Cycloastragenol upregulates SIRT1 expression, attenuates apoptosis and suppresses neuroinflammation after brain ischemia

Authors: Man Li1,2, Shi-chun Li1,2, Bao-kai Dou1,2, Ying-xiang Zou1,2, Hao-zhen Han3,4, Dong-xiang Liu3,4, Zun-ji Ke2, Zhi-fei Wang1,2
1 School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
2 Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
3 Department of Pharmacology III, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
4 University of Chinese Academy of Sciences, Beijing 100049, China
Correspondence to: Zhi-fei Wang:,
DOI: 10.1038/s41401-020-0386-6
Received: 9 November 2019
Accepted: 19 February 2020
Advance online: 16 March 2020


Cycloastragenol (CAG) is the active form of astragaloside IV isolated from Astragalus Radix, which displays multiple pharmacological effects. Silent information regulator 1 (SIRT1), a class III histone deacetylase, has been shown to play an important role in neuroprotection against cerebral ischemia. In this study, we investigated whether CAG protected against ischemic brain injury and, if so, whether the beneficial effects were associated with the regulation of SIRT1 in the ischemic brain. Mice were subjected to 45 min of middle cerebral artery occlusion (MCAO) followed by reperfusion. CAG (5, 10, 20 mg/kg) was injected intraperitoneally at the onset of reperfusion, 12 h later and then twice daily for up to three days. CAG dose-dependently reduced brain infarct volume, significantly ameliorated functional deficits, and prevented neuronal cell loss in MCAO mice. Meanwhile, CAG significantly reduced matrix metalloproteinase-9 activity, prevented tight junction degradation and subsequently ameliorated blood-brain barrier disruption. Moreover, CAG significantly upregulated SIRT1 expression in the ischemic brain but did not directly activate its enzymatic activity. Concomitant with SIRT1 upregulation, CAG reduced p53 acetylation and the ratio of Bax to Bcl-2 in the ischemic brain. CAG also inhibited NF-κB p65 nuclear translocation. As a result, CAG suppressed the mRNA expression of pro-inflammatory cytokines, including TNF-α and IL-1β, and inhibited the activation of microglia and astrocytes in the ischemic brain. Our findings suggest that CAG is neuroprotective against ischemic brain injury in mice and that its beneficial effect may involve SIRT1 upregulation and the inhibition of apoptosis and neuroinflammation in the ischemic brain.
Keywords: cycloastragenol; SIRT1; apoptosis; neuroinflammation; cerebral ischemia

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