Astragaloside IV: mechanism of action, pharmacokinetics and toxicity

General Description

Astragaloside IV, a compound found in radix astragalus, has various protective effects on heart failure (HF). It improves myocardial contraction, protects myocardial cells, inhibits left ventricular remodeling, and regulates the neuro-endocrinal system. Astragaloside IV protects against myocardial ischemia by enhancing cardiac function, reducing infarct size, and suppressing inflammation and apoptosis. It also restores calcium balance, improves calcium pumps activity, and regulates sarcoplasmic reticulum (SR) Ca2+ pump function. Astragaloside IV down-regulates the calcium-sensing receptor pathway and enhances SERCA2α activity, improving cardiac diastole. Pharmacokinetically, it has limited absorption and bioavailability, is widely distributed in tissues, and undergoes elimination through urine and feces. Astragaloside IV exhibits little toxicity, but caution is advised during pregnancy due to observed maternal toxicity at high doses. Further studies are needed to fully understand its risks and benefits.

Figure 1. Astragaloside IV

Mechanism of action

Astragaloside IV is a compound found in radix astragalus with various protective effects on heart failure (HF). It has been shown to improve myocardial contraction, protect myocardial cells, regulate the neuro-endocrinal system, and inhibit left ventricular remodeling. Astragaloside IV has demonstrated efficacy in different HF models of rodents. One of the key mechanisms of Astragaloside IV is its ability to protect against myocardial ischemia. In animal models of acute myocardial infarction (AMI), Astragaloside IV has been found to enhance cardiac function, decrease infarct size, and alleviate myocardial collagen deposition. It also suppresses inflammatory responses and reduces apoptosis, leading to improved myocardial ultrastructure. Additionally, Astragaloside IV exhibits calcium antagonistic effects, which help restore calcium balance and improve myocardial calcium pumps activity, ultimately reducing calcium-induced secondary injury. Astragaloside IV has also shown to regulate sarcoplasmic reticulum (SR) Ca2+ pump function. In HF, the function of SERCA2α, a protein responsible for pumping calcium into the SR, is down-regulated. Astragaloside IV treatment has been found to prevent the decrease in SERCA2α activity and phospholamban expression in acute HF models. It also targets the calcium-sensing receptor (CaSR) pathway, which regulates phospholamban and SERCA2α. Astragaloside IV down-regulates CaSR and PKC-α, reduces phospholamban dephosphorylation, enhances SERCA2α activity, and improves cardiac diastole. In summary, Astragaloside IV protects against myocardial ischemia and regulates SR Ca2+ pump function, thereby improving cardiac function and reducing myocardial damage. These mechanisms contribute to the beneficial effects of Astragaloside IV in the treatment of HF. ¹

Pharmacokinetics

Astragaloside IV, a special saponin, has low absorption and bioavailability due to its large molecular weight and poor solubility. It shows low permeability through Caco-2 cells and its poor absorption is not due to P-glycoprotein action. The absolute bioavailability after oral administration is very low, around 2.2% to 7.4%. Astragaloside IV is widely distributed in tissues, with high concentrations in the liver and kidney, followed by the lung, heart, and spleen. It has limited penetration of the blood-brain barrier. A significant portion of Astragaloside IV binds to plasma proteins and is eliminated through urine and feces. It exhibits linear pharmacokinetic features in rats, with a relatively short elimination half-life. Astragaloside IV undergoes little metabolism in the liver, indicating a lack of first-pass elimination. ²

Toxicity

Astragaloside IV has shown no significant toxicity or adverse reactions. Oral administration of Astragaloside IV at a dose of 10 mg/kg/d for consecutive 14 weeks did not have any detrimental effects on liver and renal function. This suggests that Astragaloside IV is safe for long-term use in these aspects. However, it should be noted that maternal toxicity of Astragaloside IV has been observed to be dose-dependent. In rats receiving doses ranging from 0.25 to 1.0 mg/kg, no maternal toxicity was observed. However, at the dose of 1.0 mg/kg/d, significant maternal toxicity was manifested, leading to delays in fur development, eye opening, and cliff parry reflex of the pups. Therefore, caution should be exercised when pregnant women consider using Astragaloside IV to treat cardiovascular diseases, as high doses may have adverse effects on maternal health and the development of offspring. In conclusion, Astragaloside IV has generally demonstrated a favorable safety profile with no apparent toxicity or adverse reactions, particularly in relation to liver and renal function. However, caution should be taken regarding its use during pregnancy, considering the observed maternal toxicity at higher doses. Further studies are necessary to fully understand the potential risks and benefits of Astragaloside IV in specific populations. ³

Reference

1. Zang Y, Wan J, Zhang Z, Huang S, Liu X, Zhang W. An updated role of astragaloside IV in heart failure. Biomed Pharmacother. 2020 Jun;126:110012.

2. Zhang WD, Zhang C, Liu RH, Li HL, Zhang JT, Mao C, Moran S, Chen CL. Preclinical pharmacokinetics and tissue distribution of a natural cardioprotective agent astragaloside IV in rats and dogs. Life Sci. 2006 Jul 17;79(8):808-815.

3. Yu SY, Ouyang HT, Yang JY, Huang XL, Yang T, Duan JP, Cheng JP, Chen YX, Yang YJ, Qiong P. Subchronic toxicity studies of Radix Astragali extract in rats and dogs. J Ethnopharmacol. 2007 Mar 21;110(2):352-355.