chiniofon and Diabetes-Mellitus--Type-2

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).. 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.. 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.. 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.

Topics: Animals; Blood Glucose; Blotting, Western; Brain; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Dopamine; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hydroxyquinolines; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Iron Chelating Agents; Mice; Mice, Transgenic; Monoamine Oxidase; Norepinephrine; Real-Time Polymerase Chain Reaction; Receptor, Insulin; Serotonin

Optimization of a screening hit from uHTS led to the discovery of TGR5 agonist 32, which was shown to have activity in a rodent model for diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Hydroxyquinolines; Mice; Quinolines; Receptors, G-Protein-Coupled; Structure-Activity Relationship; Thiophenes