טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentChillag-Talmor Orly
SubjectNeuroprotective Pathways Initiated by Rasagiline:
Involvement of PKC in Association with Bcl-2
Family Proteins
DepartmentDepartment of Medicine
Supervisor Professor Emeritus Moussa Youdim


Abstract

Rasagiline (N-propargyl-(1R)-aminoindan), a selective, irreversible and highly potent inhibitor of the monoamine oxidase (MAO) type B enzyme, is a new drug for the treatment of Parkinson’s disease, suggested to possess also a disease-modifying effect. This may be related to the neuroprotective, MAO-inhibition-independent activity of rasagiline, previously demonstrated against numerous insults in vitro and in vivo.

In this work we investigated the mechanism by which rasagiline exerts neuroprotection, using an apoptotic model of serum deprivation in rat pheochromocytoma PC12 cells. Rasagiline-induced reduction of apoptotic death was accompanied by inhibition of cleavage and activation of caspase-3, a major executioner of apoptosis; decrease in cleavage of the casapse-3 substrate, poly ADP-ribose polymerase; and attenuation of levels of the cell death regulator, Bad. These actions were blocked upon exposure to the protein kinase C (PKC) inhibitor, GF109203X, indicating the involvement of PKC in rasagiline-induced cell survival. Indeed, rasagiline directly activated PKC, and also up-regulated mRNA levels of the survival-associated isozymes PKCa and PKCe. Coordinated with these changes, rasagiline increased mRNA expression of the anti-apoptotic Bcl-2 family members, Bcl-XL and Bcl-w, while decreasing mRNA expression of the pro-apoptotic proteins Bad and Bax. Further, rasagiline up-regulated mRNA expression of brain derived neurotrophic factor, implicating possible activation of neurotrophic cascades. Exploring the role of the propargyl moiety of rasagiline, we found that propargylamine exhibited similar effects and potency compared with rasagiline.

In conclusion, this study shows that rasagiline acts via activation and regulation of PKC in association with Bcl-2 family proteins, and suggests that the propargyl moiety accounts for the neuroprotective activity of rasagiline.