Publication Details

Title :

Carnitine Supplementation Attenuates Sunitinib-Induced Inhibition of AMP-Activated Protein Kinase Downstream Signals in Cardiac Tissues

Journal:

Cardiovascular Toxicology

Impact Factor:

2.989

Authors:

Mohamed M. Sayed-Ahmed 1, Badr I. Alrufaiq 2, Ammar Alrikabi 3, Mashan L. Abdullah 4, Mohamed M. Hafez 5, Othman A. Al-Shabanah 2

Affiliations:

1 Pharmacology, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
 2 Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia
 3 Pathology Department, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
 4 King Abdullah International Medical Research Center, Riyadh, Kingdom of Saudi Arabia
 5 Virology and Immunology Units, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt

Year of Publication:

2019

DOI:

doi.org/10.1007/s12012-018-9500-0

Abstract:

This study has been initiated to investigate whether sunitinib (SUN) alters the expression of key genes engaged in mitochondrial transport and oxidation of long chain fatty acids (LCFA), and if so, whether these alterations should be viewed as a mechanism of SUN-induced cardiotoxicity, and to explore the molecular mechanisms whereby carnitine supplementation could attenuate SUN-induced cardiotoxicity. Adult male Wister albino rats were assigned to one of the four treatment groups: Rats in group 1 received no treatment but free access to tap water for 28 days. Rats in group 2 received l-carnitine (200 mg/kg/day) in drinking water for 28 days. Rats in group 3 received SUN (25 mg/kg/day) in drinking water for 28 days. Rats in group 4 received the same doses of l-carnitine and SUN in drinking water for 28 days. Treatment with SUN significantly increased heart weight, cardiac index, and cardiotoxicity enzymatic indices, as well as severe histopathological changes. Moreover, SUN significantly decreased level of adenosine monophosphate-activated protein kinase (AMPKα2), total carnitine, adenosine triphosphate (ATP) and carnitine palmitoyltransferase I (CPT I) expression and significantly increased acetyl-CoA carboxylase-2 (ACC2) expression and malonyl-CoA level in cardiac tissues. Interestingly, carnitine supplementation resulted in a complete reversal of all the biochemical, gene expression and histopathological changes-induced by SUN to the control values. In conclusion, data from this study suggest that SUN inhibits AMPK downstream signaling with the consequent inhibition of mitochondrial transport of LCFA and energy production in cardiac tissues. Carnitine supplementation attenuates SUN-induced cardiotoxicity.