Reversal of genetic brain iron accumulation by N,N′-bis(2-mercaptoethyl)isophthalamide, a lipophilic metal chelator, in mice

• Published in: Archives of toxicology Vol. 96; no. 7; pp. 1951 - 1962
• Main Authors: Cheng, Ruiying, Gadde, Rajitha, Fan, Yingfang, Kulkarni, Neha, Shevale, Nachiket, Bao, Kai, Choi, Hak Soo, Betharia, Swati, Kim, Jonghan
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.07.2022; Springer Nature B.V
• Subjects: Accumulation; Anemia; Animals; Antioxidants; Benzene Derivatives; Binding; Biomedical and Life Sciences; Biomedicine; Brain; Chelating agents; Chelating Agents - pharmacology; Chelating Agents - therapeutic use; Chelation; Cytotoxicity; Depletion; Environmental Health; Heavy metals; Humans; Inorganic Compounds; Iron; Iron - metabolism; Lipophilic; Lipophilicity; Liver; Mercury; Mice; Neuroblastoma - metabolism; Neuroblastoma cells; Neurodegenerative diseases; Neuroprotection; Occupational Medicine/Industrial Medicine; Oxidative stress; Pharmacology/Toxicology; Reactive oxygen species; Sulfhydryl Compounds; Toxicity; Iron overload; Iron chelation; Neuroprotection; Neurodegenerative disease; Labile iron
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-022-03287-1

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 2+ ) iron with a negligible binding affinity to ferric (Fe 3+ ) 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.