טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentKupershmidt Lana
SubjectThe Neuroprotective Activity of Novel Multi-Functional,Brain
-Permeable Iron Chelators in Experimental Models
of Alzheimer's Disease, Amyotrophic
Lateral Sclerosis and Aging
DepartmentDepartment of Medicine
Supervisor Professor Emeritus Moussa Youdim
Full Thesis textFull thesis text - English Version


Abstract

In the present study we examined the potential therapeutic utility of novel multi-functional, brain-permeable iron chelators M30 and HLA20 in the treatment of Alzheimer's Disease (AD), aged-related cognitive decline and Amyotrophic Lateral Sclerosis (ALS).

The current findings demonstrated that in the amyloid protein precursor /presenilin1 (APP/PS1) transgenic AD mouse model, M30 significantly attenuated cognitive deficits in a variety of tasks of learning and memory. These were accompanied by a marked decrease in several AD-like phenotypes, including cerebral APP levels, amyloid β (Aβ) levels and plaque load, phospho-APP and phospho-tau.  The levels of phospho-cyclin-dependent kinase 5 were markedly down-regulated by M30 treatment, accompanied by an increase in protein kinase B and glycogen synthase kinase-3β phosphorylation, and attenuation of hippocampal neurodegeneration. These findings suggest that M30 is a potential therapeutic agent for the prevention and treatment of AD.

Next, it was shown that M30-treated aged mice exhibited a significantly enhanced performance in variety of cognitive tasks, as compared with vehicle treated-aged control animals. M30 administration significantly reduced cerebral iron accumulation; markedly decreased cerebral Aβ plaques and significantly inhibited both monoamine oxidase (MAO)-A and -B activities in aged mice.

In order to evaluate the neuroprotective potential of the multifunctional compounds for ALS treatment, we initially studied the pharmacological activities of M30 and HLA20 in the motor-neuron-like cell line, NSC-34. This study demonstrated that M30 and HLA20 possessed a wide range of prosurvival properties in NSC-34 cells, including neuroprotective effects against various neurotoxic insults. Both compounds induced NSC-34 neuritogenesis, accompanied by a marked increase in the expression of brain-derived neurotrophic factor and growth-associated protein-43, which was inhibited by specific inhibitors, indicating the involvement of mitogen-activated protein kinase and protein kinase C pathways. In addition, we investigated the in vivo effects of M30 on the onset of motor dysfunction, survival time, and motor performance in G93A-superoxide dismutase 1 (SOD1) ALS mouse model. It was shown that chronic administration of M30 significantly extended the survival of G93A-SOD1 mice and delayed the onset of the disease.

Finally, we demonstrated that systemic chronic administration of M30 resulted in up-regulation of HIF-1α protein levels, as well HIF-1-related adaptive genes, accompanied by increase in neurotrophic factors and antioxidant enzymes gene expression and activation of several signaling neuroprotective pathways.

 Together, these results suggest that multifunctional iron chelator compounds can up-regulate a number of neuroprotective-adaptive mechanisms and pro-survival signaling pathways in the brain and might function as ideal drugs for neurodegenerative disorders.