Pharmacological Effects of Cycloastragenol

Cycloastragenol (CAG), an aglycone of astragaloside IV, is a triterpenoid saponin compound and a hydrolysis product of the main active ingredient in Astragalus membranaceus. An increasing body of evidence has indicated that CAG has a wide spectrum of pharmacological functions, which are attracting attention in the research community. Extensive pharmacological effects have been attributed to CAG, including telomerase activation, telomere elongation, anti‑inflammatory and anti-oxidative properties. Studies demonstrates that CAG stimulates telomerase activity and cell proliferation in human neonatal keratinocytes.

In particular, CAG promotes scratch wound closure of human neonatal keratinocyte monolayers in vitro. The distinct telomerase-activating property of CAG prompted evaluation of its potential application in the treatment of neurological disorders. Accordingly, Cycloastragenol induced telomerase activity and cAMP response element binding (CREB) activation in PC12 cells and primary neurons. Blockade of CREB expression in neuronal cells by RNA interference reduced basal telomerase activity, and CAG was no longer efficacious in increasing telomerase activity. CAG treatment not only induced the expression of bcl2, a CREB-regulated gene, but also the expression of telomerase reverse transcriptase in primary cortical neurons. Interestingly, oral administration of CAG for 7 days attenuated depression-like behavior in experimental mice. In conclusion, Cycloastragenol stimulates telomerase activity in human neonatal keratinocytes and rat neuronal cells, and induces CREB activation followed by tert and bcl2 expression. Furthermore, CAG may have a novel therapeutic role in depression.

Research declared that CAG significantly downregulated both CD69 and CD25 expressed on Con A activated CD3+ T cells' surface, as well as inhibiting proliferation of activated lymphocytes. In addition, CAG blocked the Con A-induced mitogenesis, exhibiting lymphocyte G0/G1-phase cell-cycle arrest with significant reduction of cells in S and G2/M phases. Meanwhile, pretreated by Cycloastragenol, a significant decline in [Ca2+]i was observed. Furthermore, CAG significantly inhibited the production of Th1 cytokines IFN-γ, TNF, IL-2, Th2 cytokines IL-4, IL-6, IL-10 and Th17 cytokine IL-17 A on Con A-activated lymphocytes. The result reinforce that CAG has important anti-inflammatory activity by inhibiting lymphocytes activation, proliferation and cytokines expression, and shows, that this effect may be related to reduction of overall intracellular Ca2+ overload.

CAG has also been reported to improve lipid metabolism. Clinical research has demonstrated that CAG activates telomerase in humans and ameliorates various biomarkers. Cycloastragenol is absorbed through the intestinal epithelium via passive diffusion and undergoes first-pass hepatic metabolism. 

Within a certain dose range, oral Cycloastragenol is relatively safe. However, underlying mechanisms associated with CAG are not clear, and thus, people should be aware of potential adverse reactions associated with CAG. According to existing studies and clinical trials, CAG is safe and has broad application prospects. 

References

[1]. Ip FC, et al. Cycloastragenol is a potent telomerase activator in neuronal cells: implications for depression management. Neurosignals. 2014;22(1):52-63.
[2]. Yu Y, et al. Cycloastragenol: An exciting novel candidate for age-associated diseases. Exp Ther Med. 2018 Sep;16(3):2175-2182.
[3]. Sun C, et al. Cycloastragenol mediates activation and proliferation suppression in concanavalin A-induced mouse lymphocyte pan-activation model. Immunopharmacol Immunotoxicol. 2017 Jun;39(3):131-139.

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