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-1β (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.
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Abbreviations
- ANOVA:
-
Analysis of variance
- ATP:
-
Adenosine triphosphate
- BAL:
-
British anti-lewisite
- Bax:
-
Bcl-2-associated X protein
- BBB:
-
Blood brain barrier
- Bcl-2:
-
B-cell lymphoma 2
- BLL:
-
Blood lead levels
- CaNa2EDTA:
-
Calcium disodium ethylenediaminetetraacetic acid
- CDC:
-
Centers for Disease Control and Prevention
- CM-H2DCFDA:
-
Chloromethyl derivative of 2',7'-Dichlorofluorescein diacetate
- CNS:
-
Central nervous system
- DMSA:
-
Dimercaptosuccinic acid
- DMSO:
-
Dimethyl sulfoxide
- DMT-1:
-
Divalent metal transporter-1
- ELISA:
-
Enzyme-linked immunosorbent assay
- EMEM:
-
Eagle’s minimum essential medium
- FPN:
-
Ferroportin
- FBS:
-
Fetal bovine serum
- FDA:
-
Food and drug administration
- GFAP:
-
Glial fibrillary acidic protein
- GSH:
-
Glutathione
- HO-1:
-
Heme oxygenase-1
- Hg:
-
Mercury
- HRP:
-
Horseradish peroxidase
- IC50 :
-
Half-maximal inhibitory concentration
- IL-1β:
-
Interleukin 1 beta
- IL-6:
-
Interleukin 6
- MPER:
-
Mammalian protein extraction reagent
- NAC:
-
N-acetyl cysteine
- NBMI:
-
N,N'-bis(2-mercaptoethyl)isophthalamide
- NF-kB:
-
Nuclear factor kappa-light-chain-enhancer of activated B cells
- NFAT:
-
Nuclear factor of activated T-cells
- Nrf2:
-
Nuclear factor erythroid 2-related factor 2
- NQO1:
-
NAD(P)H dehydrogenase quinone 1
- Pb:
-
Lead
- PbAc:
-
Lead acetate
- ROS:
-
Reactive oxygen species
- TNFα:
-
Tumor necrosis factor-alpha
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Acknowledgements
The authors would like to thank EmeraMed (Nicholasville, KY 40340) for providing the compound NBMI for this study. The authors would also like to thank Dr. Jonghan Kim (University of Massachusetts, Lowell, MA), Dr. Greg Landry, Dr. Neha Kulkarni, and Ana Lucia Gonzales Urday (MCPHS University, Boston, MA) for their contributions to the project.
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This research was funded by the MCPHS University School of Pharmacy, Boston, MA.
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Conceptualization: RG, SB; Methodology: RG, SB; Formal analysis and investigation: RG, SB; Writing—original draft preparation: RG; Writing—review and editing: SB; Funding acquisition: SB; Resources: SB; Supervision: SB.
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Gadde, R., Betharia, S. N,N′bis-(2-mercaptoethyl) isophthalamide (NBMI) exerts neuroprotection against lead-induced toxicity in U-87 MG cells. Arch Toxicol 95, 2643–2657 (2021). https://doi.org/10.1007/s00204-021-03103-2
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DOI: https://doi.org/10.1007/s00204-021-03103-2