Paroxetine mitigates cardiac remodelling by doxorubicin and increases survival

Doxorubicin (DOX) is an effective anticancer drug. However, its use is hampered by the development of very mortal cardiomyopathy. Here, we investigate whether the co-administration of the antidepressant paroxetine (P), known to exert beneficial cardiovascular effects, would provide effective cardiop...

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Autores principales:	Marija Kosić, Zorica Nešić, Sofija Glumac, Marko Vasić, Vladislav Pajović, Bojana Savić, Nina Japundžić-Žigon
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	β-adrenergic receptors Cardiotoxicity Doxorubicin GRK2 GRK3 Paroxetine Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/ae3305f41fc244d78b45f5e1dcb8c74c
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spelling	oai:doaj.org-article:ae3305f41fc244d78b45f5e1dcb8c74c2021-11-14T04:30:32ZParoxetine mitigates cardiac remodelling by doxorubicin and increases survival0753-332210.1016/j.biopha.2021.112411https://doaj.org/article/ae3305f41fc244d78b45f5e1dcb8c74c2022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221011975https://doaj.org/toc/0753-3322Doxorubicin (DOX) is an effective anticancer drug. However, its use is hampered by the development of very mortal cardiomyopathy. Here, we investigate whether the co-administration of the antidepressant paroxetine (P), known to exert beneficial cardiovascular effects, would provide effective cardioprotection. Experiments were performed in male Wistar rats randomly assigned to control group (0.5 mL/kg 0.9% NaCl, i.v., n = 7), DOX group (DOX 5 mg /kg i.v., n = 23) and DOX+P group (DOX 5 mg/kg, i.v. plus P 10 mg/kg p.o. daily, beginning five days before DOX administration and during the follow-up period, n = 11). Rats′ body weight and echocardiography parameters were monitored before and after drug/vehicle administration. Cardiac histology was performed post-mortem, as well as beta1-adrenergic receptor (β1-AR), beta2-adrenergic receptor (β2-AR), G protein-coupled receptor kinases type 2 (GRK2), type 3 (GRK3), beta-arrestin 1, and beta-arrestin 2 gene expression using RT-qPCR. DOX-treated rats exhibited bad general condition, adynamia, loss of body weight, and low survival. Echocardiography revealed two phenotypes: cardiomyopathy with left ventricular (LV) hypertrophy (DOX-HCM) and cardiomyopathy with LV dilation (DOX-DCM). In DOX-HCM rats only, there was an increased GRK2 and GRK3 gene expression and synthesis. DOX+P co-treated rats exhibited good general condition, normal spontaneous behaviour, gained weight over time, had increased survival, and preserved LV morphology and contractility. In these rats, gene expression and synthesis of GRK2 and GRK3 were decreased, while β1-AR and β2-AR were increased. Present results show for the first time that P effectively reduces DOX-induced cardiotoxicity and enhances survival.Marija KosićZorica NešićSofija GlumacMarko VasićVladislav PajovićBojana SavićNina Japundžić-ŽigonElsevierarticleβ-adrenergic receptorsCardiotoxicityDoxorubicinGRK2GRK3ParoxetineTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 145, Iss , Pp 112411- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	β-adrenergic receptors Cardiotoxicity Doxorubicin GRK2 GRK3 Paroxetine Therapeutics. Pharmacology RM1-950
spellingShingle	β-adrenergic receptors Cardiotoxicity Doxorubicin GRK2 GRK3 Paroxetine Therapeutics. Pharmacology RM1-950 Marija Kosić Zorica Nešić Sofija Glumac Marko Vasić Vladislav Pajović Bojana Savić Nina Japundžić-Žigon Paroxetine mitigates cardiac remodelling by doxorubicin and increases survival
description	Doxorubicin (DOX) is an effective anticancer drug. However, its use is hampered by the development of very mortal cardiomyopathy. Here, we investigate whether the co-administration of the antidepressant paroxetine (P), known to exert beneficial cardiovascular effects, would provide effective cardioprotection. Experiments were performed in male Wistar rats randomly assigned to control group (0.5 mL/kg 0.9% NaCl, i.v., n = 7), DOX group (DOX 5 mg /kg i.v., n = 23) and DOX+P group (DOX 5 mg/kg, i.v. plus P 10 mg/kg p.o. daily, beginning five days before DOX administration and during the follow-up period, n = 11). Rats′ body weight and echocardiography parameters were monitored before and after drug/vehicle administration. Cardiac histology was performed post-mortem, as well as beta1-adrenergic receptor (β1-AR), beta2-adrenergic receptor (β2-AR), G protein-coupled receptor kinases type 2 (GRK2), type 3 (GRK3), beta-arrestin 1, and beta-arrestin 2 gene expression using RT-qPCR. DOX-treated rats exhibited bad general condition, adynamia, loss of body weight, and low survival. Echocardiography revealed two phenotypes: cardiomyopathy with left ventricular (LV) hypertrophy (DOX-HCM) and cardiomyopathy with LV dilation (DOX-DCM). In DOX-HCM rats only, there was an increased GRK2 and GRK3 gene expression and synthesis. DOX+P co-treated rats exhibited good general condition, normal spontaneous behaviour, gained weight over time, had increased survival, and preserved LV morphology and contractility. In these rats, gene expression and synthesis of GRK2 and GRK3 were decreased, while β1-AR and β2-AR were increased. Present results show for the first time that P effectively reduces DOX-induced cardiotoxicity and enhances survival.
format	article
author	Marija Kosić Zorica Nešić Sofija Glumac Marko Vasić Vladislav Pajović Bojana Savić Nina Japundžić-Žigon
author_facet	Marija Kosić Zorica Nešić Sofija Glumac Marko Vasić Vladislav Pajović Bojana Savić Nina Japundžić-Žigon
author_sort	Marija Kosić
title	Paroxetine mitigates cardiac remodelling by doxorubicin and increases survival
title_short	Paroxetine mitigates cardiac remodelling by doxorubicin and increases survival
title_full	Paroxetine mitigates cardiac remodelling by doxorubicin and increases survival
title_fullStr	Paroxetine mitigates cardiac remodelling by doxorubicin and increases survival
title_full_unstemmed	Paroxetine mitigates cardiac remodelling by doxorubicin and increases survival
title_sort	paroxetine mitigates cardiac remodelling by doxorubicin and increases survival
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/ae3305f41fc244d78b45f5e1dcb8c74c
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Paroxetine mitigates cardiac remodelling by doxorubicin and increases survival

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