TVP1022 Protects Neonatal Rat Ventricular Myocytes against Doxorubicin-Induced Functional Derangements

Department of Physiology, Ruth and Bruce Rappaport Faculty of Medicine, Haifa 31096, Israel.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 11/2009; 332(2):413-20. DOI: 10.1124/jpet.109.161158
Source: PubMed


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.

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Available from: Alexandra (Sasha) Berdichevski, Jul 30, 2015
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    • "Moreover, PPARδ expression is also parallel reduced by DOX in cardiomyocytes. DOX is one of the widely used agents for the treatment of cancer with a limitation in clinical utility due to the irreversible cardiac toxicity [2, 27, 28]. In the current work, we demonstrated that DOX impaired cardiac function with a decrease in cardiac PPARδ expression both in vivo and in vitro. "
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    ABSTRACT: The present study investigates the changes of peroxisome proliferator-activated receptors δ (PPAR δ ) expression and troponin phosphorylation in heart of rats which were treated with doxorubicin (DOX). Wistar rats which were treated with DOX according to a previous method. The protein levels of PPAR δ and troponin phosphorylation were measured using Western blot. The PPAR δ expression in heart was markedly reduced in DOX-treated rats showing a marked decrease in cardiac dP/dT and cardiac output. Also, cardiac troponin phosphorylation was lowered in DOX-treated rats. Meanwhile, combined treatment with the agonist of PPAR δ (GW0742) reversed the decrease of cardiac dP/dT and cardiac output in DOX-treated rats. Then, primary cultured cardiomyocytes from neonatal rats were used to measure the changes of calcium concentration in cells. In addition to both decrease of PPAR δ expression and troponin phosphorylation in neonatal cardiomyocytes by DOX, a marked decrease of calcium concentration was also observed. Our results suggest the mediation of cardiac PPAR δ in DOX-induced cardiotoxicity in rats. Thus, activation of PPAR δ may restore the expression of p-TnI and the cardiac performance in DOX-induced cardio toxicity in rats.
    Full-text · Article · Feb 2013 · PPAR Research
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    • "Specifically, TVP1022 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 PKC and glycogen synthase kinase-3β [13]. TVP1022 was also found to attenuate the functional derangements (e.g., intracellular Ca2+transients and contractions properties and intercellular coupling) caused by doxorubicin in NRVM [14]. Our recent in vivo study showed that in a rat model of I/R, TVP1022 provided prominent cardioprotection, evidenced by a reduction in the infarct size, attenuation of the decline in ventricular function and diminution of mitochondrial damage caused by I/R, thus rendering this molecule a potentially novel cardioprotective drug [13]. "
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    ABSTRACT: TVP1022, the S-enantiomer of rasagiline (Azilect®) (N-propargyl-1R-aminoindan), exerts cyto/cardio-protective effects in a variety of experimental cardiac and neuronal models. Previous studies have demonstrated that the protective activity of TVP1022 and other propargyl derivatives involve the activation of p42/44 mitogen-activated protein kinase (MAPK) signaling pathway. In the current study, we further investigated the molecular mechanism of action and signaling pathways of TVP1022 which may account for the cyto/cardio-protective efficacy of the drug. Using specific receptor binding and enzyme assays, we demonstrated that the imidazoline 1 and 2 binding sites (I(1) & I(2)) are potential targets for TVP1022 (IC(50) = 9.5E-08 M and IC(50) = 1.4E-07 M, respectively). Western blotting analysis showed that TVP1022 (1-20 µM) dose-dependently increased the immunoreactivity of phosphorylated p42 and p44 MAPK in rat pheochromocytoma PC12 cells and in neonatal rat ventricular myocytes (NRVM). This effect of TVP1022 was significantly attenuated by efaroxan, a selective I(1) imidazoline receptor antagonist. In addition, the cytoprotective effect of TVP1022 demonstrated in NRVM against serum deprivation-induced toxicity was markedly inhibited by efaroxan, thus suggesting the importance of I(1)imidazoline receptor in mediating the cardioprotective activity of the drug. Our findings suggest that the I(1)imidazoline receptor represents a novel site of action for the cyto/cardio-protective efficacy of TVP1022.
    Full-text · Article · Nov 2012 · PLoS ONE
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    • "Previous studies showed that doxorubicin decreased calcium handling gene expression in cultured new born [39], adult rat ventricular cardiomyocytes [40], and rabbit in vivo model of doxorubicin cardiotoxicity [41], [42], leading to myocardial dysfunction [28]. In concert with the previous studies, here we illustrated that doxorubicin treated mice hearts exhibited reduced level of these Ca2+ handling genes, as indicators of a sarcoplasmic and contractility dysfunction. "
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    ABSTRACT: Despite its effectiveness in the treatment of various cancers, the use of doxorubicin is limited by a potentially fatal cardiomyopathy. Prevention of this cardiotoxicity remains a critical issue in clinical oncology. We hypothesized that flavaglines, a family of natural compounds that display potent neuroprotective effects, may also alleviate doxorubicin-induced cardiotoxicity. Our in vitro data established that a pretreatment with flavaglines significantly increased viability of doxorubicin-injured H9c2 cardiomyocytes as demonstrated by annexin V, TUNEL and active caspase-3 assays. We demonstrated also that phosphorylation of the small heat shock protein Hsp27 is involved in the mechanism by which flavaglines display their cardioprotective effect. Furthermore, knocking-down Hsp27 in H9c2 cardiomyocytes completely reversed this cardioprotection. Administration of our lead compound (FL3) to mice attenuated cardiomyocyte apoptosis and cardiac fibrosis, as reflected by a 50% decrease of mortality. These results suggest a prophylactic potential of flavaglines to prevent doxorubicin-induced cardiac toxicity.
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