1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University , Nanjing, P.R. China .
2 Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , Nanjing, P.R. China .
Antioxid Redox Signal. 2018 Jan 10;28(2):141-163. doi: 10.1089/ars.2017.7003. Epub 2017 Aug 29.
Microglia-mediated neuroinflammation plays an important role in focal ischemic stroke, a disorder with no effective therapeutic agents. Since microglial polarization to the M2 phenotype and reduction of oxidative stress are mediated through AMP-activated protein kinase (AMPK) and nuclear factor erythroid 2-related factor 2 (Nrf2) activation, we assessed the dual therapeutic effect of AMPK and Nrf2 activation by a novel neuroprotectant HP-1c in the treatment of ischemic stroke.
We developed a novel class of hybrids (HP-1a-HP-1f) of telmisartan and 2-(1-hydroxypentyl)-benzoate (HPBA) as a ring-opening derivative of NBP. The most promising hybrid, HP-1c, exhibited more potent anti-inflammatory and neuroprotective effects in vitro and reduced brain infarct volume and improved neurological deficits in a rat model of transient focal cerebral ischemia when compared with telmisartan alone, NBP alone, or a combination of telmisartan and NBP. HP-1c had a therapeutic window of up to 24 h, ameliorated ischemic cerebral injury in permanent focal cerebral ischemia, and improved motor function. The beneficial effects of HP-1c in ischemic stroke were associated with microglial polarization to the M2 phenotype and reduced oxidative stress. HP-1c also shifted the M1/M2 polarization in a mouse neuroinflammatory model. The anti-inflammatory and anti-oxidative effects of HP-1c were associated with AMPK-Nrf2 pathway activation for neuroprotection. We showed that HP-1c penetrates the brain, has a plasma half-life of around 3.93 h, and has no toxicity in mice. Innovation and Conclusion: Our study results suggest that HP-1c, with dual AMPK- and Nrf2-activating properties, may have potential in further studies as a novel therapy for ischemic stroke. Antioxid. Redox Signal. 28, 141-163.
小胶质细胞介导的神经炎症在局灶性缺血性中风中起重要作用，这种疾病目前尚无有效的治疗药物。由于小胶质细胞向 M2 表型极化和氧化应激的减少是通过 AMP 激活的蛋白激酶（AMPK）和核因子红细胞 2 相关因子 2（Nrf2）的激活来介导的，因此我们评估了新型神经保护剂 HP-1c 通过 AMPK 和 Nrf2 激活的双重治疗作用，以治疗缺血性中风。
我们开发了一类新的替米沙坦和 2-（1-羟戊基）苯甲酸（HPBA）的杂合体（HP-1a-HP-1f）作为 NBP 的开环衍生物。最有前途的杂合体 HP-1c 与替米沙坦、NBP 或替米沙坦和 NBP 联合应用相比，在体外具有更强的抗炎和神经保护作用，减少了大鼠短暂性局灶性脑缺血模型的脑梗死体积，改善了神经功能缺损。HP-1c 的治疗窗口长达 24 小时，改善了永久性局灶性脑缺血引起的缺血性脑损伤，并改善了运动功能。HP-1c 在缺血性中风中的有益作用与小胶质细胞向 M2 表型极化和减少氧化应激有关。HP-1c 还改变了小鼠神经炎症模型中的 M1/M2 极化。HP-1c 的抗炎和抗氧化作用与 AMPK-Nrf2 通路的激活有关。我们表明 HP-1c 可以穿透大脑，具有约 3.93 小时的血浆半衰期，并且在小鼠中没有毒性。创新和结论：我们的研究结果表明，HP-1c 具有双重 AMPK 和 Nrf2 激活特性，作为缺血性中风的新型治疗药物，可能具有进一步研究的潜力。抗氧化剂。氧化还原信号。28，141-163。
