|M.Sc Student||Soll Matan|
|Subject||Corroles, Novel Drugs for Treatment of Neurodegenerative|
|Department||Department of Chemistry||Supervisors||Professor Zeev Gross|
|Dr. Silvia Mandel|
|Full Thesis text|
Parkinson's disease (PD) is a multi-factorial degenerative disease of the central nervous system with a prevalence rate of 1 in 300. Clinical features include abnormally slow voluntary movements, stiff and asymmetric tremor. These arise from the loss of dopaminergic neurons (which release the neurotransmitter dopamine) in the substantia nigra pars compacta. Strong evidence suggests that the common cause of death of these neurons involves mitochondrial dysfunction and dopamine-dependent oxidative stress.
Corroles receive increasing attention because of the utility of their corresponding metal complexes in oxidation catalysis, reduction catalysis and biomedical applications. Metallocorroles can catalytically decompose various ROS, including peroxynitrite, which is not neutralized by natural biologic systems. This has been proven in purely chemical systems, as well as in cellular and some animal studies.
In this study we have shown that the iron(III ) complex of an amphipolar sulfonated corrole (1-Fe) reduces cell death in in vitro models of PD, based on the dopaminergic neuronal cells of embryonic substantia nigra of mouse origin (SN4741). First we demonstrated that 1-Fe prevents the death of SN4741 cells when given before intoxification by 6-hydroxydopamine (6-OHDA). Moreover, addition of 1-Fe even 30 min after administration of 6-OHDA significantly reduced cell death. This result indicates that 1-Fe not only prevents, but may also rescue SN4741 cells and recover their neuronal activity. Further research focused on validating the ability of 1-Fe to rescue SN4741 cells damaged by 6-OHDA and the mechanism of action. Important findings, which accompanied the ability to rescue dopaminergic neurons were increased expression of phenotypic dopaminergic proteins. This included tyrosine hydroxylase (TH) and dopamine transporter (DAT), which were significantly depleted following 6-OHDA damage. 1-Fe also elevated expression levels of aldehyde dehydrogenase 1 (ALDH-1) and s-phase kinase-associated protein 1 (Skp-1), which were previously disclosed as cardinal proteins in the pathogenesis of PD.
Experiments conducted within this thesis concluded that 1-Fe affects quite a wide range of intracellular mechanisms, beyond the expected antioxidant effect. To reinforce this conclusion we examined a number of vital intracellular pathways that involve neuroplasticity, growth, differentiation and survival of neurons. The findings suggested that phophatidyl inositol 3 kinase (PI3K) and protein kinase c (PKC) are involved in the neurorescue effect of 1-Fe. Furthermore, 1-Fe elevated the expression of anti-apoptotic protein Bcl-2, which is essential for proper mitochondrial function and cellular survival.