טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentBonneh-Barkay Dafna
SubjectCharacterization of the Neuroprotective Potential and
Mechanism of Action of the MAO-B Inhibitor
Rasagiline
DepartmentDepartment of Medicine
Supervisor Professor Emeritus John Finberg


Abstract

Rasagiline (N-propargyl-1-R-aminoindan) is a selective inhibitor of MAO-B currently in phase III clinical trials for the treatment of Parkinson’s disease. It resembles deprenyl in its chemical structure and pharmacological activity but unlike deprenyl is not metabolized to amphetamines.

The aim of the present study was to evaluate the neuroprotective properties of rasagiline and characterize the mechanism by which it exerts its neuroprotective effect.

Rasagiline inhibited the apoptosis induced by SIN1 and increased the survival of the cells treated with the neurotoxin Ara-C in SH-SY5Y cells.  Rasagiline increased the survival of partially differentiated PC12 after serum and nerve growth factor (NGF) deprivation or exposure to glutamate.

Rasagiline increased the survival of dopaminergic neurons in mesencephalic cultures after serum deprivation. In cerebellar granule cells, rasagiline increased the survival of neurons treated with Ara-C, BSO or glutamate but did not reduce apoptosis induced by lowering the potassium concentration to physiological levels.

Rasagiline (1nM-1mM) increased the survival of cerebellar granule cells treated with glutamate. The cell death induced by glutamate is caused by apoptosis that is induced by the activation of the NMDA receptor because the NMDAR antagonist, MK-801 protected the cells from the excitotoxicity of glutamate.

Examination of different derivatives of rasagiline and deprenyl shows that the propargyl moiety is essential to the neuroprotective effect of these molecules. Addition of rasagiline to cerebellar granule cells grown in physiological concentration of potassium induced proliferation and morphological changes in the astrocytes in the culture. In conclusion the neuroprotective effects of rasagiline may include a direct action on the neurons through inhibition of apoptosis dependent on the MAPKs: p38 and JNK and p53 as well as an indirect effect mediated by the astrocytes.