Ruan Lingyu, Li Guanghui, Zhao Wenlong, Meng Huihui, Zheng Qi, Wang Junsong
Center for Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing 210094, China.
Antioxidants (Basel). 2021 Jul 12;10(7):1112. doi: 10.3390/antiox10071112.
Ischemic stroke is the main cause of death/disability, posing a great menace to human health. Though efforts to search for therapeutic drugs are ongoing, few of them have succeeded. Adenosine A receptor (A1R) activation could ameliorate ischemic injury, representing a very tempting target for stroke treatment. Tetrahydroxy stilbene glycoside (TSG), a potent antioxidant from the well-known Chinese herb Thunb., has been reported to have notable neuroprotective activities but the underlying mechanisms are elusive. This study investigated the mechanism of TSG focusing on A1R. TSG markedly decreased mortality, neurological deficit score, cerebral infarct size and brain water content of MCAO rats, and ameliorated the disorders in purine metabolism, energy metabolism and antioxidative defense system. TSG helped the survival of SH-SY5Y cells in OGD/R by alleviating oxidative stress and glutamate release, and by maintaining calcium homeostasis. TSG effects were abolished by A1R antagonist DPCPX. Docking and binding assays confirmed the binding of TSG with A1R. In addition, TSG upregulated the A1R level lowered by MCAO and OGD/R. The downstream signals of A1R activation, ERK1/2, HIF-1α and NF-κB contributed to the neuroprotection of TSG. Moreover, void of "well-known" cardiovascular side effects of classical A1R agonists, TSG showcased its great potential for stroke treatment.
缺血性中风是导致死亡/残疾的主要原因，对人类健康构成巨大威胁。尽管一直在努力寻找治疗药物，但成功的却寥寥无几。腺苷A受体（A1R）激活可减轻缺血性损伤，是一个极具吸引力的中风治疗靶点。四羟基芪糖苷（TSG）是一种从著名中药何首乌中提取的强效抗氧化剂，据报道具有显著的神经保护活性，但其潜在机制尚不清楚。本研究以A1R为重点，探讨了TSG的作用机制。TSG显著降低了MCAO大鼠的死亡率、神经功能缺损评分、脑梗死体积和脑含水量，并改善了嘌呤代谢、能量代谢和抗氧化防御系统的紊乱。TSG通过减轻氧化应激和谷氨酸释放以及维持钙稳态，帮助SH-SY5Y细胞在OGD/R中存活。A1R拮抗剂DPCPX消除了TSG的作用。对接和结合试验证实了TSG与A1R的结合。此外，TSG上调了MCAO和OGD/R降低的A1R水平。A1R激活的下游信号ERK1/2、HIF-1α和NF-κB对TSG的神经保护作用有贡献。此外，TSG没有经典A1R激动剂“众所周知”的心血管副作用，显示出其在中风治疗方面的巨大潜力。
