Ruth and Bruce Rappaport Family Institute for Research in the Medical science

Haifa, Israel

Ruth and Bruce Rappaport Family Institute for Research in the Medical science

Haifa, Israel
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Ertracht O.,Technion - Israel Institute of Technology | Ertracht O.,Ruth and Bruce Rappaport Family Institute for Research in the Medical science | Liani E.,Technion - Israel Institute of Technology | Liani E.,Ruth and Bruce Rappaport Family Institute for Research in the Medical science | And 11 more authors.
British Journal of Pharmacology | Year: 2011

BACKGROUND AND PURPOSE Because myocardial infarction is a major cause of morbidity and mortality worldwide, protecting the heart from the ischaemia and reperfusion (I/R) damage is the focus of intense research. Based on our in vitro findings showing that TVP1022 (the S-enantiomer of rasagiline, an anti-Parkinsonian drug) possesses cardioprotective effects, in the present study we investigated the hypothesis that TVP1022 can attenuate myocardial damage in an I/R model in rats. EXPERIMENTAL APPROACH The model consisted of 30-min occlusion of the left anterior descending artery followed by 4 or 24 h reperfusion. In addition, we investigated the possible mechanisms of cardioprotection in H9c2 cells and neonatal rat ventricular myocytes (NRVM) exposed to oxidative stress induced by H 2O 2. KEY RESULTS TVP1022 (20 and 40 mg·kg -1) administered 5 min before reperfusion followed by an additional dose 4 h after reperfusion reduced the infarct size and attenuated the decline in ventricular function. TVP1022 also attenuated I/R-induced deterioration in cardiac mitochondrial integrity evaluated by mitochondrial swelling capacity. In vitro, using H9c2 cells and NRVM, TVP1022 attenuated both serum free- and H 2O 2-induced damage, preserved mitochondrial membrane potential and Bcl-2 levels, inhibited mitochondrial cytochrome c release and the increase in cleaved caspase 9 and 3 levels, and enhanced the phosphorylation of protein kinase C and glycogen synthase kinase-3β. CONCLUSIONS AND IMPLICATIONS TVP1022 provided cardioprotection in a model of myocardial infarction, and therefore should be considered as a novel adjunctive therapy for attenuating myocardial damage resulting from I/R injuries. © 2011 The British Pharmacological Society.


Berdichevski A.,Ruth and Bruce Rappaport Family Institute for Research in the Medical science | Meiry G.,Ruth and Bruce Rappaport Family Institute for Research in the Medical science | Milman F.,Ruth and Bruce Rappaport Family Institute for Research in the Medical science | Reiter I.,Ruth and Bruce Rappaport Family Institute for Research in the Medical science | And 5 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2010

Our recent studies demonstrated that propargylamine derivatives such as rasagiline (Azilect, Food and Drug Administration-approved anti-Parkinson drug) and its S-isomer TVP1022 protect cardiac and neuronal cell cultures against apoptotic-inducing stimuli. Studies on structure-activity relationship revealed that their neuroprotective effect is associated with the propargylamine moiety, which protects mitochondrial viability and prevents apoptosis by activating Bcl-2 and protein kinase C-ε and by down-regulating the proapoptotic protein Bax. Based on the established cytoprotective and neuroprotective efficacies of propargylamine derivatives, as well as on our recent study showing that TVP1022 attenuates serum starvation-induced and doxorubicin-induced apoptosis in neonatal rat ventricular myocytes (NRVMs), we tested the hypothesis that TVP1022 will also provide protection against doxorubicin-induced NRVM functional derangements. The present study demonstrates that pretreatment of NRVMs with TVP1022 (1 μM, 24 h) prevented doxorubicin (0.5 μM, 24 h)-induced elevation of diastolic [Ca 2+] i, the slowing of [Ca 2+] i relaxation kinetics, and the decrease in the rates of myocyte contraction and relaxation. Furthermore, pretreatment with TVP1022 attenuated the doxorubicin-induced reduction in the protein expression of sarco/endoplasmic reticulum calcium (Ca 2+) ATPase, Na +/Ca 2+ exchanger 1, and total connexin 43. Finally, TVP1022 diminished the inhibitory effect of doxorubicin on gap junctional intercellular coupling (measured by means of Lucifer yellow transfer) and on conduction velocity, the amplitude of the activation phase, and the maximal rate of activation (dv/ dt max) measured by the Micro-Electrode-Array system. In summary, our results indicate that TVP1022 acts as a novel cardio-protective agent against anthracycline cardiotoxicity, and therefore potentially can be coadmhence, theinistered with doxorubicin in the treatment of malignancies in humans. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.

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