Anti-Inflammatory Effects of Boldine and Reticuline Isolated from Litsea cubeba through JAK2/STAT3 and NF-κB Signaling Pathways

Abstract

The anti-inflammatory effects of boldine and reticuline isolated from Litsea cubeba were evaluated by using xylene-induced ear edema and carrageenan-induced paw edema in mice and rats. Our results demonstrated that intragastric administration with boldine and reticuline significantly mitigated ear weight in mice and decreased paw volume in rats. A combination administration of boldine (0.5 mg/kg) + reticuline (0.25 mg/kg) resulted in a potentiated inhibition in these two models. In parallel, boldine or reticuline reduce the infiltration of neutrophil leukocytes in rat paw tissue, respectively, and the combination of the two groups performed a better anti-inflammatory activity as shown in histopathologies. Boldine, reticuline, and their combination notably inhibited mRNA expressions of TNF-α, and IL-6 and reduced the phosphorylation levels of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Beyond that, their combination also can reduce the phosphorylation levels of p65 and IκBα in the pathological tissues of animals, as observed by real-time PCR and western blot analyses, respectively. These findings indicate for the first time that boldine and reticuline have not only anti-inflammatory activity but also potential synergistic effects in vivo. The underlying mechanism may relate to the inhibition on the expression of pro-inflammatory cytokines, such as TNF-α and IL-6, which may be a consequence of JAK2/STAT3 and NF-κB pathway involvements. This study provides useful data for further exploration and application of boldine and reticuline as potential anti-inflammatory medicines.

Key words

anti-inflammation - isoquinoline alkaloids - boldine - reticuline - JAK2/STAT3 - NF-κB - Litsea cubeba

^* The first two authors contributed to the paper equally.

• References

• 1 Zhang SY, Guo Q, Gao XL, Zhang SY, Chai XY, Tu PF. A phytochemical and pharmacological advance on medicinal plant Litsea cubeba (Lauraceae). China J Chin Mater Med 2014; 39: 769-776
• 2 Kong DG, Zhao Y, Li GH, Chen BJ, Wang XN, Zhou HL, Lou HX, Ren DM, Shen T. The genus Litsea in traditional Chinese medicine: an ethnomedical, phytochemical and pharmacological review. J Ethnopharmacol 2015; 164: 256-264
• 3 Lin B, Zhang H, Zhao XX, Rahman K, Wang Y, Ma XQ, Zheng CJ, Zhang QY, Han T, Qin LP. Inhibitory effects of the root extract of Litsea cubeba (lour.) per. on adjuvant arthritis in rats. J Ethnopharmacol 2013; 147: 327-334
• 4 Backhouse N, Delporte C, Givernau M, Cassels BK, Valenzuela A, Speisky H. Anti-inflammatory and antipyretic effects of boldine. Agents Actions 1994; 42: 114-117
• 5 Zhang SY, Guo Q, Gao XL, Chai XY, Tu PF. Alkaloids from roots and stems of Litsea cubeba . China J Chin Mater Med 2014; 39: 3964-3968
• 6 Zhang WW, Sun Q, Gao XL, Jiang YM, Li RT, Ye J. Anti-inflammation of spirocyclopiperzazinium salt compound LXM-10 targeting α7 nAChR and M4 mAChR and inhibiting JAK2/STAT3 pathway in rats. PLoS One 2013; 8: e66895
• 7 Zhao JJ, Guo YQ, Yang DP, Xue X, Liu Q, Zhu LP, Yin S, Zhao ZM. Chlojaponilactone B from Chloranthus japonicus: suppression of inflammatory responses via inhibition of the NF-κB signaling pathway. J Nat Prod 2016; 79: 2257-2263
• 8 Sowemimo A, Samuel F, Fageyinbo MS. Anti-inflammatory activity of Markhamia tomentosa (Benth.) K. Schum. Ex Engl. ethanolic leaf extract. J Ethnopharmacol 2013; 149: 191-194
• 9 Yonathan M, Asres K, Assefa A, Bucar F. In vivo anti-inflammatory and anti-nociceptive activities of Cheilanthes farinose . J Ethnopharmacol 2006; 108: 462-470
• 10 Sadeghi H, Hajhashemi V, Minaiyan M, Movahedian A, Talebi A. Further studies on anti-inflammatory activity of maprotiline in carrageenan-induced paw edema in rat. Int Immunopharmacol 2013; 15: 505-510
• 11 Li YC, Xian YF, Ip SP, Su ZR, Su ZY, He JJ, Xie QF, Lai XP, Lin ZX. Anti-inflammatory activity of patchouli alcohol isolated from Pogostemonis herba in animal models. Fitoterapia 2011; 82: 1295-1301
• 12 Greco WR, Bravo G, Parsons JC. The search for synergy: a critical review form a response surface perspective. Pharmacol Rev 1995; 47: 331-385
• 13 Chai X. Preliminary elaboration on emergent properties of traditional Chinese medicine. China J Chin Mater Med 2015; 40: 2480-2485
• 14 Liao JC, Tsai JC, Peng WH, Chiu YJ, Sung PJ, Tsuzoki M, Kuo YH. Anti-inflammatory activity of N-(3-florophenyl) ethylcaffeamide in mice. Int J Mol Sci 2013; 14: 15199-15211
• 15 Chen JC, Li LJ, Wen SM, He YC, Liu HX, Zheng QS. Quantitative analysis and simulation of anti-inflammatory effects from the active components of Paino powder in rats. Chin J Integr Med 2011;
• 16 Takeda K, Akira S. TLR signaling pathways. Semin Immunol 2004; 16: 3-9
• 17 Tak PP, Firestein GS. NF-κB: a key role in inflammatory diseases. J Clin Invest 2001; 107: 7-11
• 18 Thalhamer T, McGrath MA, Harnett MM. MAPKs and their relevance to arthritis and inflammation. J Rheumatol 2008; 47: 409-414
• 19 Andonegui G, Bonder CS, Green F. Endothelium-derived Toll-like receptor-4 is the key molecule in LPS-induced neutrophil sequestration into lungs. J Clin Invest 2003; 111: 1011-1020
• 20 Guo CC, Jiang Y, Li L, Hong L, Wang YQ, Shen Q, Lou Y, Hu HH, Zhou H, Yu LS, Jiang HD, Zeng S. Application of a liquid chromatography-tandem mass spectrometry method to the pharmacokinetics, tissue distribution and excretion studies of Dactylicapnos scandens in rats. J Pharm Biomed Anal 2013; 74: 92-100
• 21 Guo CC, Yu CH, Li L, Wang YQ, Wang SJ, Wang WH, Hu HH, Xu SY, Yu LS, Jiang HD, Zeng S. Rapid determination of isocorydine in rat plasma and tissues using liquid chromatography-tandem mass spectrometry and its applications to pharmacokinetics and tissue distribution. Xenobiotica 2012; 42: 466-476
• 22 Zeng RJ, Wu SD, Chen YH. Identification of metabolites of boldine in rats by ultra-performance liquid chromatography-mass spectrometry. China J Chin Mater Med 2014; 24: 42-44
• 23 Ma Y, Li Y, Li XY, Wu YL. Anti-Inflammatory effects of 4-methylcyclopentadecanone on edema models in mice. Int J Mol Sci 2012; 14: 23980-23992
• 24 Xu YG, Cao C, Shang MY, Jiang YM, Wang X, Li CL, Ye J, Cai SQ. Assessment on anti-nociception and anti-inflammation pharmacodynamics of Asarum heterotropoides var. mandshuricum and Asarum sieboldii . China J Chin Mater Med 2012; 37: 625-631
• 25 Niu XF, Li YM, Li WF, Hu H, Yao H, Li H, Mu QL. The anti-inflammatory effects of Caragana tangutica ethyl acetate extract. J Ethnopharmacol 2014; 152: 99-105