Login Register Cart 0
Generic placeholder image

Current Drug Safety

Editor-in-Chief

ISSN (Print): 1574-8863
ISSN (Online): 2212-3911

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Evaluating the Protective Effect of Melatonin on Atorvastatin-induced Mitochondrial Toxicity in Pancreatic Beta Cells

Author(s): Saeed Mehrzadi, Asieh Hosseini and Azam Hosseinzadeh*

Volume 19, Issue 4, 2024

Published on: 01 November, 2023

Page: [455 - 464] Pages: 10

DOI: 10.2174/0115748863267262231025052412

Price: $65

Abstract

Background: Atorvastatin and other statins belong to a category of cholesterollowering drugs, which may cause some damage to pancreatic cells despite their effectiveness.

Aims: The present study investigated the effects of melatonin against atorvastatin-induced toxicity on islets of Langerhans and CRI-D2 cells.

Methods: The MTT assay was used to determine cell viability. The effect of various concentrations of melatonin (0,10, 50, 100, 250, 500 and 1000 μM) on CRI-D2 cell viability was evaluated for 24 hours to determine the non-cytotoxic concentrations of melatonin. Additionally, cells were treated with different concentrations of atorvastatin (10, 100, and 150 ng/mL) for 24 hours to determine a concentration that could induce the maximum cell death. After selecting the appropriate concentrations for melatonin, cells were treated with atorvastatin (10, 100, and 150 ng/ml) and melatonin (10 and 100 μM) simultaneously for a period of 24 hours. Malondialdehyde (MDA), reactive oxygen species (ROS), superoxide dismutase, catalase, and glutathione peroxidase activity were assessed as indicators of oxidative stress. To assess mitochondrial function, the ratio of adenosine diphosphate (ADP) to adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP) were measured.

Results: Atorvastatin markedly raised ROS and MDA levels. This result was associated with a decrease in MMP, an increase in the ADP/ATP ratio, and a change in the activity of antioxidant enzymes. Atorvastatin (150 ng/mL)-induced mitochondrial damage was alleviated by concurrent melatonin and atorvastatin therapy.

Conclusion: These results suggest that melatonin has a protective effect against atorvastatininduced toxicity in the mitochondria of pancreatic cells.

Keywords: Melatonin, atorvastatin, pharmacology, toxicology, mitochondria, oxidative stress.

« Previous Next »
Graphical Abstract

[1]
Juybari KB, Hosseinzadeh A, Sharifi AM. Protective effects of atorvastatin against high glucose-induced nuclear factor-κB activation in cultured C28I2 chondrocytes. J Recept Signal Transduct Res 2019; 39(1): 1-8.
[http://dx.doi.org/10.1080/10799893.2018.1557206] [PMID: 31237181]
[2]
Hosseinzadeh A, Mehrzadi S, Rezaei M, Badavi M, Nesari A, Goudarzi M. Lovastatin attenuates glyoxal-induced toxicity on rat liver mitochondria. Hum Exp Toxicol 2021; 40(12): 2215-22.
[http://dx.doi.org/10.1177/09603271211027939] [PMID: 34165024]
[3]
Hosseinzadeh A, Bahrampour Juybari K, Kamarul T, Sharifi AM. Protective effects of atorvastatin on high glucose-induced oxidative stress and mitochondrial apoptotic signaling pathways in cultured chondrocytes. J Physiol Biochem 2019; 75(2): 153-62.
[http://dx.doi.org/10.1007/s13105-019-00666-8] [PMID: 30796627]
[4]
Diamantis E, Kyriakos G, Quiles-Sanchez LV, Farmaki P, Troupis T. The anti-inflammatory effects of statins on coronary artery disease: An updated review of the literature. Curr Cardiol Rev 2017; 13(3): 209-16.
[PMID: 28462692]
[5]
Sinitsky M, Asanov M, Sinitskaya A, et al. Atorvastatin can modulate DNA damage repair in endothelial cells exposed to Mitomycin C. Int J Mol Sci 2023; 24(7): 6783.
[http://dx.doi.org/10.3390/ijms24076783] [PMID: 37047754]
[6]
Abbasi F, Lamendola C, Harris CS, et al. Statins are associated with increased insulin resistance and secretion. Arterioscler Thromb Vasc Biol 2021; 41(11): 2786-97.
[http://dx.doi.org/10.1161/ATVBAHA.121.316159] [PMID: 34433298]
[7]
Henriksbo BD, Tamrakar AK, Phulka JS, Barra NG, Schertzer JD. Statins activate the NLRP3 inflammasome and impair insulin signaling via p38 and mTOR. Am J Physiol Endocrinol Metab 2020; 319(1): E110-6.
[http://dx.doi.org/10.1152/ajpendo.00125.2020] [PMID: 32421368]
[8]
Lai SW, Lin CL, Liao KF. Atorvastatin use associated with acute pancreatitis. Medicine 2016; 95(7): e2545.
[http://dx.doi.org/10.1097/MD.0000000000002545] [PMID: 26886597]
[9]
Bonifacio A, Mullen PJ, Mityko IS, Navegantes LC, Bouitbir J, Krähenbühl S. Simvastatin induces mitochondrial dysfunction and increased atrogin-1 expression in H9c2 cardiomyocytes and mice in vivo. Arch Toxicol 2016; 90(1): 203-15.
[http://dx.doi.org/10.1007/s00204-014-1378-4] [PMID: 25300705]
[10]
Mollazadeh H, Tavana E, Fanni G, et al. Effects of statins on mitochondrial pathways. J Cachexia Sarcopenia Muscle 2021; 12(2): 237-51.
[http://dx.doi.org/10.1002/jcsm.12654] [PMID: 33511728]
[11]
Rocha M, Apostolova N, Diaz-Rua R, Muntane J, Victor VM. Mitochondria and T2D: Role of autophagy, ER stress, and inflammasome. Trends Endocrinol Metab 2020; 31(10): 725-41.
[http://dx.doi.org/10.1016/j.tem.2020.03.004] [PMID: 32265079]
[12]
Haythorne E, Rohm M, van de Bunt M, et al. Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells. Nat Commun 2019; 10(1): 2474.
[http://dx.doi.org/10.1038/s41467-019-10189-x] [PMID: 31171772]
[13]
Sadighara M, Amirsheardost Z, Minaiyan M, et al. Toxicity of atorvastatin on pancreas mitochondria: A justification for increased risk of diabetes mellitus. Basic Clin Pharmacol Toxicol 2017; 120(2): 131-7.
[http://dx.doi.org/10.1111/bcpt.12656] [PMID: 27553485]
[14]
Bagherifard A, Hosseinzadeh A, Koosha F, et al. Melatonin and bone-related diseases: An updated mechanistic overview of current evidence and future prospects. Osteoporos Int 2023; 34(10): 1677-701.
[http://dx.doi.org/10.1007/s00198-023-06836-1] [PMID: 37393580]
[15]
Hemati K, Pourhanifeh MH, Fatemi I, Hosseinzadeh A, Mehrzadi S. Anti-degenerative effect of melatonin on intervertebral disc: Protective contribution against inflammation, oxidative stress, apoptosis, and autophagy. Curr Drug Targets 2022; 23(7): 711-8.
[http://dx.doi.org/10.2174/1389450123666220114151654] [PMID: 35034592]
[16]
Hosseinzadeh A, Bagherifard A, Koosha F, et al. Melatonin effect on platelets and coagulation: Implications for a prophylactic indication in COVID-19. Life Sci 2022; 307: 120866.
[http://dx.doi.org/10.1016/j.lfs.2022.120866] [PMID: 35944663]
[17]
Bahrami N, Goudarzi M, Hosseinzadeh A, Sabbagh S, Reiter RJ, Mehrzadi S. Evaluating the protective effects of melatonin on di(2-ethylhexyl) phthalate-induced testicular injury in adult mice. Biomed Pharmacother 2018; 108: 515-23.
[http://dx.doi.org/10.1016/j.biopha.2018.09.044] [PMID: 30243084]
[18]
Mehrzadi S, Pourhanifeh MH, Mirzaei A, Moradian F, Hosseinzadeh A. An updated review of mechanistic potentials of melatonin against cancer: Pivotal roles in angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress. Cancer Cell Int 2021; 21(1): 188.
[http://dx.doi.org/10.1186/s12935-021-01892-1] [PMID: 33789681]
[19]
Pourhanifeh MH, Mehrzadi S, Hosseinzadeh A. Melatonin and regulation of miRNAs: Novel targeted therapy for cancerous and noncancerous disease. Epigenomics 2021; 13(1): 65-81.
[http://dx.doi.org/10.2217/epi-2020-0241] [PMID: 33350862]
[20]
Pourhanifeh MH, Dehdashtian E, Hosseinzadeh A, Sezavar SH, Mehrzadi S. Clinical application of melatonin in the treatment of cardiovascular diseases: Current evidence and new insights into the cardioprotective and cardiotherapeutic properties. Cardiovasc Drugs Ther 2020; 1-25.
[PMID: 32926271]
[21]
Hosseinzadeh A, Dehdashtian E, Jafari-Sabet M, Mehrzadi S. The effects of vitamin D3 and melatonin combination on pentylenetetrazole-induced seizures in mice. Cent Nerv Syst Agents Med Chem 2022; 22(2): 118-24.
[22]
Hosseinzadeh A, Mehrzadi S, Dehdashtian E, Karimi MY. The anticonvulsant activity of thiamine, vitamin D3, and melatonin combination on pentylenetetrazole-induced seizures in mice. Curr Drug Ther 2022; 17(4): 281-8.
[http://dx.doi.org/10.2174/1574885517666220531104009]
[23]
Dehdashtian E, Hosseinzadeh A, Hemati K, Karimi MY, Fatemi I, Mehrzadi S. Anti-convulsive effect of thiamine and melatonin combination in mice: Involvement of oxidative stress. Cent Nerv Syst Agents in Med Chem 2021; 21(2): 125-9.
[http://dx.doi.org/10.2174/1871524921666210623161212]
[24]
Liampas I, Siokas V, Brotis A, Vikelis M, Dardiotis E. Endogenous melatonin levels and therapeutic use of exogenous melatonin in migraine: Systematic review and meta‐analysis. Headache 2020; 60(7): 1273-99.
[http://dx.doi.org/10.1111/head.13828] [PMID: 32352572]
[25]
Liampas I, Siokas V, Brotis A, et al. Meta‐analysis of melatonin levels in cluster headache—Review of clinical implications. Acta Neurol Scand 2020; 142(4): 356-67.
[http://dx.doi.org/10.1111/ane.13317] [PMID: 32677039]
[26]
Mehrzadi S, Karimi MY, Fatemi A, Reiter RJ, Hosseinzadeh A. SARS-CoV-2 and other coronaviruses negatively influence mitochondrial quality control: Beneficial effects of melatonin. Pharmacol Ther 2021; 224: 107825.
[http://dx.doi.org/10.1016/j.pharmthera.2021.107825] [PMID: 33662449]
[27]
Pourhanifeh MH, Kamali M, Mehrzadi S, Hosseinzadeh A. Melatonin and neuroblastoma: A novel therapeutic approach. Mol Biol Rep 2021; 48(5): 4659-65.
[http://dx.doi.org/10.1007/s11033-021-06439-1] [PMID: 34061325]
[28]
Moradian F, Pourhanifeh MH, Mehrzadi S, Karimi-Behnagh A, Hosseinzadeh A. Therapeutic potentials of melatonin in the treatment of lymphoma: A review of current evidence. Fundam Clin Pharmacol 2022; 36(5): 777-89.
[http://dx.doi.org/10.1111/fcp.12780] [PMID: 35384044]
[29]
Chou Y-C, Wang Y-K, Charng M-J, Ueng Y-F. Determination of serum atorvastatin concentrations in lipid-controlling patients with and without myalgia syndrome. Yao Wu Shi Pin Fen Xi 2013; 21(2): 147-53.
[30]
Kussmaul L, Hamprecht B, Dringen R. The detoxification of cumene hydroperoxide by the glutathione system of cultured astroglial cells hinges on hexose availability for the regeneration of NADPH. J Neurochem 1999; 73(3): 1246-53.
[http://dx.doi.org/10.1046/j.1471-4159.1999.0731246.x] [PMID: 10461918]
[31]
Ghafour-boroujerdi E, Rahmani S, Sanadgol N, Baeeri M, Hassani S. Investigation of alpha-lipoic acid effect on memory impairment considering strain-dependent differences in mice. Life Sci 2021; 281: 119766.
[http://dx.doi.org/10.1016/j.lfs.2021.119766] [PMID: 34186041]
[32]
Ward NC, Watts GF, Eckel RH. Statin toxicity. Circ Res 2019; 124(2): 328-50.
[http://dx.doi.org/10.1161/CIRCRESAHA.118.312782] [PMID: 30653440]
[33]
Urbano F, Bugliani M, Filippello A, et al. Atorvastatin but not pravastatin impairs mitochondrial function in human pancreatic islets and rat β-Cells. Direct effect of oxidative stress. Sci Rep 2017; 7(1): 11863.
[http://dx.doi.org/10.1038/s41598-017-11070-x] [PMID: 28928397]
[34]
Bonifacio A, Sanvee GM, Bouitbir J, Krähenbühl S. The AKT/mTOR signaling pathway plays a key role in statin-induced myotoxicity. Biochim Biophys Acta Mol Cell Res 2015; 1853(8): 1841-9.
[http://dx.doi.org/10.1016/j.bbamcr.2015.04.010] [PMID: 25913013]
[35]
Bouitbir J, Charles AL, Echaniz-Laguna A, et al. Opposite effects of statins on mitochondria of cardiac and skeletal muscles: A ‘mitohormesis’ mechanism involving reactive oxygen species and PGC-1. Eur Heart J 2012; 33(11): 1397-407.
[http://dx.doi.org/10.1093/eurheartj/ehr224] [PMID: 21775390]
[36]
Mehrzadi S, Hemati K, Reiter RJ, Hosseinzadeh A. Mitochondrial dysfunction in age-related macular degeneration: Melatonin as a potential treatment. Expert Opin Ther Targets 2020; 24(4): 359-78.
[http://dx.doi.org/10.1080/14728222.2020.1737015]
[37]
Hosseinzadeh A, Kamrava SK, Joghataei MT, et al. Apoptosis signaling pathways in osteoarthritis and possible protective role of melatonin. J Pineal Res 2016; 61(4): 411-25.
[http://dx.doi.org/10.1111/jpi.12362] [PMID: 27555371]
[38]
Pourhanifeh MH, Hosseinzadeh A, Dehdashtian E, Hemati K, Mehrzadi S. Melatonin: New insights on its therapeutic properties in diabetic complications. Diabetol Metab Syndr 2020; 12(1): 30.
[http://dx.doi.org/10.1186/s13098-020-00537-z] [PMID: 32280378]
[39]
Pourhanifeh MH, Mehrzadi S, Kamali M, Hosseinzadeh A. Melatonin and gastrointestinal cancers: Current evidence based on underlying signaling pathways. Eur J Pharmacol 2020; 886: 173471.
[http://dx.doi.org/10.1016/j.ejphar.2020.173471] [PMID: 32877658]
[40]
Dehdashtian E, Pourhanifeh MH, Hemati K, Mehrzadi S, Hosseinzadeh A. Therapeutic application of nutraceuticals in diabetic nephropathy: Current evidence and future implications. Diabetes Metab Res Rev 2020; 36(8): e3336.
[http://dx.doi.org/10.1002/dmrr.3336] [PMID: 32415805]
[41]
Suofu Y, Li W, Jean-Alphonse FG, et al. Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. Proc Natl Acad Sci USA 2017; 114(38): E7997-8006.
[http://dx.doi.org/10.1073/pnas.1705768114] [PMID: 28874589]
[42]
Zhang JJ, Meng X, Li Y, et al. Effects of melatonin on liver injuries and diseases. Int J Mol Sci 2017; 18(4): 673.
[http://dx.doi.org/10.3390/ijms18040673] [PMID: 28333073]
[43]
Mehrzadi S, Kamrava SK, Dormanesh B, et al. Melatonin synergistically enhances protective effect of atorvastatin against gentamicin-induced nephrotoxicity in rat kidney. Can J Physiol Pharmacol 2016; 94(3): 265-71.
[http://dx.doi.org/10.1139/cjpp-2015-0277] [PMID: 26762621]
[44]
Nikoui V, Hosseinzadeh A, Khotab SJ, Mousavi SZ, Abolmaali M, Mehrzadi S. Antidepressant-like properties of melatonin and atorvastatin combination following the restraint stress in mice: A study of oxidative stress factors. Cent Ner Sys Agents Med Chem 2023; 23(1): 32-9.
[http://dx.doi.org/10.2174/1871524923666221121111501]
[45]
Gürpınar T, Ekerbicer N, Uysal N, Barut T, Tarakçı F, Tuğlu M. The histologic evaluation of atorvastatin and melatonin treatment on oxidative stress and apoptosis of diabetic rat pancreas. Kafkas Univ Vet Fak Derg 2010; 16(4): 547-52.
[46]
Dayoub JC, Ortiz F, López LC, et al. Synergism between melatonin and atorvastatin against endothelial cell damage induced by lipopolysaccharide. J Pineal Res 2011; 51(3): 324-30.
[http://dx.doi.org/10.1111/j.1600-079X.2011.00892.x] [PMID: 21585521]
[47]
Orendáš P, Kubatka P, Bojková B, et al. Melatonin potentiates the anti-tumour effect of pravastatin in rat mammary gland carcinoma model. Int J Exp Pathol 2014; 95(6): 401-10.
[http://dx.doi.org/10.1111/iep.12094] [PMID: 25270735]
[48]
Kubatka P, Bojková B, Kassayová M, et al. Combination of Pitavastatin and melatonin shows partial antineoplastic effects in a rat breast carcinoma model. Acta Histochem 2014; 116(8): 1454-61.
[http://dx.doi.org/10.1016/j.acthis.2014.09.010] [PMID: 25450902]
[49]
Simko F, Pechanova O, Pelouch V, et al. Effect of melatonin, captopril, spironolactone and simvastatin on blood pressure and left ventricular remodelling in spontaneously hypertensive rats. J Hypertens 2009; 27(6): S5-S10.
[http://dx.doi.org/10.1097/01.hjh.0000358830.95439.e8] [PMID: 19633453]
[50]
Koç O, Tüz HH, Ocak M, Bilecenoğlu B, Fırat A, Kaymaz FF. Can the combination of simvastatin and melatonin create a synergistic effect on bone regeneration? J Oral Maxillofac Surg 2021; 79(8): 1672-82.
[http://dx.doi.org/10.1016/j.joms.2020.12.044] [PMID: 33524327]

Rights & Permissions Print Cite
Article Metrics
8
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy