title: Molecular targets of the multifunctional iron-chelating drug, M30, in the brains of mouse models of type 2 diabetes mellitus.
abstract: OBJECTIVE
  Neurodegenerative diseases are now recognized to be multifunctional, whereby a heterogeneous set of reactions acts independently or cooperatively, leading eventually to the demise of neurons. This has led our group to design and synthesize the multifunctional, nontoxic, brain-permeable, iron chelator compound M30 with a range of pharmacological properties. Here, we have characterized the molecular targets of M30 in the brains of animal models of type 2 diabetes mellitus (T2DM).
  
  
  METHODS
  Effects of M30 on molecular mechanisms associated with neuroprotection in the CNS were investigated-in the high-fat diet (HFD) and ob/ob transgenic mouse models of T2DM, using real-time PCR and Western blotting analyses. Brain monoamine oxidase (MAO) activity and catecholamine levels, and peripheral glucose tolerance were assayed after treatment in vivo.
  
  
  RESULTS
  M30 increased cerebral levels of insulin and insulin receptor and phosphorylated-GSK-3β in HFD mice, compared with vehicle-treated HFD mice. In both T2DM mice models, M30 treatment significantly up-regulated cerebral hypoxia-inducible factor (HIF)-1α protein levels and induced the expression of several HIF-1 target genes involved in neuroprotection, glycolysis, neurogenesis, oxidative stress and anti-inflammation. Additionally, M30 inhibited MAO-A and -B activities in the cerebellum. Accordingly, M30 administration significantly reduced brain levels of dopamine metabolites and increased levels of 5-HT and noradrenaline. Glucose tolerance was also improved after M30 treatment in both models of T2DM.
  
  
  CONCLUSIONS
  In the brain of HFD and ob/ob transgenic mice, M30 exerted a variety of beneficial neuroprotective regulatory effects that may act synergistically to delay or prevent neurodegenerative processes associated with T2DM.
authors: Eve Topf Center for Neurodegenerative Diseases Research, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors: Danit
authors: D
authors: Mechlovich
authors: Tamar
authors: T
authors: Amit
authors: Orit
authors: O
authors: Bar-Am
authors: Orly
authors: O
authors: Weinreb
authors: Moussa B H
authors: MB
authors: Youdim
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006912:Hydroxyquinolines / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008995:Monoamine Oxidase / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism
chemical_list: C517687:5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline; D001786:Blood Glucose; C497443:Hif1a protein, mouse; D006912:Hydroxyquinolines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D007502:Iron Chelating Agents; D012701:Serotonin; D008995:Monoamine Oxidase; D011972:Receptor, Insulin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D004298:Dopamine; D009638:Norepinephrine