טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentMalka Assaf
SubjectThe Cardioprotective Efficacy of TVP1022 in Experimental
Models of Myocardial Infarction
DepartmentDepartment of Medicine
Supervisor Professor Emeritus Ofer Binah
Full Thesis textFull thesis text - English Version


Abstract


The current cornerstone treatment of myocardial infarction (MI) is restoration of coronary blood flow by means of thrombolytic therapy or primary percutaneous coronary intervention. However, reperfusion of ischemic myocardium can actually provoke tissue damage leading to cell death, defined as "ischemia/reperfusion injury". TVP1022 (the S-isomer of rasagiline (Azilect?), FDA-approved anti-Parkinson drug) was found to exert a significant anti-apoptotic and cytoprotective efficacy in in vitro cultures of neuronal cells and cardiomyocytes, as well as cardioprotective activities against various cardiac insults such as chronic heart failure and Ischemia/reperfusion in rat models. Therefore, we tested the hypothesis that TVP1022 will provide cardioprotection against ischemia/reperfusion injury and post-MI remodeling in vivo. Accordingly, the specific aims of the present study were: (1) To investigate post-MI, left ventricular remodeling by evaluating cardiac performance and structural changes; (2) To investigate the cardioprotective efficacy of TVP1022 on post-MI left ventricular remodeling by analyzing cardiac function, morphology, structure, and cellular and molecular markers.

TVP1022 was tested in two myocardial ischemia/reperfusion models: (1) Left anterior descending artery ligation-induced MI in the rat; (2) mid-left anterior descending artery ligation-induced MI in the pig. In both models TVP1022 was initially administered post-occlusion-pre-reperfusion, with chronic daily administrations during the follow-up period. Cardiac performance and left ventricular remodeling were evaluated by using customary and advanced echocardiographic methods, hemodynamic measurements by Millar Mikro-Tip? catheter and histopathological techniques.

The results show that in both models TVP1022 treatment showed beneficial effects. Cardiac dysfunction and post-MI remodeling process were markedly attenuated. The ability of TVP1022 to attenuate cardiac damage induced by MI renders this molecule a potential cardio-protective drug for treating acute coronary syndrome patients.