The essentiality of Bcl-2, PKC and proteasome–ubiquitin complex activations in the neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline

Youdim, Moussa B. H.; Amit, Tamar; Falach-Yogev, Merav; Bar, Orit; Maruyama, Wakkako; Naoi, M

doi:10.1016/s0006-2952(03)00535-5

Cited by 81 publications

(58 citation statements)

References 39 publications

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“…Kim et al (2006) also showed that increased caspase 3 activity was doxorubicin/ROS-mediated, via SR Ca 2ϩ release, indicating the important role of Ca 2ϩ in cardiomyocyte apoptosis. Respecting the cytoprotective efficacy of TVP1022, this molecule was shown to induce superoxide dismutase and catalase in neuronal cultures and in vivo , to inhibit the apoptotic cascade and to protect mitochondrial viability in NRVM and neuronal cells (Youdim et al, , 2003Kleiner et al, 2008). Collectively, these activities probably caused ROS reduction and improved myocyte viability, thereby attenuating doxorubicin-induced cardiotoxicity.…”

Section: Tvp1022 Attenuated the Deleterious Effects Of Doxorubicin Onmentioning

confidence: 98%

“…Nevertheless, despite these deleterious side effects, the benefits of anthracyclines outweigh the risks, and thus doxorubicin continues to serve as an important anticancer drug. Based on the established cytoprotective and neuroprotective efficacies of propargylamine derivatives Youdim et al, 2003) as well as on our recent study (Kleiner et al, 2008) showing that TVP1022 (the Sisomer of rasagiline, Azilect, Food and Drug Administrationapproved anti-Parkinson drug) attenuates serum starvationinduced and doxorubicin-induced apoptosis in neonatal rat ventricular myocytes (NRVM), in the present study we tested the hypothesis that TVP1022 will provide protection against doxorubicin-induced functional derangements in NRVM. Indeed, in support of this hypothesis, we demonstrated that TVP1022 markedly attenuated the deleterious effects of doxorubicin on the [Ca 2ϩ ] i transients, the contractions and intercellular coupling, rending this drug a potential cardioprotective agent against anthracycline cardiotoxicity.…”

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confidence: 99%

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

Berdichevski

Meiry²,

Milman³

et al. 2009

J Pharmacol Exp Ther

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Our recent studies demonstrated that propargylamine derivatives such as rasagiline (Azilect, Food and Drug Administrationapproved anti-Parkinson drug) and its S-isomer TVP1022 protect cardiac and neuronal cell cultures against apoptoticinducing 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-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 doxorubicininduced NRVM functional derangements. The present study demonstrates that pretreatment of NRVMs with TVP1022 (1 M, 24 h) prevented doxorubicin (0.5 M, 24 h)-induced elevation of diastolic [Ca 2ϩ ] i , the slowing of [Ca 2ϩ ] 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 2ϩ ) ATPase, Na ϩ /Ca 2ϩ 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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Section: Tvp1022 Attenuated the Deleterious Effects Of Doxorubicin Onmentioning

confidence: 98%

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confidence: 99%

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

Berdichevski

Meiry²,

Milman³

et al. 2009

J Pharmacol Exp Ther

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“…Previously, we demonstrated that the neuroprotective efficacies of the monoamine oxidase (MAO)-B inhibitor rasagiline are similar to those of the non-MAO inhibitor TVP1022, suggesting that cytoprotection is not due to MAO inhibition. 8,10 Furthermore, we recently reported that pretreat-ment of neonatal rat ventricular myocytes with TVP1022 or propargylamine attenuated doxorubicin and serum starvationinduced apoptosis. 9 More recently, we reported that TVP1022 increased phospho-protein kinase C and phospho-(Ser 9) glycogen synthase kinase-3␤ levels in H9c2 cardiomyoblasts and neonatal rat ventricular myocytes and prevented H 2 O 2 -induced damage in H9c2 by preserving the mitochondrial membrane potential and inhibiting cytochrome c release from the mitochondria.…”

Section: Clinical Perspective On P 473mentioning

confidence: 99%

TVP1022 Attenuates Cardiac Remodeling and Kidney Dysfunction in Experimental Volume Overload-Induced Congestive Heart Failure

Abassi¹,

Barac²,

Kostin³

et al. 2011

Circ: Heart Failure

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Background-Despite the availability of many pharmacological and mechanical therapies, the mortality rate among patients with congestive heart failure (CHF) remains high. We tested the hypothesis that TVP1022 (the S-isomer of rasagiline; Azilect), a neuroprotective and cytoprotective molecule, is also cardioprotective in the settings of experimental CHF in rats. Methods and Results-In rats with volume overload-induced CHF, we investigated the therapeutic efficacy of TVP1022 (7.5 mg/kg) on cardiac function, structure, biomarkers, and kidney function. Treatment with TVP1022 for 7 days before CHF induction prevented the increase in left ventricular end-diastolic area and end-systolic area, and the decrease in fractional shortening measured 14 days after CHF induction. Additionally, TVP1022 pretreatment attenuated CHF-induced cardiomyocyte hypertrophy, fibrosis, plasma and ventricular B-type natriuretic peptide levels, and reactive oxygen species expression. Further, in CHF rats, TVP1022 decreased cytochrome c and caspase 3 expression, thereby contributing to the cardioprotective efficacy of the drug. TVP1022 also enhanced the urinary Na ϩ excretion and improved the glomerular filtration rate. Similar cardioprotective effects were obtained when TVP1022 was given to rats after CHF induction. Conclusions-TVP1022 attenuated the adverse functional, structural, and molecular alterations in CHF, rendering this drug a promising candidate for improving cardiac and renal function in this disease state. (Circ Heart Fail. 2011;4:463-473.)

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“…In the present study, we found that neither Ara A nor wortmannin completely inhibited the activation of GSK-3β and the opening of mPTP mediated by Gs-Rb1, which suggested that other pathways exist that help to control the effect of Gs-Rb1 on GSK-3β and mPTP. Some studies have shown that the activation of intracellular kinase cascades, especially PKC [57] , PKG [58] and mTOR/p70s6K [59][60][61] , plays a key role in preventing cardiomyocytes from ischemic/reperfusion injury. However, whether these signal transduction networks, together with AMPK and PI3K pathways, modulate the Gs-Rb1 inhibition of mPTP opening requires further study.…”

Section: Wwwchinapharcom Kong Hl Et Almentioning

confidence: 99%

Ginsenoside Rb1 protects cardiomyocytes against CoCl2-induced apoptosis in neonatal rats by inhibiting mitochondria permeability transition pore opening

Kong

Zhao

et al. 2010

Acta Pharmacol Sin

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Aim: To investigate whether mitochondria permeability transition pore (mPTP) opening was involved in ginsenoside Rb1 (Gs-Rb1) induced anti-hypoxia effects in neonatal rat cardiomyocytes ex vivo. Methods: Cardiomyocytes were randomly divided into 7 groups: control group, hypoxia group (500 µmol/L CoCl 2 ), Gs-Rb1 200 µmol/L group (CoCl 2 intervention+Gs-Rb1), wortmannin (PI3K inhibitor) 0.5 µmol/L group, wortmannin+Gs-Rb1 group, adenine 9-β-Darabinofuranoside (Ara A, AMPK inhibitor) 500 µmol/L group, and Ara A and Gs-Rb1 group. Apoptosis rate was determined by using flow cytometry. The opening of the transient mPTP was assessed by using co-loading with calcein AM and CoCl 2 in high conductance mode. Expression of GSK-3β, cytochrome c, caspase-3 and poly (ADP-ribose) polymerase (PARP) was measured by using Western blotting. ΔGSK-3β was defined as the ratio of p-Ser9-GSK-3β to total GSK-3β. Results: CoCl 2 significantly stimulated mPTP opening and up-regulated the level of ΔGSK-3β. There was a statistically significant positive correlation between apoptosis rate and mPTP opening, between apoptosis rate and ΔGSK-3β, and between mPTP opening and ΔGSK-3β. Gs-Rb1 significantly inhibited mPTP opening induced by hypoxia (41.3%±2.0%, P<0.001) . Gs-Rb1 caused a 77.3%±3.2% reduction in the expression of GSK-3β protein (P<0.001) and a significant increase of 1.182±0.007-fold (P=0.0001) in p-Ser9-GSK-3β compared with control group. Wortmannin and Ara A significantly inhibited the effect of Gs-Rb1 on mPTP opening and ΔGSK-3β. Gs-Rb1 significantly decreased expression of cytochrome c (66.1%±1.7%, P=0.001), caspase-3 (56.5%±2.7%, P=0.001) and cleaved poly ADP-ribose polymerase (PARP) (57.9%±1.4%, P=0.001). Conclusion: Gs-Rb1 exerted anti-hypoxia effect on neonatal rat cardiomyocytes by inhibiting GSK-3β-mediated mPTP opening.

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The essentiality of Bcl-2, PKC and proteasome–ubiquitin complex activations in the neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline

Cited by 81 publications

References 39 publications

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

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

TVP1022 Attenuates Cardiac Remodeling and Kidney Dysfunction in Experimental Volume Overload-Induced Congestive Heart Failure

Ginsenoside Rb1 protects cardiomyocytes against CoCl2-induced apoptosis in neonatal rats by inhibiting mitochondria permeability transition pore opening

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