@article {Berdichevskijpet.109.161158, author = {Alexandra Berdichevski and Gideon Meiry and Felix Milman and Irina Reiter and Oshra Sedan and Sivan Eliyahu and Heather Duffy and Moussa Youdim and Ofer Binah}, title = {TVP1022 protects neonatal rat ventricular myocytes against doxorubicin-induced functional derangements}, elocation-id = {jpet.109.161158}, year = {2009}, doi = {10.1124/jpet.109.161158}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Our recent studies demonstrated that propargylamine derivatives such as rasagiline (Azilect, FDA-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 (PKC)-ϵ and by down-regulating the pro-apoptotic 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 (NRVM), we tested the hypothesis that TVP1022 will also provide protection against doxorubicin-induced NRVM functional derangements. The present study demonstrates that pretreatment of NRVM with TVP1022 (1 {\textmu}mol/L, 24 hrs) prevented doxorubicin (0.5 {\textmu}mol/L, 24 hrs)-induced elevation of diastolic [Ca2+]i, the slowing of [Ca2+]i relaxation kinetic, and the decrease in the rates of myocytes contraction and relaxation. Furthermore, pretreatment with TVP1022 attenuated the doxorubicin-induced reduction in the protein expression of sarco/endoplasmic reticulum calcium (Ca2+) ATPase (SERCA2), Na+/Ca2+ exchanger 1 (NCX1) and total connexin43 (total Cx43). Finally, TVP1022 diminished the inhibitory effect of doxorubicin on gap junctional intercellular coupling (measured by means Lucifer yellow transfer), and on conduction velocity, QRS amplitude and dV/dtmax measured by the Micro-Electrode-Array (MEA) system. In summary, our results indicate that TVP1022 acts as a novel cardioprotective agent against anthracyclines cardiotoxicity, and therefore potentially can be co-administered with doxorubicin in the treatment of human malignancies.The American Society for Pharmacology and Experimental Therapeutics}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/early/2009/11/13/jpet.109.161158}, eprint = {https://jpet.aspetjournals.org/content/early/2009/11/13/jpet.109.161158.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }