Magnesium lithospermate B possesses inhibitory activity on Na<sup>+</sup>,K<sup>+</sup>-ATPase and neuroprotective effects against ischemic stroke

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Aim: To determine whether ginsenosides with various sugar attachments may act as active components responsible for the cardiac therapeutic effects of ginseng and sanqi (the roots of Panax ginseng and Panax notoginseng) via the same molecular mechanism triggered by cardiac glycosides, such as ouabain and digoxin. Methods: The structural similarity between ginsenosides and ouabain was analyzed. The inhibitory potency of ginsenosides and ouabain on Na+/K+-ATPase activity was examined and compared. Molecular modeling was exhibited for the docking of ginsenosides to Na+/K+-ATPase. Results: Ginsenosides with sugar moieties attached only to the C-3 position of the steroid-like structure, equivalent to the sugar position in cardiac glycosides, and possessed inhibitory potency on Na+/K+-ATPase activity. However, their inhibitory potency was significantly reduced or completely abolished when a monosaccharide was linked to the C-6 or C-20 position of the steroid-like structure; replacement of the monosaccharide with a disaccharide molecule at either of these positions caused the disappearance of the inhibitory potency. Molecular modeling and docking confirmed that the difference in Na+/K+-ATPase inhibitory potency among ginsenosides was due to the steric hindrance of sugar attachment at the C-6 and C-20 positions of the steroid-like structure. Conclusion: The cardiac therapeutic effects of ginseng and sanqi should be at least partly attributed to the effective inhibition of Na+/K+-ATPase by their metabolized ginsenosides with sugar moieties attached only to the C-3 position of the steroid-like structure

Section: Discussionmentioning

confidence: 99%

Effect of sugar positions in ginsenosides and their inhibitory potency on Na+/K+-ATPase activity

Chen¹,

Chung²,

et al. 2008

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“…Oleanolic acid, a steroid-like compound and moderate inhibitor of Na + /K + -ATPase, also displayed neuroprotective effect against focal cerebral ischemic injury [100] . Furthermore, the same phenomenon was observed when we examined the neuroprotective effect of MLB against ischemic stroke in a similar brain slice assay model [74] . Taken together, these experimental data support that inhibiting Na + /K + -ATPase may provide neuroprotection in the context of ischemia as well as other neurodegenerative conditions.…”

Section: Inhibition Of Na + /K + -Atpase and Its Potential Neuroprotementioning

confidence: 60%

“…In contrast, MLB is generally regarded as an antioxidant without notable toxicity [74] . Similar results were found in our studies: severe cell toxicity accompanied with dendritic shrink was observed in SH-SY5Y cells treated with ouabain, but not in those treated with MLB [75] .…”

Section: Wwwchinapharcom Chen Rjy Et Almentioning

confidence: 99%

“…In spite of being a non-steroid compound, MLB possesses potent inhibition on Na + /K + -ATPase in vitro [74] . The molecular organization and configuration of MLB in the 3D structure is somewhat similar to ouabain, a cardiac glycoside with a rigid steroid backbone ( Figure 3A), although they are totally different compounds with distinct molecular weights (584.65 for ouabain and 740.67 for MLB).…”

Section: Introductionmentioning

confidence: 99%

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Active ingredients in Chinese medicines promoting blood circulation as Na+/K+-ATPase inhibitors

Chen¹,

Jinn

Chen³

et al. 2011

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The positive inotropic effect of cardiac glycosides lies in their reversible inhibition on the membrane-bound Na + /K + -ATPase in human myocardium. Steroid-like compounds containing a core structure similar to cardiac glycosides are found in many Chinese medicines conventionally used for promoting blood circulation. Some of them are demonstrated to be Na + /K + -ATPase inhibitors and thus putatively responsible for their therapeutic effects via the same molecular mechanism as cardiac glycosides. On the other hand, magnesium lithospermate B of danshen is also proposed to exert its cardiac therapeutic effect by effectively inhibiting Na + /K + -ATPase. Theoretical modeling suggests that the number of hydrogen bonds and the strength of hydrophobic interaction between the effective ingredients of various medicines and residues around the binding pocket of Na + /K + -ATPase are crucial for the inhibitory potency of these active ingredients. Ginsenosides, the active ingredients in ginseng and sanqi, substantially inhibit Na + /K + -ATPase when sugar moieties are attached only to the C-3 position of their steroid-like structure, equivalent to the sugar position in cardiac glycosides. Their inhibitory potency is abolished, however, when sugar moieties are linked to C-6 or C-20 position of the steroid nucleus; presumably, these sugar attachments lead to steric hindrance for the entrance of ginsenosides into the binding pocket of Na + /K + -ATPase. Neuroprotective effects of cardiac glycosides, several steroid-like compounds, and magnesium lithospermate B against ischemic stroke have been accordingly observed in a cortical brain slice-based assay model, and cumulative data support that effective inhibitors of Na + /K + -ATPase in the brain could be potential drugs for the treatment of ischemic stroke.

“…Recently several compounds showing inhibitory potency on Na + ,K + -ATPase, such as cardiac glycosides, ginsenosides, and magnesium lithospermate B (the major water soluble ingredient in the dried roots of medicinal plant Salvia miltiorrhiza), were demonstrated to provide neuroprotection against ischemic stroke in a cortical brain slicebased compound screening platform [6,37,38] . Similarly, oleanolic acid, showing inhibitory potency on Na + ,K + -ATPase in this study, has also been demonstrated to display neuroprotective effect against focal cerebral ischemic injury [39] .…”

Section: Discussionmentioning

confidence: 99%

Steroid-like compounds in Chinese medicines promote blood circulation via inhibition of Na+/K+-ATPase

Chen¹,

Chung²,

et al. 2010

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Aim: To examine if steroid-like compounds found in many Chinese medicinal products conventionally used for the promotion of blood circulation may act as active components via the same molecular mechanism triggered by cardiac glycosides, such as ouabain. Methods: The inhibitory potency of ouabain and the identified steroid-like compounds on Na + /K + -ATPase activity was examined and compared. Molecular modeling was exhibited for the docking of these compounds to Na + /K + -ATPase. Results: All the examined steroid-like compounds displayed more or less inhibition on Na + /K + -ATPase, with bufalin (structurally almost equivalent to ouabain) exhibiting significantly higher inhibitory potency than the others. In the pentacyclic triterpenoids examined, ursolic acid and oleanolic acid were moderate inhibitors of Na + /K + -ATPase, and their inhibitory potency was comparable to that of ginsenoside Rh2. The relatively high inhibitory potency of ursolic acid or oleanolic acid was due to the formation of a hydrogen bond between its carboxyl group and the Ile322 residue in the deep cavity close to two K + binding sites of Na + /K + -ATPase. Moreover, the drastic difference observed in the inhibitory potency of ouabain, bufalin, ginsenoside Rh2, and pentacyclic triterpenoids is ascribed mainly to the number of hydrogen bonds and partially to the strength of hydrophobic interaction between the compounds and residues around the deep cavity of Na + /K + -ATPase. Conclusion: Steroid-like compounds seem to contribute to therapeutic effects of many cardioactive Chinese medicinal products. Chinese herbs, such as Prunella vulgaris L, rich in ursolic acid, oleanolic acid and their glycoside derivatives may be adequate sources for cardiac therapy via effective inhibition on Na + /K + -ATPase.