The novel multifunctional, iron-chelating drugs M30 and HLA20 protect pancreatic beta-cell lines from oxidative stress damage.
Increasing evidence suggests that oxidative stress (OS)-induced pancreatic beta-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 beta-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 beta-cells, which might be of therapeutic use in the treatment of diabetes mellitus.
Eve Topf Center of Excellence for Neurodegenerative Diseases Research and Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion, Israel.
Danit
D
Mechlovich
Tamar
T
Amit
Silvia A
SA
Mandel
Orit
O
Bar-Am
Konstantin
K
Bloch
Pnina
P
Vardi
Moussa B H
MB
Youdim
D000818:Animals; D000975:Antioxidants; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D045304:Cytochromes c / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006861:Hydrogen Peroxide / Q000633:toxicity; D006912:Hydroxyquinolines / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles
C517687:5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline; D000975:Antioxidants; D004396:Coloring Agents; D006912:Hydroxyquinolines; D007502:Iron Chelating Agents; D008996:Monoamine Oxidase Inhibitors; D016877:Oxidants; D010879:Piperazines; D013778:Tetrazolium Salts; D013844:Thiazoles; C505060:5-((4-prop-2-ynylpiperazin-1-yl)methyl)quinolin-8-ol; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D002374:Catalase; D053148:Caspase 3; C022616:thiazolyl blue