Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
CNS Neurol Disord Drug Targets. 2018;17(5):370-382. doi: 10.2174/1871527317666180502110205.
Hydroxysafflor yellow A (HSYA) was reported to suppress inflammation in ischaemic microglia. However, the mechanism through which HSYA inhibits inflammation caused by cerebral ischaemia and reperfusion injury remains unknown. Here, we have mimicked acute cerebral ischaemia and reperfusion injury by subjecting male Sprague-Dawley rats to transient middle cerebral artery occlusion for 90 minutes and have demonstrated that toll-like receptor 9 (TLR9) was upregulated from day 3 after reperfusion, accompanied by the persistent activation of the pro-inflammatory nuclear factor-κB (NF-κB) pathway from 6 hours to day 7. HSYA was injected intraperitoneally at a dose of 6 mg/kg per day, which activated TLR9 in microglia of ischaemic cortex at 6 hours after reperfusion and then obviously suppressed the NF-κB pathway from day 1 to day 7. Meanwhile, HSYA also activated the anti-inflammatory pathway through interferon regulatory factor 3 from day 1 to day 3. The anti-inflammatory effect of HSYA was partially reversed by TLR9-siRNA interference in primary microglia, which was stimulated by oxygen-glucose deprivation and reoxygenation treatment. The regulation of TLR9-mediated inflammation by HSYA was consistent with the recovery of neurological deficits in rats.
Therefore, our findings support that HSYA exerts anti-inflammatory effects by reprogramming the TLR9 signalling pathway during treatment of acute cerebral ischaemia and reperfusion injury.
羟基红花黄色素 A（HSYA）被报道可抑制缺血性小胶质细胞炎症。然而，HSYA 抑制脑缺血再灌注损伤引起的炎症的机制尚不清楚。在这里，我们通过对雄性 Sprague-Dawley 大鼠进行短暂性大脑中动脉闭塞 90 分钟来模拟急性脑缺血再灌注损伤，结果表明 TLR9 从再灌注后第 3 天开始上调，并伴随着促炎核因子-κB（NF-κB）通路从 6 小时到第 7 天的持续激活。HSYA 以 6 毫克/千克/天的剂量腹腔注射，可在再灌注后 6 小时激活缺血皮质的小胶质细胞中的 TLR9，然后从第 1 天到第 7 天明显抑制 NF-κB 通路。同时，HSYA 还通过干扰素调节因子 3从第 1 天到第 3 天激活抗炎通路。在原代小胶质细胞中，通过 TLR9-siRNA 干扰部分逆转了 HSYA 的抗炎作用，该作用是由氧葡萄糖剥夺和再氧合处理刺激的。HSYA 对 TLR9 介导的炎症的调节与大鼠神经功能缺损的恢复一致。
因此，我们的研究结果支持 HSYA 通过在急性脑缺血再灌注损伤治疗过程中重新编程 TLR9 信号通路发挥抗炎作用。
