Abstract
Objective
The present study aimed to evaluate the anti-inflammatory and analgesic activities of the ginsenoside metabolite compound K (CK) and its mechanisms.
Methods
Mice model of xylene-induced ear swelling and rat model of carrageenan-induced paw swelling were used to evaluate the effect of CK on acute inflammation. The analgesic effect of CK was evaluated on heat-, acetic acid-, and carrageenan-induced hyperalgesia. The levels of prostaglandin E2 (PGE2), cyclooxygenase-1 (COX-1), and COX-2 in carrageenan-induced rat paw swelling and gastric mucosa were detected by enzyme-linked immunosorbent assay (ELISA). COX-1 and COX-2 expressions in carrageenan-induced rat paw swelling and gastric mucosa were detected by western blotting. In vitro effect of CK (10−9, 10−8, 10−7, 10−6, 10−5 M) on COX-1 and COX-2 activities was evaluated by measuring the production of 6-keto-PGF1α and PGE2 in rat peritoneal macrophages.
Results
CK at doses of 7, 14, 28, 56, 112, and 224 mg/kg alleviated xylene-induced ear oedema, whereas CK at 40, 80, and 160 mg/kg alleviated carrageenan-induced paw oedema. CK at 224 mg/kg showed an analgesic effect against acetic acid-induced pain. CK at 40, 80, and 160 mg/kg significantly increased rat inflammatory pain threshold, but had no effect on heat-induced pain threshold. CK at 10, 20, 40, 80, and 160 mg/kg reduced PGE2 level in the paw tissue, but showed no effect on that in the gastric mucosa. CK at 20, 40, 80, and 160 mg/kg decreased COX-2 expression in the paw tissue and gastric mucosa, but exhibited no effect on COX-1 expression or on COX-1 and COX-2 activities.
Conclusion
CK exerted anti-inflammatory and analgesic effects, possibly by reducing the catalytic synthesis of PGE2 via downregulation of COX-2 expression.
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References
Abdel-Salam OM (2005) Anti-inflammatory, antinociceptive, and gastric effects of Hypericum perforatum in rats. Sci World J 5:586–595
Alhouayek M, Muccioli GG (2014) COX-2-derived endocannabinoid metabolites as novel inflammatory mediators. Trends Pharmacol Sci 35:284–292
Alvarez-Soria MA, Herrero-Beaumont G, Moreno-Rubio J, Calvo E, Santillana J, Egido J, Largo R (2008) Long-term NSAID treatment directly decreases COX-2 and mPGES-1 production in the articular cartilage of patients with osteoarthritis. Osteoarthr Cartil 16:1484–1493
Atta AH, Abo EL-Sooud K (2004) The antinociceptive effect of some Egyptian medicinal plant extracts. J Ethnopharmacol 95(2–3):235–238
Baamonde A, Lastra A, Villazón M, Bordallo J, Hidalgo A, Menéndez L (2004) Involvement of endogenous endothelins in thermal and mechanical inflammatory hyperalgesia in mice. Naunyn Schmiedebergs Arch Pharmacol 369:245–251
Chandrasekhar S, Harvey AK, Yu XP, Chambers MG, Oskins JL, Lin C, Seng TW, Thibodeaux SJ, Norman BH, Hughes NE, Schiffler MA, Fisher MJ (2016) Identification and characterization of novel microsomal prostaglandin E synthase-1 inhibitors for analgesia. J Pharmacol Exp Ther 356:635–644
Chen J, Wu H, Wang Q, Chang Y, Liu K, Song S, Yuan P, Fu J, Sun W, Huang Q, Liu L, Wu Y, Zhang Y, Zhou A, Wei W (2014) Ginsenoside metabolite compound k alleviates adjuvant-induced arthritis by suppressing T cell activation. Inflammation 37:1608–1615
Chen J, Wu H, Wang Q, Chang Y, Liu K, Wei W (2015) Ginsenoside metabolite compound K suppresses T-cell priming via modulation of dendritic cell trafficking and costimulatory signals, resulting in alleviation of collagen-induced arthritis. J Pharmacol Exp Ther 353:71–79
Chen J, Wang Q, Wu H, Liu K, Wu Y, Chang Y, Wei W (2016) The ginsenoside metabolite compound K exerts its anti-inflammatory activity by downregulating memory B cell in adjuvant-induced arthritis. Pharm Biol 54(7):1280–1288
Christensen LP (2009) Ginsenosides chemistry, biosynthesis, analysis, and potential health effects. Adv Food Nutr Res 55:1–99
Cunha TM, Verri WA Jr, Silva JS, Poole S, Cunha FQ, Ferreira SH (2005) A cascade of cytokines mediates mechanical inflammatory hypernociception in mice. Proc Natl Acad Sci USA 102:1755–1760
Díaz-Muñoz MD, Osma-García IC, Cacheiro-Llaguno C, Fresno M, Iñiguez MA (2010) Coordinated upregulation of cyclooxygenase-2 and microsomal prostaglandin E synthase 1 transcription by nuclear factor kappa B and early growth response-1 in macrophages. Cell Signal 22(10):1427–1436
Eldahshan OA, Abdel-Daim MM (2015) Phytochemical study, cytotoxic, analgesic, antipyretic and anti-inflammatory activities of strychnos nux-vomica. Cytotechnology 67:831–844
Funk CD (2001) Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294:1871–1875
Hishe HZ, Ambech TA, Hiben MG, Fanta BS (2018) Anti-nociceptive effect of methanol extract of leaves of Senna singueana in mice. J Ethnopharmacol 217:49–53
Joh EH, Lee IA, Jung IH, Kim DH (2011) Ginsenoside Rb1 and its metabolite compound K inhibit IRAK-1 activation–the key step of inflammation. Biochem Pharmacol 82(3):278–286
Khan MJ, Saraf S, Saraf S (2017) Anti-inflammatory and associated analgesic activities of HPLC standardized alcoholic extract of known ayurvedic plant Schleichera oleosa. J Ethnopharmacol 197:257–265
Li J, Zhong W, Wang W, Hu S, Yuan J, Zhang B, Hu T, Song G (2014) Ginsenoside metabolite compound K promotes recovery of dextran sulfate sodium-induced colitis and inhibits inflammatory responses by suppressing NF-κB activation. PLoS One 9(2):e87810
Liao Z, Milas L (2004) COX-2 and its inhibition as a molecular target in the prevention and treatment of lung cancer. Expert Rev Anticancer Ther 4:543–560
Liu KK, Wang QT, Yang SM, Chen JY, Wu HX, Wei W (2014) Ginsenoside compound K suppresses the abnormal activation of T lymphocytes in mice with collagen-induced arthritis. Acta Pharmacol Sin 35:599–612
Mao Q, Shi L, Wang ZG, Luo YH, Wang YY, Li X, Lu M, Ju JM, Xu JD, Kong M, Zhou SS, Shen MQ, Li SL (2017) Chemical profiles and pharmacological activities of Chang-Kang-Fang, a multi-herb Chinese medicinal formula, for treating irritable bowel syndrome. J Ethnopharmacol 201:123–135
Park EK, Shin YW, Lee HU, Kim SS, Lee YC, Lee BY, Kim DH (2005) Inhibitory effect of ginsenoside Rb1 and compound K on NO and prostaglandin E2 biosyntheses of RAW264.7 cells induced by lipopolysaccharide. Biol Pharm Bull 28(4):652–656
Rajakrishnan V, Manoj VR, Subba Rao G (2008) Computer-aided, rational design of a potent and selective small peptide inhibitor of cyclooxygenase 2 (COX2). J Biomol Struct Dyn 25:535–542
Sandes S, Heimfarth L, Brito RG, Santos PL, Gouveia DN, Carvalho A, Quintans JSS, da Silva-Júnior EF, de Aquino TM (2018) Evidence for the involvement of TNF-α, IL-1β and IL-10 in the antinociceptive and anti-inflammatory effects of indole-3-guanyl hydrazone hydrochloride, an aromatic aminoguanidine, in rodents. Chem Biol Interact 286:1–10
Shajib MS, Rashid RB, Ming LC, Islam S, Sarker M, Moklesur R, Nahar L, Sarker SD, Datta BK, Rashid MA (2018) Polymethoxyflavones from Nicotiana plumbaginifolia (Solanaceae) exert antinociceptive and neuropharmacological effects in mice. Front Pharmacol 9:85
Valério DA, Cunha TM, Arakawa NS, Lemos HP, Da Costa FB, Parada CA, Ferreira SH, Cunha FQ, Verri WA Jr (2007) Anti-inflammatory and analgesic effects of the sesquiterpene lactone budlein A in mice: inhibition of cytokine production-dependent mechanism. Eur J Pharmacol 562:155–163
Wang Y, Chen J, Luo X, Zhang Y, Si M, Wu H, Yan C, Wei W (2016) Ginsenoside metabolite compound K exerts joint-protective effect by interfering with synoviocyte function mediated by TNF-α and Tumor necrosis factor receptor type 2. Eur J Pharmacol 771:48–55
Williams CS, Mann M, DuBois RN (1999) The role of cyclooxygenases in inflammation, cancer, and development. Oncogene 18:7908–7916
Woolf CJ, Max MB (2001) Mechanism-based pain diagnosis: issues for analgesic drug development. Anesthesiology 95:241–249
Wu H, Chen J, Wang Q, Jia X, Song S, Yuan P, Liu K, Liu L, Zhang Y, Zhou A, Wei W (2014) Ginsenoside metabolite compound K attenuates inflammatory responses of adjuvant-induced arthritis rats. Immunopharmacol Immunotoxicol 36:124–129
Yang CS, Ko SR, Cho BG, Shin DM, Yuk JM, Li S, Kim JM, Evans RM, Jung JS, Song DK, Jo EK (2008) The ginsenoside metabolite compound K, a novel agonist of glucocorticoid receptor, induces tolerance to endotoxin-induced lethal shock. J Cell Mol Med 12(5A):1739–1753
Zheng S, Wang Q, He Q, Song X, Ye D, Gao F, Jin S, Lian Q (2011) Novel biphasic role of Lipoxin A (4) on expression of cyclooxygenase-2 in lipopolysaccharide-stimulated lung fibroblasts. Mediat Inflamm 2011:745340
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (Nos. 81503084, 81330081).
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WW contributed to the design of the study, served as the study coordinator, and helped to review the manuscript. JC designed the study, performed the experiments, collected the data and wrote the manuscript. MS, YW, LL, YZ, AZ helped perform the experiments and interpret the data. All authors read and approved the final manuscript.
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Chen, J., Si, M., Wang, Y. et al. Ginsenoside metabolite compound K exerts anti-inflammatory and analgesic effects via downregulating COX2. Inflammopharmacol 27, 157–166 (2019). https://doi.org/10.1007/s10787-018-0504-y
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DOI: https://doi.org/10.1007/s10787-018-0504-y