Oxymatrine

Oxymatrine (matrine oxide, matrine N-oxide, matrine 1-oxide) is one of many quinolizidine alkaloid compounds extracted from the root of Sophora flavescens, a Chinese herb. It is very similar in structure to matrine, which has one less oxygen atom. Oxymatrine has a variety of effects in vitro and in animal models, including protection against apoptosis, tumor and fibrotic tissue development, and inflammation.[1][2][3] Furthermore, oxymatrine has been shown to decrease cardiac ischemia[4] (decreased blood perfusion), myocardial injury,[5] arrhythmias[6] (irregular heartbeats), and improve heart failure by increasing cardiac function.[7]

Oxymatrine
Names
IUPAC name
(7aS,13aR,13bR,13cS)dodecahydro-1H,5H,10H-dipyrido[2,1-f:3′,2′,1′-ij][1,6]naphthyridin-10-one 4-oxide
Other names
Matrine oxide, matrine N-oxide, matrine 1-oxide
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.106.342
UNII
Properties
C15H24N2O2
Molar mass 264.369 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Role in cardiac fibrosis
See also: TGF beta signaling pathway

Recent research has shown that oxymatrine prevents cardiac fibrosis in rats.[8] The development of fibrotic tissue in the heart occurs when fibroblasts produce excessive amounts of collagen (particularly types I and III),[9] which accumulate and deposit in the heart. The excessive transformation to fibrotic tissue negatively affects the function and structure of the heart. Additionally, excessive amounts of collagen in the ventricles lead to alterations in gene expression, deposition of extracellular matrix, wall thickening, and ventricular remodeling in a manner that promotes dysfunction.[10]

The mechanism by which oxymatrine may inhibit fibrosis is still unidentified. One theory that has been proposed is that oxymatrine inhibits a key signaling pathway involved in collagen production. One of the main signaling receptors involved in this pathway is the TGF-β1 co-receptor (complex of type I and type II receptors), which acts as a trans-membrane protein serine/threonine kinase.[11] A receptor assembly factor first activates TGF-β1 type I receptor and then type II. Receptor I is then able to bind proteins Smad2 and Smad3, which form a complex with Smad4. This complex accumulates in the nucleus, and binds to promoter elements of the collagen gene, stimulating the production of collagen.[12]

In rats, oxymatrine also inhibits the expression of the Smad3 ligand which binds to TGF-β1 type I and activates the signal transduction pathway.[8] A dose–response relationship was observed with increasing intragastric concentrations of oxymatrine resulting in decreased expression of Smad3. By inhibiting this pathway, less collagen was produced and deposited in the heart, preventing the formation of cardiac fibrosis.[8] Huang and Chen (2013) claim that oxymatrine may even be involved in inhibiting the expression of TGF-β1 receptors, which would further support that oxymatrine attenuates the signal transduction pathway involved in collagen production.[10] They also reported that inhibition of the TGF-β1 receptor may also prevent ventricular remodeling.[10]

Future studies

Effects of oxymatrine on heart disease in humans has not been studied and the long term side-effects of clinical oxymatrine use have not yet been identified.

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References
  1. Ma L, Wen S, Zhan Y, He Y, Liu X, Jiang J (2008) Anticancer effects of the Chinese medicine matrine on murine hepatocellular carcinoma cells. Planta Med 74:245–251
  2. Jiang H, Hou C, Zhang S, Xie H, Zhou W, Jin Q, Cheng X, Qian R, Zhang X (2007) Matrine upregulates the cell cycle protein E2F-1 and triggers apoptosis via the mitochondrial pathway in K562 cells. Eur J Pharmacol 559:98–108
  3. Yamazaki M (2000) The pharmacological studies on matrine and oxymatrine. Yakugaku Zasshi 120:1025–1033
  4. Hong-li, S., Li, L., Shang, L., Zhao, D., Dong, D., Qiao, G., Liu, Y., Chu, W., Yang, B. (2008) Cardioprotective effects and underlying mechanisms of oxymatrine against Ischemic myocardial injuries of rats. Phytotherapy Research 22: 985-989
  5. Zhang M, Wang X, Wang X, Hou X, Teng P, Jiang Y, Zhang L, Yang X, Tian J, Li G, Cao J, Xu H, Li Y, Wang Y. (2013), Oxymatrine protects against myocardial injury via inhibition of JAK2/STAT3 signaling in rat septic shock. Mol Mod Rep 7(4): 1293-1299.
  6. Cao Y, Shan, J, Li, L, Gao, J, Shen, Z, Wang, Y, Xu, C, Sun, H. (2010) Antiarrhythmic Effects and Ionic Mechanisms of Oxymatrine from Sophora flavescens. Phytotherapy Research 24: 1844-1849.
  7. Hu, S, Tang, Y, Shen, Y, Ao, H, Bai, J, Wang, Y, Yang, Y. (2011) Protective effect of oxymatrine on chronic rat heart failure. J Physiol Sci 61: 363-372.
  8. Shen, X, Yang, Y, Xiao, T, Peng, J, Liu, X. (2011) Protective effect of oxymatrine on myocardial fibrosis induced by acute myocardial infarction in rats involved in TGF-b1-Smads signal pathway. Journal of Asian Natural Products Research 13: 215-224
  9. Kacimi, R., Gerdes, A. (2003) Alterations in G protein and MAP kinase signaling pathways during cardiac remodeling in hypertension and heart failure. Hypertension 41: 968–977
  10. Huang, X, Chen, X. (2012) Effect of oxymatrine, the active component from Radix Sophorae flavescentis (Kushen), on ventricular remodeling in spontaneously hypertensive rats. Phytomedicine 20: 202-212.
  11. Levy, L, Hill, CS. (2006). Alterations in components of the TGF-β superfamily signaling pathways in human cancer. Cytokine and Growth Factor Reviews 17(1): 41-58.
  12. S.J. Wicks, T. Grocott, K. Haros, M. Maillard, P. ten Dijke, and A. Chantry (2006) Reversible ubiquitination regulates the Smad/TGF-beta signalling pathway. Biochem. Soc. Trans. 34: 761-763
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