Eleutheroside B: A Promising Compound with Cardiac and Neuroprotective Effects

Eleutheroside B (EB) is the main active constituent derived from the Chinese herb Acanthopanax senticosus (AS) that has been reported to possess cardioprotective effects. In this study we investigated the effects of EB on cardiac electrophysiology and its suppression on atrial fibrillation (AF).

Eleutheroside B, a selective late sodium current inhibitor

Eleutheroside B (EB, also called syringin), which is the main bioactive constituent derived from the dietetic herb Acanthopanax senticosus (AS) known as Siberian ginseng, is used to treat a variety of diseases in traditional Chinese medicine. Eleutheroside B has been widely reported to possess various pharmacological activities, including antifatigue, anticancer, anti-inflammatory, antiirradiation , and antidiabetic activities. Moreover, Eleutheroside B also has immunomodulatory actions and neuroprotective effects. In addition to the effects mentioned above, accumulating research has shown that EB exerts cardioprotective functions, such as defending cardiomyocytes against oxidative stress injury and myocardial structural changes, including myocardial hypertrophy. Eleutheroside B has also been demonstrated to protect against arrhythmia caused by myocardial ischemia/reperfusion in rats, but its antiarrhythmic mechanism has not been clarified. As far as we know, arrhythmogenesis is mainly due to abnormal electrical activity, which has been determined by multiple transmembrane ionic channel currents. Studies on ionic channel currents are distinctly of great significance in expounding the mechanisms of arrhythmogenesis and the action of antiarrhythmic drugs. However, thus far, no relative study is available on the effects of EB on cardiac ion channels.[1]

Eleutheroside B originates from the traditional tonic herb Ciwujia with efficacy for good health and is used extensively in China, Russia, Korea. and Japan. However, the effects of EB on ion channels in atrial myocytes remain unclear. Our study was the first to elaborate this issue and investigate its potential anti-AF mechanisms. The key findings of this study showed that EB preferentially inhibited INaL far beyond the INaT, while EB had no inhibitory effects on ICaL, IK, or AP. In addition, EB concentration-dependently inhibited ATX II-increased INaL in atrial myocytes. In contrast, Eleutheroside B allowed ICaL and IK to remain unaffected at a high concentration (800 μM). In particular, no significant inhibition from Eleutheroside B on IK avoids the accompanying proarrhythmic effects due to IK-prolonged APD and improves its safety for drug use. These results indicate that EB has the potential to become a more effective and specific INaL inhibitor. At present, EB has not yet been available as a drug in clinical usage, and thus, studies on the variety pharmacological actions of EB have mainly focused on animal models and human cells. A previous study showed that EB (100 mg/kg, i.p.) possesses hepatoprotective effects and improves the survival rates of mice with hepatic failure. Furthermore, Eleutheroside B is the main bioactive ingredient of Ciwujia, serving as one of the most popular herbal dietary supplements used over the years in America and England. Taken together, EB has shown the characteristics of low toxicity, high safety, low adverse effects and good tolerance. Last but not least, the biggest highlight of our study is that we are the first to discover that EB has a selective inhibitory effect on INaL rather than the other ion channels in atrial myocytes and this study illuminates the underlying mechanisms of EB on anti-AF actions.

Eleutheroside B alleviates oxidative stress and neuroinflammation

In the pursuit of effective treatment strategies for high altitude diseases, particularly HACE, traditional Chinese medicine has gained increasing recognition within the scientific community. Eleutherococcus senticosus, also named as Ciwujia, is a dual-purpose herbal medicine in the Aracanaceae family that can be used for both food and medicine. It has been traditionally utilized in TCM for its abilities to combat fatigue and improve memory. Modern pharmacological studies further validates the significant neuroprotective, anti-inflammatory, and anti-oxidant properties of Eleutherococcus senticosus. Eleutheroside B (EB), a key component of Eleutherococcus senticosus, exhibits noteworthy pharmacological effects including anti-oxidation, anti-fatigue and neuroprotection. Our previous study have shown that Eleutheroside B against HACE were associated with the inhibition of ferroptosis and necroptosis through Nrf2-antioxidant response signaling, inhibiting the progression of acute mountain sickness. To test this hypothesis, a rat model of HACE was established and the therapeutic effects of Eleutheroside B were evaluated through measurements of brain water content, histopathological observation, assessment of oxidative stress and inflammation factors. Additionally, molecular docking, molecular dynamics simulation, and Western blotting were employed to elucidate its molecular mechanism, thereby providing novel scientific evidence and potential therapeutic targets for HACE prevention and treatment. This study not only holds significant scientific value, but contributes positively to the advancement of plateau medicine.[2]

This research has examined the significant impact of EB in reducing high-altitude cerebral edema, showing its positive effects in decreasing oxidative stress and neuroinflammation. These results indicate that Eleutheroside B may effectively protect rats from HACE by regulating the JAK2/STAT3 signaling pathway. This regulation mechanism effectively reduces oxidative stress and neuroinflammation caused by hypoxia at high altitudes, thus alleviating symptoms of HACE. The additional experimental results further support the dual anti-inflammatory and anti-oxidative effects of Eleutheroside B, a natural compound, highlighting its potential significance in addressing inflammatory and oxidative stress issues associated with high altitude hypoxia. These findings not only provide a scientific basis for using Eleutheroside B to treat high altitude cerebral edema but also offer new insights and opportunities for developing natural pharmaceuticals in the future.

References

[1]Zhang, Pp., Guo, Zf., Zhang, Ph. et al. Eleutheroside B, a selective late sodium current inhibitor, suppresses atrial fibrillation induced by sea anemone toxin II in rabbit hearts. Acta Pharmacol Sin 42, 209–217 (2021).

[2]He, Yacong et al. “Eleutheroside B alleviates oxidative stress and neuroinflammation by inhibiting the JAK2/STAT3 signaling pathway in a rat high altitude cerebral edema model.” Frontiers in pharmacology vol. 15 1506483. 15 Nov. 2024, doi:10.3389/fphar.2024.1506483