טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentKleiner Yana
SubjectCardioprotective Efficacy of TVP1022 and other
Propargylamines
DepartmentDepartment of Medicine
Supervisors Professor Emeritus Ofer Binah
Professor Emeritus Moussa Youdim
Full Thesis textFull thesis text - English Version


Abstract

Cardiac death is the leading cause of morbidity and mortality in man; some 12 million people suffer from cardiac diseases in the USA alone, and there are a half a million deaths annually. Cardiac cells and neuronal (nerve) cells are similar, in that they share comparable mitochondrial-dependent mechanisms for life and death. It is also recognized that cell death contributes to serious pathological conditions, such as mechanical overload, myocardial ischemia and infarction. The mechanisms by which cell death occurs is similar in a number of diseases including Parkinson’s, Alzheimer's, cardiovascular diseases and also diabetes and kidney disease. Hence, due to the similarity of how neuronal and cardiac cells die, we hypothesized that similar type of drugs could be effective in treating both neurological and heart diseases. Based on the above mentioned considerations, the major goal of this M.Sc. Thesis was to investigate the cardioprotective efficacy of TVP1022 and other propargylamines against myocardial damage and death caused by several provocative stimuli, including doxorubicin and those mimicking myocardial ischemia (serum starvation). In addition, some molecular mechanisms responsible for cardioprotection were studied. The hypothesis was tested in H9c2 cardiac cell line and neonatal rat ventricular myocytes (NRVM). Our main findings were: (1) In embryonic rat heart cell line H9c2, serum starvation-induced apoptosis was inhibited by TVP1022 and propargylamine. (2) In NRVM, serum starvation-induced and doxorubicin-induced apoptosis was inhibited by TVP1022, propargylamine and the novel bifunctional propargylamines M30 and HLA20. (3) In NRVM treatment with propargylamine derivatives increased the Bcl-2/Bax ratio, thus predisposing cells to anti-apoptotic state. (4) The cytoprotective effects of TVP1022 and other propargylamines were shown to reside in the propargylamine moiety.

In conclusion, the molecular mechanisms of the cardioprotective activities of tested propargylamines are very similar to those described for neuroprotection. Thus, we propose that propargylamine derivatives should be considered as potential therapeutic agents for preventing and treating cardiovascular disorders.