N,N'bis-(2-mercaptoethyl) isophthalamide (NBMI) exerts neuroprotection against lead-induced toxicity in U-87 MG cells.

ABSTRACT

N,N'-bis(2-mercaptoethyl)isophthalamide (NBMI) is a novel lipophilic heavy metal chelator and thiol redox antioxidant. This study was designed to investigate the neuroprotective activity of NBMI in U-87 MG cells exposed to lead acetate (PbAc). Cells were pretreated with NBMI for 24 h prior to a 48 h exposure to PbAc. Cell death (55%, p < 0.0001) and reduction of intracellular GSH levels (0.70-fold, p < 0.005) induced by 250 µM Pb were successfully attenuated by NBMI pretreatment at concentrations as low as 10 µM. A similar pretreatment with the FDA-approved Pb chelator dimercaptosuccinic acid (DMSA) proved ineffective, indicating a superior PKPD profile for NBMI. Pretreatment with NBMI successfully counteracted Pb-induced neuroinflammation by reducing IL-1ß (0.59-fold, p < 0.05) and GFAP expression levels. NBMI alone was also found to significantly increase ferroportin expression (1.97-fold, p < 0.05) thereby enhancing cellular ability to efflux heavy metals. While no response was observed on the apoptotic pathway, this study demonstrated for the first time that necrotic cell death induced by Pb in U-87 MG cells is successfully attenuated by NBMI. Collectively these data demonstrate NBMI to be a promising neuroprotective compound in the realm of Pb poisoning.