PMID- 25073425
OWN - NLM
STAT- MEDLINE
DCOM- 20150728
LR  - 20211021
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 171
IP  - 24
DP  - 2014 Dec
TI  - Molecular targets of the multifunctional iron-chelating drug, M30, in the brains 
      of mouse models of type 2 diabetes mellitus.
PG  - 5636-49
LID - 10.1111/bph.12862 [doi]
AB  - BACKGROUND AND PURPOSE: 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). EXPERIMENTAL APPROACH: 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. KEY RESULTS: M30 increased cerebral levels of 
      insulin and insulin receptor and phosphorylated-GSK-3beta in HFD mice, compared with 
      vehicle-treated HFD mice. In both T2DM mice models, M30 treatment significantly 
      up-regulated cerebral hypoxia-inducible factor (HIF)-1alpha 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 AND IMPLICATIONS: 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.
CI  - (c) 2014 The British Pharmacological Society.
FAU - Mechlovich, Danit
AU  - Mechlovich D
AD  - Eve Topf Center for Neurodegenerative Diseases Research, Faculty of Medicine, 
      Technion-Israel Institute of Technology, Haifa, Israel.
FAU - Amit, Tamar
AU  - Amit T
FAU - Bar-Am, Orit
AU  - Bar-Am O
FAU - Weinreb, Orly
AU  - Weinreb O
FAU - Youdim, Moussa B H
AU  - Youdim MB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline)
RN  - 0 (Blood Glucose)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hydroxyquinolines)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Insulin)
RN  - 0 (Iron Chelating Agents)
RN  - 333DO1RDJY (Serotonin)
RN  - EC 1.4.3.4 (Monoamine Oxidase)
RN  - EC 2.7.10.1 (Receptor, Insulin)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (Gsk3b protein, mouse)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - VTD58H1Z2X (Dopamine)
RN  - X4W3ENH1CV (Norepinephrine)
SB  - IM
MH  - Animals
MH  - Blood Glucose/metabolism
MH  - Blotting, Western
MH  - Brain/*drug effects/metabolism
MH  - Diabetes Mellitus, Type 2/*metabolism
MH  - Diet, High-Fat
MH  - Disease Models, Animal
MH  - Dopamine/metabolism
MH  - Glycogen Synthase Kinase 3/drug effects/metabolism
MH  - Glycogen Synthase Kinase 3 beta
MH  - Hydroxyquinolines/*pharmacology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/drug effects/metabolism
MH  - Insulin/metabolism
MH  - Iron Chelating Agents/*pharmacology
MH  - Mice
MH  - Mice, Transgenic
MH  - Monoamine Oxidase/drug effects/metabolism
MH  - Norepinephrine/metabolism
MH  - Real-Time Polymerase Chain Reaction
MH  - Receptor, Insulin/drug effects/metabolism
MH  - Serotonin/metabolism
PMC - PMC4290707
EDAT- 2014/07/31 06:00
MHDA- 2015/07/29 06:00
PMCR- 2015/12/01
CRDT- 2014/07/31 06:00
PHST- 2014/04/10 00:00 [received]
PHST- 2014/05/25 00:00 [revised]
PHST- 2014/07/23 00:00 [accepted]
PHST- 2014/07/31 06:00 [entrez]
PHST- 2014/07/31 06:00 [pubmed]
PHST- 2015/07/29 06:00 [medline]
PHST- 2015/12/01 00:00 [pmc-release]
AID - 10.1111/bph.12862 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2014 Dec;171(24):5636-49. doi: 10.1111/bph.12862.