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.