CUED Publications database

TVP1022 protects neonatal rat ventricular myocytes against doxorubicin-induced functional derangements

Berdichevski, A and Meiry, G and Milman, F and Reiter, I and Sedan, O and Eliyahu, S and Duffy, HS and Youdim, MB and Binah, O (2010) TVP1022 protects neonatal rat ventricular myocytes against doxorubicin-induced functional derangements. Journal of Pharmacology and Experimental Therapeutics, 332. pp. 413-420. ISSN 0022-3565

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Abstract

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 ] , the slowing of [Ca ] 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 ) ATPase, Na /Ca 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 ) 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. 2+ 2+ 2+ + 2+ i i max

Item Type: Article
Uncontrolled Keywords: Animals Animals, Newborn Calcium Calcium-Binding Proteins Cardiotonic Agents Cardiotoxins Cells, Cultured Connexin 43 Doxorubicin Indans Intercellular Junctions Myocardial Contraction Myocytes, Cardiac Rats Rats, Sprague-Dawley
Subjects: UNSPECIFIED
Divisions: Div C > Materials Engineering
Depositing User: Cron Job
Date Deposited: 06 Nov 2018 01:51
Last Modified: 10 Apr 2021 00:24
DOI: 10.1124/jpet.109.161158