Ding Ai-Jun, Wu Gui-Sheng, Tang Bin, Hong Xuechuan, Zhu Michael X, Luo Huai-Rong
State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China.
University of Chinese Academy of Sciences, Beijing, 100039, China.
Mol Cell Biochem. 2017 Feb;426(1-2):101-109. doi: 10.1007/s11010-016-2884-x. Epub 2016 Nov 16.
With the growth of aging population, there is increasing demand to develop strategy to improve the aging process and aging-related diseases. Benzimidazole and its derivatives are crucial heterocyclic backbone of many drugs and compounds with diverse therapeutic applications, including alleviation of aging-related diseases. Here, we investigate if the benzimidazole derivative n-butyl-[1H]-benzimidazol-2-amine (M084), a novel inhibitor of TRPC4 and TRPC5 channels and antidepressant, could affect the lifespan of Caenorhabditis elegans (C. elegans). Our results showed that M084 could extend the lifespan of C. elegans, delay age-related decline of phenotypes, and improve stress resistance. M084 could not extend the lifespan of the loss-of-function mutants of daf-16, daf-2, pdk-1, aak-2, clk-1, isp-1, sir-2.1, and skn-1. M084 could decrease the ATP level and increase the gene expression of mitochondrial unfolded protein response factors. Thus, M084 might inhibit the mitochondrial respiration, activate mitochondrial unfolded protein response and AMPK, recruite SIR-2.1 and SKN-1, and finally through the transcription factor DAF-16, delay the aging process of C. elegans. Our findings reveal the new pharmaceutical potential of benzimidazole derivatives and provide clue for developing novel anti-aging agents.
随着老龄化人口的增长，开发改善衰老过程和与衰老相关疾病的策略的需求日益增加。苯并咪唑及其衍生物是许多具有不同治疗应用的药物和化合物的关键杂环骨架，包括缓解与衰老相关的疾病。在此，我们研究苯并咪唑衍生物正丁基-[1H]-苯并咪唑-2-胺（M084），一种新型的瞬时受体电位阳离子通道4（TRPC4）和瞬时受体电位阳离子通道5（TRPC5）通道抑制剂及抗抑郁药，是否会影响秀丽隐杆线虫（线虫）的寿命。我们的结果表明，M084可以延长线虫的寿命，延缓与年龄相关的表型衰退，并提高抗应激能力。M084不能延长daf-16、daf-2、pdk-1、aak-2、clk-1、isp-1、sir-2.1和skn-1功能缺失突变体的寿命。M084可以降低ATP水平并增加线粒体未折叠蛋白反应因子的基因表达。因此，M084可能抑制线粒体呼吸，激活线粒体未折叠蛋白反应和AMPK，募集SIR-2.1和SKN-1，最终通过转录因子DAF-16延缓线虫的衰老过程。我们的研究结果揭示了苯并咪唑衍生物的新药物潜力，并为开发新型抗衰老药物提供了线索。
