The Novel Multifunctional, Iron-Chelating Drugs M30 and HLA20 Protect Pancreatic β-Cell Lines from Oxidative Stress Damage

Abstract

Increasing evidence suggests that oxidative stress (OS)-induced pancreatic ␤-cell impairments is involved in diabetes and diabetic complications. Our group has recently synthesized two multifunctional nontoxic, lipophilic, ironchelating 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 ironcomplexing 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 ␤-cells (INS-1E and RINm) against OS-induced cytotoxicity. We found that M30 and HLA20 markedly and dose-dependently inhibited H 2 O 2 -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 H 2 O 2 -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 H 2 O 2 -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 ␤-cells, which might be of therapeutic use in the treatment of diabetes mellitus.

M30 Antagonizes Indoleamine 2,3-Dioxygenase Activation and Neurodegeneration Induced by Corticosterone in the Hippocampus

“…Remarkably, these aberrant changes could be neutralized by the concurrent administration of M30, highlighting the antioxidant property of M30 against oxidative stress in addition to the MAO inhibition. These results are eventually in line with previous reports demonstrating M30 treatment can ameliorate oxidative stress in in-vivo studies by restoring antioxidant capacity and chelating excessive free radicals [39, 40]. …”

8-Hydroxyquinolines: a review of their metal chelating properties and medicinal applications

“…8HQ derivatives have been reported as potent antioxidants,32,37,152,153 which arises from their chelating ability. It is widely known that mixed ligand metal complexes can commonly occur in biological fluids from various bioactive ligands with metal ions 154.…”

“…Antidiabetic activity of other 8HQ derivatives, such as M30 and HLA-20, have been reported to function through different mechanisms 34,152. The liver is the center of Fe homeostasis, and hepatic enzymes are found to be key regulators of hepatic gluconeogenesis 34.…”

Inhibition of caspase-9 aggravates acute liver injury through suppression of cytoprotective autophagy

“…It reduces H 2 O 2 -triggered oxidative stress by enhancing the expression of antioxidant enzymes in insulin-producing β-cells, indicating its antioxidant property9. Additionally, it can also protect the liver against ethanol-mediated injury10.…”