טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentRozenfeld Danit
SubjectMolecular Neuroprotective Targets of the Novel Multi-
Functional Iron-Chelating Drug, M30, in
Experimental Models of Type 2 Diabetes
Mellitus & Alzheimer's Disease
DepartmentDepartment of Medicine
Supervisor Professor Emeritus Moussa Youdim
Full Thesis textFull thesis text - English Version


Abstract

Epidemiological evidence supports a close association between Type 2 Diabetes mellitus (T2DM) and Alzheimer’s diseases (AD). We have synthesized a multifunctional non-toxic, brain permeable iron chelator drug, M30, possessing neuroprotective propargyl monoamine oxidase (MAO) inhibitory and iron-chelating moieties, from our prototype iron chelator VK28. In the present study, we evaluated the anti-apoptotic activity of M30 against oxidative insult and analyzed the in vivo molecular neuroprotective targets of M30 in experimental models of T2DM (high fat diet (HFD) and ob/ob Tg mice models) and AD (amyloid precursor protein (APP)/presenilin 1(PS1) Tg mouse model), regarding several common neurodegenerative mechanisms linking between these diseases.

Initially, we demonstrated that the novel multifunctional, iron-chelating drugs M30 and HLA20 protect pancreatic beta-cell lines from oxidative stress damage.

In vivo studies demonstrated that M30 (5 mg/kg PO; three times weekly for 5 months) increased cerebral levels of insulin/InsR and phospho glycogen synthase kinase (p-GSK-3β) in the HFD mice, as compared to vehicle-treated HFD mice. Moreover, M30 treatment produced a significant up-regulation of cerebral hypoxia-inducible factor (HIF)-1α protein levels and induced the expression of HIF-1-targets genes involved in neuroprotection and glycolysis (e.g. (glucose transporter (GLUT)-1, GLUT-3, enolase-1, and aldolase), angiogenesis neurogenesis, oxidative stress and anti-inflammation in HFD and ob/ob Tg mice.

Additionally, we found that M30 caused a significant inhibition of both MAO-A and -B activities in the cerebellum of HFD and ob/ob Tg mice. In accordance with its MAO inhibitory properties, M30 administration significantly reduced brain levels of the metabolites of dopamine, 3,4-Dihydroxyphenylacetic acid and homovanillic acid and increased the levels of serotonin and noradrenaline. In both HFD and ob/ob Tg mice, M30 increased cerebral mRNA expression levels of the antioxidative enzyme, catalase and prevented the increase in protein levels of the AD APP.

In the APP/ PS1 AD mouse model, we demonstrated that chronic treatment with M30 (1 and 5 mg/kg PO; three times weekly for 6 months) significantly elevated the levels of cortical insulin and InsR, transcript and protein, respectively, and increased the levels of the p-GSK-3β. In addition, in this AD mouse model, M30 up-regulated the levels of HIF-1α and induced the expression of HIF-1α target genes involved in glycolysis.

Together, all these beneficial effects of M30, including cerebral regulation of insulin/InsR/p-GSK-3β levels, activation of HIF-1 pathway and neuroprotective/glycolytic genes, MAO inhibition, up-regulation of catalase and reduction of APP expression, may prevent or delay common neurodegenerative molecular processes in T2DM and AD.