The Novel Multi-Target Iron Chelator, M30 Modulates HIF-1α-Related Glycolytic Genes and Insulin Signaling Pathway in the Frontal Cortex of APP/PS1 Alzheimer’s Disease Mice
2014
Increasing evidence suggests that dysregulation of brain insulin/insulin receptor (InsR) and insulin signaling
cascade are associated with the pathogenesis of Alzheimer’s disease (AD). Our group has designed and synthesized a series
of multi-target iron chelating, brain permeable compounds for AD. One leading multi-target compound, M30 possesses
the neuroprotective N-propargyl moiety of the anti-Parkinsonian, monoamine oxidase (MAO)-B inhibitor,
rasagiline (Azilect®) and the antioxidant-iron chelating moiety of an 8-hydroxyquinoline derivative of the iron chelator,
VK28. Positive outcomes for the behavioral/cognitive and neuroprotective effects of M30 were recently obtained in preclinical
experimental studies, regarding pathological aspects relevant to ageing and AD. We report that chronic treatment
with M30 (1 and 5 mg/kg p.o; three times a week for 9 months) significantly elevated cortical insulin and InsR transcript
and protein expression, respectively and increased the phosphorylated form of glycogen synthase kinase-3β in the frontal
cortex of amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice. In addition, M30 treatment upregulated
the levels of hypoxia-inducible factor (HIF)-1α and expression of its target genes involved in glycolysis including,
aldolase A, enolase-1 and glucose transporter-1 (Glut-1), in the frontal cortex of APP/PS1 mice. Treatment with M30
also lead to an increase in the hepatic protein expression levels of InsR and Glut-1 and lowered the increase in blood glucose
levels following glucose tolerance test. The present findings indicate that the multifunctional iron chelating drug,
M30 regulates major brain glucose metabolism parameters and thus, might be beneficial for AD, in which impaired neuronal
insulin signaling and Glut expression have been implicated.
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