Abstract
Increasing evidence suggests that oxidative stress (OS)-induced pancreatic β-cell impairments is involved in diabetes and diabetic complications. Our group has recently synthesized two multifunctional nontoxic, lipophilic, iron-chelating drugs, 5-{N-methyl-N-propargylaminomethyl}-8-hydroxyquinoline (M30) and 5-{4-propargylpiperazin-1-ylmethyl}-8-hydroxyquinoline (HLA20), for the treatment of various OS-mediated pathogeneses. These compounds contain the N-propargylamine cytoprotective moiety of the antiparkinsonian drug rasagiline (Azilect) and the iron-complexing component 8-hydroxyquinoline. The aim of this research was to evaluate the protective effect of the multifunctional iron-chelating drugs on rat insulin-producing pancreatic β-cells (INS-1E and RINm) against OS-induced cytotoxicity. We found that M30 and HLA20 markedly and dose-dependently inhibited H2O2-induced cytotoxicity, associated with decreased intracellular reactive oxygen species formation and increased catalase activity. In accordance, the catalase inhibitor 3-amino-1,2,4-triazol blocked the protective action of M30 against H2O2-induced damage. Both compounds significantly increased the levels of the iron-responsive protein transferrin receptor indicating their iron-chelating effect. Further mechanistic studies showed that M30 and HLA20 attenuated H2O2-induced mitochondrial membrane potential loss, decreased the release of cytochrome c into the cytoplasm, and inhibited the activation of caspase-3, suggesting that these drugs may produce cytoprotective effects via the preservation of mitochondrial function. These results indicate that the novel drugs, M30 and HLA20 display significant cytoprotective activity against OS-induced cytotoxicity in insulin producing β-cells, which might be of therapeutic use in the treatment of diabetes mellitus.
Footnotes
This work was supported by the Phyllis and Joseph Gurwin Foundation [Grant 2008721].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.164269.
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ABBREVIATIONS:
- ROS
- reactive oxygen species
- DM
- diabetes mellitus
- STZ
- streptozotocin
- OS
- oxidative stress
- M30
- 5-{N-methyl-N-propargylaminomethyl}-8-hydroxyquinoline
- HLA20
- 5-{4-propargylpiperazin-1-ylmethyl}-8-hydroxyquinoline
- TfR
- transferrin receptor
- DFO
- deferoxamine
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide
- DCF-DA
- 2′,7′-dichlorofluorescein diacetate
- ATZ
- 3-amino-1,2,4-triazol
- ELISA
- enzyme-linked immunosorbent assay
- ΔΨm
- mitochondrial membrane potential
- JC-1
- 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide
- PBS
- phosphate-buffered saline.
- Received November 30, 2009.
- Accepted March 11, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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