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.

环雌三醇（CAG）是从黄芪中分离出的黄芪甲苷IV的活性形式，具有多种药理作用。沉默信息调节剂1（SIRT1）是III类组蛋白脱乙酰基酶，已显示在针对脑缺血的神经保护中起重要作用。在这项研究中，我们调查了CAG是否能预防缺血性脑损伤，如果是，则其有益作用是否与缺血性脑SIRT1的调节有关。对小鼠进行45分钟的大脑中动脉闭塞（MCAO），然后再灌注。在再灌注开始时，腹膜内注射CAG（5、10、20 mg / kg），在12小时后，然后每天两次，最多三天。CAG剂量依赖性地减少了MCAO小鼠的脑梗塞体积，显着改善了功能缺陷，并防止了神经元细胞的丢失。同时，CAG会显着降低基质金属蛋白酶9活性，防止了紧密连接的退化，并改善了血脑屏障的破坏。此外，CAG显着上调缺血性脑中SIRT1的表达，但没有直接激活其酶促活性。与SIRT1上调同时，CAG降低了缺血性脑中p53的乙酰化作用以及Bax与Bcl-2的比率。CAG还抑制NF-κBp65核移位。结果，CAG抑制了促炎性细胞因子包括TNF-α和IL-1β的mRNA表达，并抑制了缺血性脑中小胶质细胞和星形胶质细胞的活化。我们的发现表明，CAG对小鼠缺血性脑损伤具有神经保护作用，其有益作用可能涉及SIRT1上调以及对缺血性脑中细胞凋亡和神经炎症的抑制作用。