in mice lacking inducible nitric oxide synthase. Nature. 375, 408-411. https://doi.org/10.1038/375408a0
  32. Yanpallewar, S. U., Sen, S., Tapas, S., Kumar, M., Raju, S. S. and Acharya, S. B. (2003) Effect of Azadirachta indica on paracetamolinduced hepatic damage in albino rats. Phytomedicine. 10, 391-396. https://doi.org/10.1078/0944-7113-00230
  33. Yazar, E., Bulbul, A., Avci, G. E., Er, A., Uney, K., Elmas, M. and Tras, B. (2010) Effects of enrofl oxacin, fl unixin meglumine and dexamethasone on disseminated intravascular coagulation, cytokine levels and adenosine deaminase activity in endotoxaemia in rats. Acta. Vet. Hung. 58, 357-367. https://doi.org/10.1556/AVet.58.2010.3.8

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