Stabilization of Mitochondrial Function by Ellagic Acid Prevents Celecoxib-induced Toxicity in Rat Cardiomyocytes and Isolated Mitochondria

Abstract

The possible action of polyphenolic compounds in the reduction of reactive oxygen species (ROS) and mitochondrial toxicity may suggest them as putative agents for the treatment of drug-induced mitochondrial dysfunction and cardiotoxicity. This study was designed to explore protective effect of ellagic acid (EA) against celecoxib-induced cellular and mitochondrial toxicity in cardiomyocytes and their isolated mitochondria. In order to do this, isolated cardiomyocytes and mitochondria were pretreated with 3 different concentrations of EA (10, 50 and 100 µM), after which celecoxib (16 µg/ml) was added to promote deleterious effects on cells and mitochondria. Using flow cytometry and biochemical methods, the parameters of cellular and mitochondrial toxicity were investigated. Our results showed that celecoxib (16 µg/ml) caused a significant decrease in cell viability, mitochondrial membrane potential (MMP), glutathione (GSH) in intact cardiomyocytes and succinate dehydrogenase (SDH) activity, MMP collapse, and mitochondrial swelling, and a significant increase in reactive oxygen species (ROS) formation, lipid peroxidation (LP) and oxidative stress in isolated mitochondria. Also, our results revealed that co-administration of EA (50 and 100 µM) with celecoxib significantly attenuated the cellular and mitochondrial toxicity effects. In this study, we showed that simultaneous treatment with of EA ameliorated the cellular and mitochondrial toxicity induced by celecoxib, with cardiomyocytes presenting normal activity compared to the control group, and mitochondria retaining their normal activity.

Gallic acid inhibits celecoxib-induced mitochondrial permeability transition and reduces its toxicity in isolated cardiomyocytes and mitochondria

“…31 Previous studies and our results in the current work have shown abnormalities in mitochondrial functions such as defects in the SDH activity (mitochondrial complex II), ROS formation, mitochondrial swelling, MMP collapse, lipid peroxidation, and a vicious cycle of free radical formation. 8,31 Due to the high energy demand of the heart, in comparison with other tissues, mitochondria are abundant in heart tissue and about constituting 45% of the cardiomyocytes volume. 32 Accordingly, it can be anticipated that the development of antioxidant and mitochondrial protective agents is a rational strategy to prevent drug-induced oxidative damage and cardiotoxicity.…”

“…Rat heart mitochondria were isolated from the male Wistar rats by the standard technique. 8 After deep anesthesia with a combination of ketamine (50 mg/kg) and xylazine (10 mg/ kg), hearts were quickly excised, chopped, cleared from blood vessels, and homogenized with a glass homogenizer in a 10-fold volume of the mitochondrial isolation buffer at 4°C. The homogenized heart tissue was centrifuged at 1000× g for 10 min, and the pellet was removed.…”

“…3 Celecoxib as selective COX 2 inhibitor dose-dependently induces mitochondria swelling, ROS formation, and cytochrome c release and exerts inhibitory effects on the ETC. 7,8 Rat embryonic H9c2 cardiac cells treated to celecoxib demonstrated a decrease in cell viability, and this was associated with a decrease in the expression of Bcl2 protein. 9 Above studies suggest that mitochondria are the main target organelles through which celecoxib exerts its toxic effect on cardiac cells.…”

Inhibition of Mitochondria Permeability Transition Pore and Antioxidant Effect of Delta-9-Tetrahydrocannabinol Reduces Aluminum Phosphide-Induced Mitochondrial Dysfunction and Cytotoxicity

“…Using the standard protocol and technique, mitochondria were isolated from the heart of male Wistar rats as previously described (Atashbar et al, 2021). The animals were deeply anesthetized with a mixture of ketamine (50 mg/kg) and xylazine (10 mg/kg).…”

Pretreatment of ellagic acid protects ifosfamide-induced acute nephrotoxicity in rat kidneys: A mitochondrial, histopathological and oxidative stress approaches

“…EA is found in vegetables and fruits, such as blackcurrants, walnuts, grapes, raspberries and strawberries [13] . The antioxidant, anti-inflammatory, mitochondrial protection effects of EA have reported in various studies [14] , [15] , [16] , [17] , [18] . Beneficial effects of EA have reported on nephrotoxicity, nephropathy and kidney injury in different models.…”