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The cardioprotective efficacy of TVP1022 in a rat model of ischaemia/reperfusion.

AbstractBACKGROUND 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(2) O(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(2) O(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.
AuthorsOffir Ertracht, Esti Liani, Noa Bachner-Hinenzon, Orit Bar-Am, Luba Frolov, Elena Ovcharenko, Huda Awad, Shany Blum, Yaron Barac, Tamar Amit, Dan Adam, Moussa Youdim, Ofer Binah
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 163 Issue 4 Pg. 755-69 (Jun 2011) ISSN: 1476-5381 [Electronic] England
PMID21323905 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
Chemical References
  • Cardiotonic Agents
  • Indans
  • Proto-Oncogene Proteins c-bcl-2
  • rasagiline
  • Cytochromes c
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Protein Kinase C
  • Glycogen Synthase Kinase 3
  • Caspase 3
  • Caspase 9
Topics
  • Animals
  • Cardiotonic Agents (pharmacology)
  • Caspase 3 (metabolism)
  • Caspase 9 (metabolism)
  • Cells, Cultured
  • Cytochromes c (metabolism)
  • Glycogen Synthase Kinase 3 (metabolism)
  • Glycogen Synthase Kinase 3 beta
  • Indans (pharmacology)
  • Male
  • Membrane Potentials (drug effects)
  • Mitochondria (drug effects, metabolism)
  • Myocardial Infarction (metabolism, prevention & control)
  • Myocardium (metabolism)
  • Protein Kinase C (metabolism)
  • Proto-Oncogene Proteins c-bcl-2 (metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury (metabolism, prevention & control)

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