טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentAluf Yuval
SubjectThe Association between Dopamine and Oxidative Stress in a
Rat Model of Parkinson's Disease
DepartmentDepartment of Medicine
Supervisors Professor Emeritus John Finberg
Professor Jacob Vaya
Full Thesis textFull thesis text - English Version


Abstract

Compensatory mechanisms in early stage Parkinson's disease (PD) postpone the onset of clinical symptoms of the disease, and are a possible cause of oxidative stress (OS) generation and accelerated neurodegeneration. Dopamine (DA), a key player in PD, is a highly reactive molecule that can be metabolized by monoamine oxidase (MAO), or undergo auto-oxidization to form DA quinone, and both these pathways can result in an increase in OS.

In this thesis, we have established an early stage PD rat model of partial dopaminergic degeneration, and examined the molecular changes in the dopaminergic and non-dopaminergic systems. The increased DA turnover despite constant level of DA after the gliosis seen post 6-OHDA treatment highlighted the growing role of MAO B in the compensation despite the lack of clinical symptoms.

In this work, we lay down the connection between partial lesion (50%) of the nigro-striatal dopaminergic pathway and the resulting compensatory mechanisms of the remaining neurons to increased extracellular OS in the striatum. By setting up a new system, we used a novel free radical trap, scavenging only extracellular, not intracellular, reactive oxygen species (ROS), thus can differentiate between intra- and extra-cellular OS, we characterized the contribution of DA to this OS either through metabolism by MAO or auto oxidation.

We revealed the antioxidant defense mechanism, that when sensing the increased OS, is up regulating some of the enzymes responsible for detoxifying the harmful ROS, and thus can protect against further degeneration and progression of the disease. This protection is discovered due to the compartmentalization of OS sensing, by microdialysis of the marker molecule vs tissue markers for OS. The lack of this antioxidant compensation is a suggested failure of the PD patient mechanism of defense, hence continued progression of the disease.

In our work, we also determined the importance of MAO B inhibition using rasagiline, its effect on presynaptic dopaminergic signaling, and its role in reducing intra- and extra-cellular OS which was not explicable by its ability to decrease DA oxidative metabolism. Rasagiline, thus possess additional antioxidant properties, not directly linked to MAO inhibition, and is a potential neuroprotective drug.