HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

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-epsilon 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 microM, 24 h) prevented doxorubicin (0.5 microM, 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 cardioprotective agent against anthracycline cardiotoxicity, and therefore potentially can be coadmhence, theinistered with doxorubicin in the treatment of malignancies in humans.
AuthorsAlexandra Berdichevski, Gideon Meiry, Felix Milman, Irena Reiter, Oshra Sedan, Sivan Eliyahu, Heather S Duffy, Moussa B Youdim, Ofer Binah
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 332 Issue 2 Pg. 413-20 (Feb 2010) ISSN: 1521-0103 [Electronic] United States
PMID19915070 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Calcium-Binding Proteins
  • Cardiotonic Agents
  • Cardiotoxins
  • Connexin 43
  • Indans
  • rasagiline
  • Doxorubicin
  • Calcium
Topics
  • Animals
  • Animals, Newborn
  • Calcium (metabolism)
  • Calcium-Binding Proteins (metabolism)
  • Cardiotonic Agents (pharmacology)
  • Cardiotoxins (pharmacology)
  • Cells, Cultured
  • Connexin 43 (metabolism)
  • Doxorubicin (adverse effects, antagonists & inhibitors)
  • Indans (pharmacology)
  • Intercellular Junctions (drug effects)
  • Myocardial Contraction (drug effects)
  • Myocytes, Cardiac (drug effects, metabolism)
  • Rats
  • Rats, Sprague-Dawley

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: