Abstract
Aim:
To examine if magnesium lithospermate B (MLB) extracted from Danshen, the dried roots of Salvia miltiorrhiza, may act as an active component responsible for the cardiac therapeutic effect of this traditional Chinese herb via the same molecular mechanism triggered by cardiac glycosides, such as ouabain and digoxin. Moreover, we wanted to test if MLB may provide neuroprotection against ischemic stroke as observed for cardiac glycosides.
Methods:
Similarity in the chemical structure and molecular configuration between MLB and ouabain was analyzed. The inhibition potency of MLB and ouabain on Na+,K+-ATPase activity of a commercial product, as well as in purified membrane fractions from rat brain and heart tissues, was examined and compared. Neuroprotective effect of MLB against ischemic stroke was also evaluated using a cortical brain slice-based assay model.
Results:
Dose-dependent inhibition on the commercial Na+,K+- ATPase equivalent to that for ouabain was observed for MLB of approximately half dosage by weight. This relative potency of ouabain and MLB was also observed for their inhibition on Na+,K+-ATPase activity of plasma membrane purified from rat tissues, although these 2 inhibitors exhibited somewhat lower competence in these crude extracts. In ischemic gerbil brains, post-treatment with MLB significantly reduced the infarct size, visualized by 2,3,5-triphenyltetrazolium chloride staining, by approximately 55% when compared with the control group.
Conclusion:
These results evidently suggest that the cardiac therapeutic effect of Danshen should be at least partly attributed to the effective inhibition of Na+,K+- ATPase by MLB, and that MLB provides anti-ischemic neuroprotection in gerbils subjected to focal ischemia and reperfusion.
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Li XC, Yu C, Sun WK, Liu GY, Jia JY, Wang YP . Pharmaco kinetics of magnesium lithospermate B after intravenous administration in beagle dogs. Acta Pharmacol Sin 2004; 25: 1402–7.
Lu Y, Foo LY . Polyphenolics of Salvia–a review. Phytochemistry 2002; 59: 117–40.
Tanaka T, Morimoto S, Nonaka G, Nishioka I, Yokozawa T, Chung HY, et al. Magnesium and ammonium-potassium lithospermates B, the active principles having a uremia-preventive effect from Salvia miltiorrhiza. Chem Pharm Bull 1989; 37: 340–4.
Shigematsu T, Tajima S, Nishikawa T, Murad S, Pinnell SR, Nishioka I . Inhibition of collagen hydroxylation by lithospermic acid magnesium salt, a novel compound isolated from Salviae miltiorrhizae Radix. Biochim Biophys Acta 1994; 25: 79–83.
O K, Lynn EG, Vazhappilly R, Au-Yeung KK, Zhu DY, Siow YL . Magnesium tanshinoate B (MTB) inhibits low density lipoprotein oxidation. Life Sci 2001; 68: 903–12.
Yokozawa T, Lee TW, Oura H, Nonaka G, Nishioka I . Effect of magnesium lithospermate B in rats with sodium-induced hypertension and renal failure. Nephron 1992; 60: 460–4.
Fung KP, Wu J, Zeng LH, Wong HN, Lee CM, Hon PM . Lithospermic acid B as an antioxidant-based protector of cultured ventricular myocytes and aortic endothelial cells of rabbits. Life Sci 1993; 53: 189–93.
Yokozawa T, Chung HY, Dong E, Oura H . Confirmation that magnesium lithospermate B has a hydroxyl radical-scavenging action. Exp Toxicol Pathol 1995; 47: 341–4.
Kasimu R, Tanaka K, Tezuka Y, Gong ZN, Li JX, Basnet P . Comparative study of seventeen Salvia plants: aldose reductase inhibitory activity of water and MeOH extracts and liquid chromatography-mass spectrometry (LC-MS) analysis of water extracts. Chem Pharm Bull 1998; 46: 500–4.
Wu XJ, Wang YP, Wang W, Sun WK, Xu YM, Xuan LJ . Free radical scavenging and inhibition of lipid peroxidation by magnesium lithospermate B. Acta Pharmacol Sin 2000; 21: 855–8.
Withering W . An account of the foxglove and some of its medical uses: with practical remarks on dropsy, and other diseases. London: GGJ and Robinson J; 1785.
Li-Saw-Hee FL, Lip GY . Digoxin revisted. QJM 1998; 91: 259–64.
Lin SC, Way EL . A high affinity Ca2+ ATP-ase enriched nerve-ending plasma membranes. Brain Res 1982; 235: 387–92.
Wang JK, Portbury S, Thomas MB, Barney S, Ricca DJ, Morris DL, et al. Cardiac glycosides provide neuroprotection against ischemic stroke: Discovery by a brain slice-based compound screening platform. Proc Natl Acad Sci USA 2006; 103: 10 461–6.
Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, et al. DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res 2006; 34: D668–72.
Lin SC, Way EL . Characterization of calcium-activated and magnesium-activated ATP-ase of brain nerve endings. J Neurochem 1984; 42: 1697–706.
Muszbek L . A highly sensitive method for the measurement of the ATPase activity. Anal Biochem 1977; 77: 286–8.
Goldberg H, Fernander A . Simplified method of the estimation of inorganic phosphorus in body fluids. Clin Chem 1996; 12: 871–5.
Yang DY, Tsai TH, Cheng CH, Lee CW, Chen SH, Cheng FC . Simultaneous monitoring of extracellular glucose, pyruvate, lactate and glutamate in gerbil cortex during focal cerebral ischemia by dural probe microdialysis. J Chromatogr A 2001; 913: 349–54.
Bederson JB, Pitts LH, Germano SM, Nishmura MC, Davis RL, Bartkowski HM . Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. Stroke 1986; 17: 1304–8.
Kjeldsen K, Norgaard A, Gheorghiade M . Myocardial Na,K-ATPase: the molecular basis for the hemodynamic effect of digoxin therapy in congestive heart failure. Cardiovasc Res 2002; 55: 710–3.
Quadri L, Cerri A, Ferrari P, Folpini E, Mabilia M, Melloni P . Synthesis and structure-activity relationships of 17- (hydrazonomethyl)- 5-androstane-3,14-diol derivatives that bind to Na+,K+- ATPase receptor. J Med Chem 1996; 39: 3385–93.
De Munari S, Barassi P, Cerri A, Fedrizzi G, Gobbini M, Mabilia M, et al. New approach to the design of novel inhibitors of Na+,K+-ATPase: 17-substituted seco-D 5-androstane as cassaine analogues. J Med Chem 1998; 41: 3033–40.
Gobbini M, Barassi P, Cerri A, De Munari S, Fedrizzi G, Santagostino M, et al. 17-O-aminoalkyloxime derivatives of 3, 14-dihydroxy-5-androstane and 3-hydroxy-14-oxo-seco-D-5- androstane as inhibitors of the digitalis receptor on Na+,K+-ATPase. J Med Chem 2001; 44: 3821–30.
Cerri A, Almirante N, Barassi P, Benicchio A, De Munari S, Marazzi G, et al. Synthesis and inotropic activity of 1- (Oaminoalkyloximes) of perhydroindene derivatives as simplified digitalis-like compounds acting on the Na+,K+-ATPase. J Med Chem 2002; 45: 189–207.
Ball WJJ, Farr CD, Paula S, Keenan SM, Delisle RK, Welsh WJ . Three-dimensional structure-activity relationship modeling of digoxin inhibition and docking to Na+,K+-ATPase. Ann N Y Acad Sci 2003; 986: 296–7.
Cerri A, Almirante N, Barassi P, Benicchio A, Fedrizzi G, Ferrari P, et al. 17 -O-aminoalkyloximes of 5-androstane-3,14-diol with digitalis-like activity: synthesis, cardiotonic activity, structure-activity relationships and molecular modeling of the Na+,K+-ATPase receptor. J Med Chem 2000; 43: 2332–49.
Qiu LY, Koenderink JB, Swarts HG, Willems PH, De Pont JJ . Phe783, Thr797, and Asp804 in transmembrane hairpin M5-M6 of Na+,K+-ATPase play a key role in ouabain binding. J Biol Chem 2003; 278: 47 240–4.
Jiang RW, Lau KM, Hon PM, Mak TC, Woo KS, Fung KP . Chemistry and biological activities of caffeic acid derivatives from Salvia miltiorrhiza. Curr Med Chem 2005; 12: 237–46.
Johnson EM Jr, Deckwerth TL . Molecular mechanisms of developmental neuronal death. Annu Rev Neurosci 1993; 16: 31–46.
Browne KD, Leoni MJ, Iwata A, Chen XH, Smith DH . Acute treatment with MgSO4 attenuates long-term hippocampal tissue loss after brain trauma in the rat. J Neurosci Res 2004; 77: 878–83.
Wang M, Berlin JR . Channel phosphorylation and modulation of L-type Ca2+ currents by cytosolic Mg2+ concentration. Am J Physiol Cell Physiol 2006; 291: C83–92.
Lee JM, Grabb MC, Zipfel GJ, Choi DW . Brain tissue responses to ischemia. J Clin Invest 2000; 106: 723–31.
Hochachka PW . Defense strategies against hypoxia and hypothermia. Science 1986; 231: 234–41.
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Project supported by a grant to Jason TC Tzen from the Jason Life Tech Inc, Taiwan China (No GD95301-Biotech).
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Tzen, J., Jinn, Tr., Chen, Yc. et al. Magnesium lithospermate B possesses inhibitory activity on Na+,K+-ATPase and neuroprotective effects against ischemic stroke. Acta Pharmacol Sin 28, 609–615 (2007). https://doi.org/10.1111/j.1745-7254.2007.00544.x
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DOI: https://doi.org/10.1111/j.1745-7254.2007.00544.x
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