抗氧化是脑缺血再灌注损伤（CIRI）治疗的有效途径。现有抗氧化剂多为单抗氧化剂，因仅清除活性氧（ROS）或仅激活抗氧化通路而疗效有待提高。我们前期设计、筛选得到一个脑室给药后疗效明显优于单抗氧化剂的双抗氧化剂3a，表明“双抗氧化剂”具有更好的抗氧化活性和CIRI保护效果，但3a血脑屏障通透性差制约了其成药。基于此，设计优化得到活性更佳、通透性好的A11，腹腔给药后，其疗效优于依达拉奉；进一步免疫印迹和RNA测序分析表明其可能通过上调Nlrp12，激活p21/Nrf2通路。据此假设：A11基于直接及激活Nlrp12/p21/Nrf2信号轴间接清除ROS的双抗氧化机制，起到良好CIRI治疗作用。本项目拟通过双氧水、糖氧剥夺等模型确证A11的体外抗氧化活性；通过高表达、沉默等手段阐明其体外抗氧化机制；通过MCAO模型确证疗效并阐明体内机制。本项目将为CIRI的抗氧化剂研究提供新的策略和候选新药。

Antioxidation is an effective way to treat cerebral ischemia reperfusion injury (CIRI). Most of antioxidants are mono-mechanism antioxidants, and their efficacy needs to be improved because they only scavenge reactive oxygen species (ROS) or only activate antioxidant pathways. We have designed and screened in the early stage to obtain a double-mechanism antioxidant 3a that is significantly better than mono-mechanism antioxidants in intraventricular administration, indicating that "double-mechanism antioxidants" have better antioxidant activity and CIRI protective effect. But the poor permeability of the blood-brain barrier of 3a restricted the proprietary drug. Based on this, the design is optimized to obtain A11 with better activity and better permeability, its efficacy is better than edaravone after intraperitoneal administration. Furthermore, Western Blot and RNA sequencing analysis show that it may activate p21/Nrf2 pathway by up-regulating Nlrp12. Accordingly, we hypothesis: A11 with novel dual-antioxidant mechanism of directly scavenging ROS and indirectly through activating the Nlrp12/p21/Nrf2 signaling plays a good role in the treatment of CIRI. This project intends to confirm the in vitro antioxidant activity of A11 through models such as hydrogen peroxide and sugar-oxygen deprivation; to elucidate its in vitro antioxidant mechanism through high expression and silencing experiment; to confirm the efficacy and elucidate the in vivo mechanism through MCAO model. This project will provide new strategies and candidate drugs for CIRI's antioxidant research.