טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentSagi Yotam
SubjectPharmacological and Molecular Mechanisms of Neuroprotective
Action of anti-Alzheimer's and anti Parkinson's
Drugs Ladostigil (TV3326), TV3279, and
Rasagiline
DepartmentDepartment of Medicine
Supervisor Professor Emeritus Moussa Youdim


Abstract

Recent controlled clinical studies with rasagiline (N-propargyl-1R-aminoindan), a second generation irreversible monoamine oxidase B inhibitor, anti-Parkinson's

disease (PD) drug, suggest that it may possess disease modifying activity. In line with this, chronic low doses of rasagiline administered to mice subsequently to the neurotoxin 1 methyl-4 phenyl 1,2,3,6 tetrahydropyridine (MPTP), rescued cell count and function of substantia nigra pars compacta dopaminergic neurons. Employing proteomic and genomic screening tools combined with a biology-based clustering method we found that rasagiline induces a number of cell signaling mediators associated with the tyrosine kinase receptor (Trk) pathway, in parallel with a specific increase in the Trk-downstream effecter. Confirmatory immunohistochemical analysis indicated that this effect was associated with activation of the substrate of PI3K, Akt and phosphorylative inactivation of glycogen synthase kinase-3β and Raf1.

Recently we have developed novel multifunctional drug for the treatment of dementia co-morbid with Parkinsonism, by combining the pharmacophore of rasagiline with the carbamate cholinesterase inhibitor moiety. Ladostigil, (TV3326, ((R)-[(N-propargyl- (3R) aminoindan-5-yl) ethyl -methyl carbamate])) is a cholinesterase and brain-selective monoamine oxidase (MAO) A-B, inhibitor. We found that ladostigil possess a unique biochemical profile, which corresponds to a motor behavior performance, in vivo. Furthermore, ladostigil also protected from MPTP, in mice.

Our results demonstrate the essentiality of the activation of Ras-PI3K-Akt survival pathway in rasagiline-mediated neurorescue effect, suggesting that it may recruit this mechanism in its disease modifying action in PD patients. Also, the novel multifunctional drug, ladostigil, may improve motor symptoms in subjects suffering from striatal reduction of acetylcholine and dopamine, including dementia co-morbid with Parkinsonism.