Cheng Ruiying, Gadde Rajitha, Fan Yingfang, Kulkarni Neha, Shevale Nachiket, Bao Kai, Choi Hak Soo, Betharia Swati, Kim Jonghan
Department of Biomedical and Nutritional Sciences, University of Massachusetts Lowell, Lowell, MA, USA.
Department of Pharmaceutical Sciences, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA.
Arch Toxicol. 2022 Jul;96(7):1951-1962. doi: 10.1007/s00204-022-03287-1. Epub 2022 Apr 21.
N,N'-bis(2-mercaptoethyl)isophthalamide (NBMI) is a novel lipophilic metal chelator and antioxidant used in mercury poisoning. Recent studies have suggested that NBMI may also bind to other metals such as lead and iron. Since NBMI can enter the brain, we evaluated if NBMI removes excess iron from the iron-loaded brain and ameliorates iron-induced oxidative stress. First, NBMI exhibited preferential binding to ferrous (Fe) iron with a negligible binding affinity to ferric (Fe) iron, indicating a selective chelation of labile iron. Second, NBMI protected SH-SY5Y human neuroblastoma cells from the cytotoxic effects of high iron. NBMI also decreased cellular labile iron and lessened the production of iron-induced reactive oxygen species in these cells. Deferiprone (DFP), a commonly used oral iron chelator, failed to prevent iron-induced cytotoxicity or labile iron accumulation. Next, we validated the efficacy of NBMI in Hfe H67D mutant mice, a mouse model of brain iron accumulation (BIA). Oral gavage of NBMI for 6 weeks decreased iron accumulation in the brain as well as liver, whereas DFP showed iron chelation only in the liver, but not in the brain. Notably, depletion of brain copper and anemia were observed in BIA mice treated with DFP, but not with NBMI, suggesting a superior safety profile of NBMI over DFP for long-term use. Collectively, our study demonstrates that NBMI provides a neuroprotective effect against BIA and has therapeutic potential for neurodegenerative diseases associated with BIA.
N,N'-双(2-巯基乙基)间苯二甲酰胺（NBMI）是一种用于汞中毒治疗的新型亲脂性金属螯合剂和抗氧化剂。最近的研究表明，NBMI也可能与其他金属如铅和铁结合。由于NBMI能够进入大脑，我们评估了NBMI是否能从铁过载的大脑中清除过量铁，并减轻铁诱导的氧化应激。首先，NBMI对亚铁（Fe²⁺）表现出优先结合，而对铁离子（Fe³⁺）的结合亲和力可忽略不计，这表明其对不稳定铁具有选择性螯合作用。其次，NBMI保护SH-SY5Y人神经母细胞瘤细胞免受高铁的细胞毒性作用。NBMI还降低了细胞内的不稳定铁水平，并减少了这些细胞中铁诱导的活性氧的产生。去铁酮（DFP），一种常用的口服铁螯合剂，未能预防铁诱导的细胞毒性或不稳定铁的积累。接下来，我们在Hfe H67D突变小鼠（一种脑铁积累（BIA）的小鼠模型）中验证了NBMI的疗效。连续6周经口灌胃给予NBMI可降低大脑以及肝脏中的铁积累，而DFP仅在肝脏中显示出铁螯合作用，在大脑中则没有。值得注意的是，在用DFP治疗的BIA小鼠中观察到脑铜缺乏和贫血，但在用NBMI治疗的小鼠中未观察到，这表明NBMI长期使用的安全性优于DFP。总的来说，我们的研究表明，NBMI对BIA具有神经保护作用，并且对与BIA相关的神经退行性疾病具有治疗潜力。
