Mitochondrial Permeability Transition Pore Sealing Agents and Antioxidants Protect Oxidative Stress and Mitochondrial Dysfunction Induced by Naproxen, Diclofenac and Celecoxib

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) like naproxen, diclofenac and celecoxib used to reduce pain. Many of these drugs have been associated with an increased risk of cardiovascular disease (CVD). The molecular mechanism(s) by which NSAIDs induce CVD up to now is unknown. We investigated the effects of naproxen, diclofenac and celecoxib with different structures and mechanism action on isolated rat heart mitochondria. All tested NSAIDs increased reactive oxygen species (ROS) formation, mitochondrial membrane collapse (MMP), mitochondrial swelling, lipid peroxidation, and glutathione and ATP depletion, which all of them play important roles in developing cardiotoxicity. We reported that mitochondrial permeability transition (MPT) pore sealing agents and antioxidants have the capacity to significantly prevent mitochondrial toxicity. Therefore, the inhibition of mitochondrial oxidative stress and mitochondrial dysfunction by MPT pore sealing agents and antioxidants can double confirm NSAID-induced cardiomyocytes toxicity is resulted from induction of apoptosis signaling trough ROS-mediated mitochondrial permeability transition.

Key words

nonsteroidal anti-inflammatory drugs - mitochondria - naproxen - diclofenac - celecoxib - antioxidants

• References

• 1 Ghosh R, Hwang SM, Cui Z. et al. Different effects of the nonsteroidal anti-inflammatory drugs meclofenamate sodium and naproxen sodium on proteasome activity in cardiac cells. Journal of Molecular and Cellular Cardiology 2016; 94: 131-144
• 2 Danelich IM, Wright SS, Lose JM. et al. Safety of nonsteroidal antiinflammatory drugs in patients with cardiovascular disease. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 2015; 35: 520-535
• 3 Helin-Salmivaara A, Virtanen A, Vesalainen R. et al. NSAID use and the risk of hospitalization for first myocardial infarction in the general population: A nationwide case–control study from Finland. European Heart Journal 2006; 27: 1657-1663
• 4 Mamdani M, Juurlink DN, Lee DS. et al. Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: A population-based cohort study. The Lancet 2004; 363: 1751-1756
• 5 Bhala N, Emberson J, Merhi A et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Meta-analyses of individual participant data from randomised trials. In Elsevier; 2013
• 6 Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. jama 2001; 286: 954-959
• 7 Turrens JF, Boveris A. Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria. Biochemical Journal 1980; 191: 421-427
• 8 Ghosh R, Alajbegovic A, Gomes AV. NSAIDs and cardiovascular diseases: Role of reactive oxygen species. Oxidative Medicine and Cellular Longevity 2015; 2015: 536962
• 9 Giordano FJ. Oxygen, oxidative stress, hypoxia, and heart failure. The Journal of Clinical Investigation 2005; 115: 500-508
• 10 Boonstra J, Post JA. Molecular events associated with reactive oxygen species and cell cycle progression in mammalian cells. Gene 2004; 337: 1-13
• 11 Inoue A, Muranaka S, Fujita H. et al. Molecular mechanism of diclofenac-induced apoptosis of promyelocytic leukemia: Dependency on reactive oxygen species, Akt, Bid, cytochrome and caspase pathway. Free Radical Biology and Medicine 2004; 37: 1290-1299
• 12 Liou J-Y, Wu C-C, Chen B-R. et al. Nonsteroidal anti-inflammatory drugs induced endothelial apoptosis by perturbing peroxisome proliferator-activated receptor-δ transcriptional pathway. Molecular pharmacology 2008; 74: 1399-1406
• 13 Ballinger SW. Mitochondrial dysfunction in cardiovascular disease. Free Radical Biology and Medicine 2005; 38: 1278-1295
• 14 Gostimskaya I, Galkin A. Preparation of highly coupled rat heart mitochondria. Journal of Visualized Experiments: JoVE 2010; 43: 2202
• 15 Sedmak JJ, Grossberg SE. A rapid, sensitive, and versatile assay for protein using Coomassie brilliant blue G250. Analytical Biochemistry 1977; 79: 544-552
• 16 Dong L-F, Low P, Dyason JC. et al. α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II. Oncogene 2008; 27: 4324
• 17 Bo H, Jiang N, Ma G. et al. Regulation of mitochondrial uncoupling respiration during exercise in rat heart: Role of reactive oxygen species (ROS) and uncoupling protein 2. Free Radical Biology and Medicine 2008; 44: 1373-1381
• 18 Emaus RK, Grunwald R, Lemasters JJ. Rhodamine 123 as a probe of transmembrane potential in isolated rat-liver mitochondria: spectral and metabolic properties. Biochimica et Biophysica Acta (BBA)-Bioenergetics 1986; 850: 436-448
• 19 Di Lisa F, Menabò R, Canton M. et al. Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+and is a causative event in the death of myocytes in post-ischemic reperfusion of the heart. Journal of Biological Chemistry 2000; 276: 2571-2575
• 20 Buege JA, Aust SD. [30] Microsomal lipid peroxidation. In Methods in enzymology. Elsevier; 1978: 302-310
• 21 Hissin PJ, Hilf R. A fluorometric method for determination of oxidized and reduced glutathione in tissues. Analytical Biochemistry 1976; 74: 214-226
• 22 O'Brien P, Siraki A. Accelerated cytotoxicity mechanism screening using drug metabolising enzyme modulators. Current Drug Metabolism 2005; 6: 101-109
• 23 Nadanaciva S, Aleo MD, Strock CJ. et al. Toxicity assessments of nonsteroidal anti-inflammatory drugs in isolated mitochondria, rat hepatocytes, and zebrafish show good concordance across chemical classes. Toxicology and Applied Pharmacology 2013; 272: 272-280
• 24 Varga ZV, Ferdinandy P, Liaudet L. et al. Drug-induced mitochondrial dysfunction and cardiotoxicity. American Journal of Physiology-Heart and Circulatory Physiology 2015; 309: H1453-H1467
• 25 Paino I, Ximenes V, Da Fonseca L. et al. Effect of therapeutic plasma concentrations of non-steroidal anti-inflammatory drugs on the production of reactive oxygen species by activated rat neutrophils. Brazilian Journal of Medical and Biological Research 2005; 38: 543-551
• 26 Paulson SK, Vaughn MB, Jessen SM. et al. Pharmacokinetics of celecoxib after oral administration in dogs and humans: Effect of food and site of absorption. Journal of Pharmacology and Experimental Therapeutics 2001; 297: 638-645
• 27 Schulz M, Schmoldt A. Therapeutic and toxic blood concentrations of more than 800 drugs and other xenobiotics. Die Pharmazie-An International Journal of Pharmaceutical Sciences 2003; 58: 447-474
• 28 Orrenius S, Gogvadze V, Zhivotovsky B. Mitochondrial oxidative stress: Implications for cell death. Annu Rev Pharmacol Toxicol 2007; 47: 143-183
• 29 Harris DA, Das A. Control of mitochondrial ATP synthesis in the heart. Biochemical Journal 1991; 280: 561
• 30 Pourahmad J, Hosseini MJ. Application of isolated mitochondria in toxicological and clinical studies. Iran J Pharm Res 2012; 11: 703-704