title: Effects of novel neuroprotective and neurorestorative multifunctional drugs on iron chelation and glucose metabolism.
abstract: Iron accumulation and iron-related oxidative stress are involved in several pathological conditions and provide a rationale for the development of iron chelators as novel promising therapeutic strategies. Thus, we have recently synthesized multifunctional non-toxic, brain permeable iron chelating compounds, M30 and HLA20, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase (MAO)-B inhibitor, rasagiline and the antioxidant-iron chelating moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Here, we examined the hepatic regulatory effects of these novel compounds using two experimental approaches: chelation activity and glucose metabolism parameters. The present study demonstrated that M30 and HLA20 significantly decreased intracellular iron content and reduced ferritin expression levels in iron-loaded hepatoma Hep3B cells. In electron microscopy analysis, M30 was shown to reduce the electron-dense deposits of siderosomes by ~30 %, as well as down-regulate cytosolic ferritin particles observed in iron-overloaded cells. In vivo studies demonstrated that M30 administration (1 mg/kg, P.O. three times a week) reduced hepatic ferritin levels; increased hepatic insulin receptor and glucose transporter-1 levels and improved glucose tolerance in C57BL/6 mice and in a mouse model of type-2 diabetes, the ob/ob (leptin(-/-)). The results clearly indicate that the novel multifunctional drugs, especially M30, display significant capacity of chelating intracellular iron and regulating glucose metabolism parameters. Such effects can have therapeutic significance in conditions with abnormal local or systemic iron metabolism, including neurological diseases.
authors.affiliation: Pediatric Research and Electron Microscopy Unit, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. mdyulia@tx.technion.ac.il
authors.forename: Yulia
authors.initials: Y
authors.lastname: Pollak
authors.forename: Danit
authors.initials: D
authors.lastname: Mechlovich
authors.forename: Tamar
authors.initials: T
authors.lastname: Amit
authors.forename: Orit
authors.initials: O
authors.lastname: Bar-Am
authors.forename: Irena
authors.initials: I
authors.lastname: Manov
authors.forename: Silvia A
authors.initials: SA
authors.lastname: Mandel
authors.forename: Orly
authors.initials: O
authors.lastname: Weinreb
authors.forename: Esther G
authors.initials: EG
authors.lastname: Meyron-Holtz
authors.forename: Theodore C
authors.initials: TC
authors.lastname: Iancu
authors.forename: Moussa B H
authors.initials: MB
authors.lastname: Youdim
mesh_terms: D000818:Animals; D001572:Benzofurans; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005290:Ferric Compounds / Q000494:pharmacology; D005293:Ferritins / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D006912:Hydroxyquinolines / Q000737:chemistry / Q000494:pharmacology; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D020738:Leptin / Q000172:deficiency; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D011804:Quinolines
chemical_list: C576715:(3aS,4S,9bS)-N-(2-(8-cyano-1-formyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo(3,2-c)quinolin-4-yl)-2-methylpropyl)-4,6-difluorobenzofuran-2-carboxyamide; C517687:5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline; D001572:Benzofurans; D005290:Ferric Compounds; D006912:Hydroxyquinolines; D007502:Iron Chelating Agents; D020738:Leptin; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D010879:Piperazines; D000644:Quaternary Ammonium Compounds; D011804:Quinolines; C505060:5-((4-prop-2-ynylpiperazin-1-yl)methyl)quinolin-8-ol; D005293:Ferritins; D007501:Iron; D005947:Glucose; C013531:ferric ammonium citrate