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Abstract
Objective: The present study was designed to evaluate the effects of Atorvastatin (ATO) plus Melatonin (MEL) on streptozocin-induced Diabetic Retinopathy (DR) in rats.
Methods: Diabetes was induced in Wistar rats with an intraperitoneal injection of streptozocin (50 mg/kg). Animals were randomly assigned to one of the following groups (8 rats/group): Control group, Diabetic group, Diabetic + MEL group (20 mg/kg/day), Diabetic + ATO group (10 mg/kg/day), Diabetic + MEL + ATO group (as above). Treatments were started one week after induction of diabetes and continued for 7 weeks. At the end of the experiment, angiography was performed and the rats were killed and retinas were harvested for pathological and molecular examinations. Results: Administration of MEL reduced the fluorescein leakage, MDA and ROS levels compared to diabetic group. Treatment with ATO only reduced ROS levels compared to diabetic group. In addition, administration of ATO plus MEL decreased these indices compared to the diabetic and ATO groups. Histologically, retinal vascular congestion was not observed in the combined ATO and MEL group as compared to the diabetic, ATO, and MEL groups. Conclusion: These data provide evidence for the therapeutic value of MEL in combination with ATO in clinical practice for prevention of DR.Keywords: Atorvastatin, melatonin, diabetic retinopathy, fluorescein angiography, reactive oxygen species, vascular.
[1]
Wong TY, Cheung CM, Larsen M, Sharma S, Simó R. Diabetic retinopathy. Nat Rev Dis Primers 2016; 2: 16012.
[http://dx.doi.org/10.1038/nrdp.2016.12] [PMID: 27159554]
[http://dx.doi.org/10.1038/nrdp.2016.12] [PMID: 27159554]
[2]
Kaeidi A, Hajializadeh Z, Jahandari F, Fatemi I. Leptin attenuates oxidative stress and neuronal apoptosis in hyperglycemic condition. Fundam Clin Pharmacol 2019; 33(1): 75-83.
[http://dx.doi.org/10.1111/fcp.12411] [PMID: 30203422]
[http://dx.doi.org/10.1111/fcp.12411] [PMID: 30203422]
[3]
Wang W, Lo ACY. Diabetic retinopathy: pathophysiology and treatments. Int J Mol Sci 2018; 19(6): E1816.
[http://dx.doi.org/10.3390/ijms19061816] [PMID: 29925789]
[http://dx.doi.org/10.3390/ijms19061816] [PMID: 29925789]
[4]
Yao Y, Li R, Du J, Li X, Zhao L, Long L, et al. Tumor necrosis factor-alpha and diabetic retinopathy: Review and meta-analysis. Clinica chimica acta; international journal of clinical chemistry 2018 Jun; 28485: 210-7.
[5]
Rasoulian B, Hajializadeh Z, Esmaeili-Mahani S, Rashidipour M, Fatemi I, Kaeidi A. Neuroprotective and antinociceptive effects of rosemary (Rosmarinus officinalis L.) extract in rats with painful diabetic neuropathy. J Physiol Sci 2019; 69(1): 57-64.
[http://dx.doi.org/10.1007/s12576-018-0620-x] [PMID: 29754274]
[http://dx.doi.org/10.1007/s12576-018-0620-x] [PMID: 29754274]
[6]
Liu G, Xu D, Wang F. New insights into diabetic retinopathy by OCT angiography. Diabetes Res Clin Pract 2018; 142: 243-53.
[http://dx.doi.org/10.1016/j.diabres.2018.05.043] [PMID: 29879494]
[http://dx.doi.org/10.1016/j.diabres.2018.05.043] [PMID: 29879494]
[7]
Parveen A, Kim JH, Oh BG, Subedi L, Khan Z, Kim SY. phytochemicals: target-based therapeutic strategies for diabetic retinopathy. Molecules 2018; 23(7): E1519.
[http://dx.doi.org/10.3390/molecules23071519] [PMID: 29937497]
[http://dx.doi.org/10.3390/molecules23071519] [PMID: 29937497]
[8]
Ferreira AM, Marques da Silva P. Defining the Place of Ezetimibe/Atorvastatin in the Management of Hyperlipidemia. American journal of cardiovascular drugs : drugs, devices, and other interventions 2017 Jun; 17(3): 169-81.
[9]
Kaviani E, Rahmani M, Kaeidi A, et al. Protective effect of atorvastatin on d-galactose-induced aging model in mice. Behav Brain Res 2017; 334: 55-60.
[http://dx.doi.org/10.1016/j.bbr.2017.07.029] [PMID: 28750834]
[http://dx.doi.org/10.1016/j.bbr.2017.07.029] [PMID: 28750834]
[10]
Li H, Wang C, Zhang S, et al. Safety profile of atorvastatin 80 mg: a meta-analysis of 17 randomized controlled trials in 21,910 participants. Drug Saf 2016; 39(5): 409-19.
[http://dx.doi.org/10.1007/s40264-016-0394-0] [PMID: 26860922]
[http://dx.doi.org/10.1007/s40264-016-0394-0] [PMID: 26860922]
[11]
Taghipour Z, Kaviani E, Kaeidi A, Shamsizadeh A, Hassanshahi J, Fatemi I. Atorvastatin attenuates D-galactose-induced hepatorenal toxicity in mice: an experimental study with histopathological evaluations. Physiology and Pharmacology 2019; 23(1): 36-43.
[12]
Sironi L, Cimino M, Guerrini U, et al. Treatment with statins after induction of focal ischemia in rats reduces the extent of brain damage. Arterioscler Thromb Vasc Biol 2003; 23(2): 322-7.
[http://dx.doi.org/10.1161/01.ATV.0000044458.23905.3B] [PMID: 12588778]
[http://dx.doi.org/10.1161/01.ATV.0000044458.23905.3B] [PMID: 12588778]
[13]
Piermartiri TC, Vandresen-Filho S, de Araújo Herculano B, et al. Atorvastatin prevents hippocampal cell death due to quinolinic acid-induced seizures in mice by increasing Akt phosphorylation and glutamate uptake. Neurotox Res 2009; 16(2): 106-15.
[http://dx.doi.org/10.1007/s12640-009-9057-6] [PMID: 19526287]
[http://dx.doi.org/10.1007/s12640-009-9057-6] [PMID: 19526287]
[14]
Piermartiri TC, Figueiredo CP, Rial D, et al. Atorvastatin prevents hippocampal cell death, neuroinflammation and oxidative stress following amyloid-β(1-40) administration in mice: evidence for dissociation between cognitive deficits and neuronal damage. Exp Neurol 2010; 226(2): 274-84.
[http://dx.doi.org/10.1016/j.expneurol.2010.08.030] [PMID: 20816828]
[http://dx.doi.org/10.1016/j.expneurol.2010.08.030] [PMID: 20816828]
[15]
Bar-On P, Crews L, Koob AO, et al. Statins reduce neuronal α-synuclein aggregation in in vitro models of Parkinson’s disease. J Neurochem 2008; 105(5): 1656-67.
[http://dx.doi.org/10.1111/j.1471-4159.2008.05254.x] [PMID: 18248604]
[http://dx.doi.org/10.1111/j.1471-4159.2008.05254.x] [PMID: 18248604]
[16]
Bi MC, Song XJ, Shi H, Xue WX, Xu CL, Song E. Effect of atorvastatin on diabetic rat endothelial cells and retinal lesions. Genet Mol Res 2015; 14(2): 5462-7.
[http://dx.doi.org/10.4238/2015.May.22.16] [PMID: 26125742]
[http://dx.doi.org/10.4238/2015.May.22.16] [PMID: 26125742]
[17]
Fernandes R, Bento CF, Matafome P, Sena CM, Seiça RM, Pereira P. Atorvastatin-mediated protection of the retina in a model of diabetes with hyperlipidemia. Can J Physiol Pharmacol 2014; 92(12): 1037-43.
[http://dx.doi.org/10.1139/cjpp-2014-0212] [PMID: 25404034]
[http://dx.doi.org/10.1139/cjpp-2014-0212] [PMID: 25404034]
[18]
Ozkiris A, Erkiliç K, Koç A, Mistik S. Effect of atorvastatin on ocular blood flow velocities in patients with diabetic retinopathy. Br J Ophthalmol 2007; 91(1): 69-73.
[http://dx.doi.org/10.1136/bjo.2006.098285] [PMID: 16973667]
[http://dx.doi.org/10.1136/bjo.2006.098285] [PMID: 16973667]
[19]
Claustrat B, Leston J. Melatonin: Physiological effects in humans. Neurochirurgie 2015; 61(2-3): 77-84.
[http://dx.doi.org/10.1016/j.neuchi.2015.03.002] [PMID: 25908646]
[http://dx.doi.org/10.1016/j.neuchi.2015.03.002] [PMID: 25908646]
[20]
Majidinia M, Sadeghpour A, Mehrzadi S, Reiter RJ, Khatami N, Yousefi B. Melatonin: A pleiotropic molecule that modulates DNA damage response and repair pathways. J Pineal Res 2017; 63(1): e12416.
[http://dx.doi.org/10.1111/jpi.12416] [PMID: 28439991]
[http://dx.doi.org/10.1111/jpi.12416] [PMID: 28439991]
[21]
Mehrzadi S, Safa M, Kamrava SK, Darabi R, Hayat P, Motevalian M. Protective mechanisms of melatonin against hydrogen-peroxide-induced toxicity in human bone-marrow-derived mesenchymal stem cells. Can J Physiol Pharmacol 2017; 95(7): 773-86.
[http://dx.doi.org/10.1139/cjpp-2016-0409] [PMID: 28177678]
[http://dx.doi.org/10.1139/cjpp-2016-0409] [PMID: 28177678]
[22]
Prado NJ, Ferder L, Manucha W, Diez ER. Anti-inflammatory effects of melatonin in obesity and hypertension. Curr Hypertens Rep 2018; 20(5): 45.
[http://dx.doi.org/10.1007/s11906-018-0842-6] [PMID: 29744660]
[http://dx.doi.org/10.1007/s11906-018-0842-6] [PMID: 29744660]
[23]
Bonnefond A, Froguel P. Disentangling the Role of Melatonin and its Receptor MTNR1B in Type 2 Diabetes: Still a Long Way to Go? Curr Diab Rep 2017; 17(12): 122.
[http://dx.doi.org/10.1007/s11892-017-0957-1] [PMID: 29063374]
[http://dx.doi.org/10.1007/s11892-017-0957-1] [PMID: 29063374]
[24]
Majidinia M, Reiter RJ, Shakouri SK, et al. The multiple functions of melatonin in regenerative medicine. Ageing Res Rev 2018; 45: 33-52.
[http://dx.doi.org/10.1016/j.arr.2018.04.003] [PMID: 29630951]
[http://dx.doi.org/10.1016/j.arr.2018.04.003] [PMID: 29630951]
[25]
Galano A, Reiter RJ. Melatonin and its metabolites vs. oxidative stress: From individual actions to collective protection. J Pineal Res 2018; 65(1): e12514.
[http://dx.doi.org/10.1111/jpi.12514] [PMID: 29888508]
[http://dx.doi.org/10.1111/jpi.12514] [PMID: 29888508]
[26]
Goudarzi M, Khodayar MJ, Hosseini Tabatabaei SMT, Ghaznavi H, Fatemi I, Mehrzadi S. Pretreatment with melatonin protects against cyclophosphamide-induced oxidative stress and renal damage in mice. Fundam Clin Pharmacol 2017; 31(6): 625-35.
[http://dx.doi.org/10.1111/fcp.12303] [PMID: 28692163]
[http://dx.doi.org/10.1111/fcp.12303] [PMID: 28692163]
[27]
Aminzadeh A, Mehrzadi S. Melatonin attenuates homocysteine-induced injury in human umbilical vein endothelial cells. Fundam Clin Pharmacol 2018; 32(3): 261-9.
[http://dx.doi.org/10.1111/fcp.12355] [PMID: 29436019]
[http://dx.doi.org/10.1111/fcp.12355] [PMID: 29436019]
[28]
Carpentieri A, Díaz de Barboza G, Areco V, Peralta López M, Tolosa de Talamoni N. New perspectives in melatonin uses. Pharmacol Res 2012; 65(4): 437-44.
[http://dx.doi.org/10.1016/j.phrs.2012.01.003] [PMID: 22311380]
[http://dx.doi.org/10.1016/j.phrs.2012.01.003] [PMID: 22311380]
[29]
Zamfir Chiru AA, Popescu CR, Gheorghe DC. Melatonin and cancer. J Med Life 2014; 7(3): 373-4.
[PMID: 25408757]
[PMID: 25408757]
[30]
Di Bella G, Mascia F, Gualano L, Di Bella L. Melatonin anticancer effects: review. Int J Mol Sci 2013; 14(2): 2410-30.
[http://dx.doi.org/10.3390/ijms14022410] [PMID: 23348932]
[http://dx.doi.org/10.3390/ijms14022410] [PMID: 23348932]
[31]
Gögenur I, Kücükakin B, Panduro Jensen L, Reiter RJ, Rosenberg J. Melatonin reduces cardiac morbidity and markers of myocardial ischemia after elective abdominal aortic aneurism repair: a randomized, placebo-controlled, clinical trial. J Pineal Res 2014; 57(1): 10-5.
[http://dx.doi.org/10.1111/jpi.12138] [PMID: 24708480]
[http://dx.doi.org/10.1111/jpi.12138] [PMID: 24708480]
[32]
Jahanban-Esfahlan R, Mehrzadi S, Reiter RJ, Seidi K, Majidinia M, Baghi HB, et al. Melatonin in regulation of inflammatory pathways in rheumatoid arthritis and osteoarthritis: Involvement of circadian clock genes. Br J Pharmacol 2017.
[PMID: 28585236]
[PMID: 28585236]
[33]
Perepechaeva ML, Stefanova NA, Grishanova AY. Expression of genes for AhR and Nrf2 signal pathways in the retina of OXYS rats during the development of retinopathy and melatonin-induced changes in this process. Bull Exp Biol Med 2014; 157(4): 424-9.
[http://dx.doi.org/10.1007/s10517-014-2582-1] [PMID: 25110076]
[http://dx.doi.org/10.1007/s10517-014-2582-1] [PMID: 25110076]
[34]
Wiechmann AF, Summers JA. Circadian rhythms in the eye: The physiological significance of melatonin receptors in ocular tissues. Prog Retin Eye Res 2008; 27(2): 137-60.
[http://dx.doi.org/10.1016/j.preteyeres.2007.10.001] [PMID: 18316227]
[http://dx.doi.org/10.1016/j.preteyeres.2007.10.001] [PMID: 18316227]
[35]
Huang H, Wang Z, Weng SJ, Sun XH, Yang XL. Neuromodulatory role of melatonin in retinal information processing. Prog Retin Eye Res 2013; 32: 64-87.
[http://dx.doi.org/10.1016/j.preteyeres.2012.07.003] [PMID: 22986412]
[http://dx.doi.org/10.1016/j.preteyeres.2012.07.003] [PMID: 22986412]
[36]
Mehrzadi S, Motevalian M, Rezaei Kanavi M, Fatemi I, Ghaznavi H, Shahriari M. Protective effect of melatonin in the diabetic rat retina. Fundam Clin Pharmacol 2018; 32(4): 414-21.
[http://dx.doi.org/10.1111/fcp.12361] [PMID: 29495082]
[http://dx.doi.org/10.1111/fcp.12361] [PMID: 29495082]
[37]
Salido EM, Bordone M, De Laurentiis A, et al. Therapeutic efficacy of melatonin in reducing retinal damage in an experimental model of early type 2 diabetes in rats. J Pineal Res 2013; 54(2): 179-89.
[http://dx.doi.org/10.1111/jpi.12008] [PMID: 22946773]
[http://dx.doi.org/10.1111/jpi.12008] [PMID: 22946773]
[38]
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]
[http://dx.doi.org/10.1139/cjpp-2015-0277] [PMID: 26762621]
[39]
Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95(2): 351-8.
[http://dx.doi.org/10.1016/0003-2697(79)90738-3] [PMID: 36810]
[http://dx.doi.org/10.1016/0003-2697(79)90738-3] [PMID: 36810]
[40]
Goudarzi M, Mombeini MA, Fatemi I, et al. Neuroprotective effects of Ellagic acid against acrylamide-induced neurotoxicity in rats. Neurol Res 2019; 41(5): 419-28.
[http://dx.doi.org/10.1080/01616412.2019.1576319] [PMID: 30735102]
[http://dx.doi.org/10.1080/01616412.2019.1576319] [PMID: 30735102]
[41]
Shinomol GK. Muralidhara. Differential induction of oxidative impairments in brain regions of male mice following subchronic consumption of Khesari dhal (Lathyrus sativus) and detoxified Khesari dhal. Neurotoxicology 2007; 28(4): 798-806.
[http://dx.doi.org/10.1016/j.neuro.2007.03.002] [PMID: 17451808]
[http://dx.doi.org/10.1016/j.neuro.2007.03.002] [PMID: 17451808]
[42]
Ozdemir G, Ergün Y, Bakariş S, Kılınç M, Durdu H, Ganiyusufoğlu E. Melatonin prevents retinal oxidative stress and vascular changes in diabetic rats. Eye (Lond) 2014; 28(8): 1020-7.
[http://dx.doi.org/10.1038/eye.2014.127] [PMID: 24924441]
[http://dx.doi.org/10.1038/eye.2014.127] [PMID: 24924441]
[43]
Zhang X, Wang N, Barile GR, Bao S, Gillies M. Diabetic retinopathy: neuron protection as a therapeutic target. Int J Biochem Cell Biol 2013; 45(7): 1525-9.
[http://dx.doi.org/10.1016/j.biocel.2013.03.002] [PMID: 23506699]
[http://dx.doi.org/10.1016/j.biocel.2013.03.002] [PMID: 23506699]
[44]
Sharma S, Purohit S, Sharma A, et al. Elevated serum levels of soluble TNF receptors and adhesion molecules are associated with diabetic retinopathy in patients with type-1 diabetes. Mediators Inflamm 2015; 2015: 279393.
[http://dx.doi.org/10.1155/2015/279393] [PMID: 26339132]
[http://dx.doi.org/10.1155/2015/279393] [PMID: 26339132]
[45]
Liochev SI. Reactive oxygen species and the free radical theory of aging. Free Radic Biol Med 2013; 60: 1-4.
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.02.011] [PMID: 23434764]
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.02.011] [PMID: 23434764]
[46]
Arimon M, Takeda S, Post KL, Svirsky S, Hyman BT, Berezovska O. Oxidative stress and lipid peroxidation are upstream of amyloid pathology. Neurobiol Dis 2015; 84: 109-19.
[http://dx.doi.org/10.1016/j.nbd.2015.06.013] [PMID: 26102023]
[http://dx.doi.org/10.1016/j.nbd.2015.06.013] [PMID: 26102023]
[47]
Al-Olayan EM, El-Khadragy MF, Abdel Moneim AE. The protective properties of melatonin against aluminium-induced neuronal injury. Int J Exp Pathol 2015; 96(3): 196-202.
[http://dx.doi.org/10.1111/iep.12122] [PMID: 25891353]
[http://dx.doi.org/10.1111/iep.12122] [PMID: 25891353]
[48]
Kolli VK, Abraham P, Isaac B, Kasthuri N. Preclinical efficacy of melatonin to reduce methotrexate-induced oxidative stress and small intestinal damage in rats. Dig Dis Sci 2013; 58(4): 959-69.
[http://dx.doi.org/10.1007/s10620-012-2437-4] [PMID: 23053903]
[http://dx.doi.org/10.1007/s10620-012-2437-4] [PMID: 23053903]
[49]
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]
[http://dx.doi.org/10.1111/jpi.12362] [PMID: 27555371]
[50]
Hosseinzadeh A, Javad-Moosavi SA, Reiter RJ, Hemati K, Ghaznavi H, Mehrzadi S. Idiopathic Pulmonary Fibrosis (IPF) signaling pathways and protective roles of melatonin. Life Sci 2018; 201: 17-29.
[http://dx.doi.org/10.1016/j.lfs.2018.03.032] [PMID: 29567077]
[http://dx.doi.org/10.1016/j.lfs.2018.03.032] [PMID: 29567077]
[51]
Dehdashtian E, Mehrzadi S, Yousefi B, Hosseinzadeh A, Reiter RJ, Safa M, et al. Diabetic retinopathy pathogenesis and the ameliorating effects of melatonin; involvement of autophagy, inflammation and oxidative stress. Life Sci 2017.
[PMID: 29203148]
[PMID: 29203148]
[52]
Jiang T, Chang Q, Cai J, Fan J, Zhang X, Xu G. Protective effects of melatonin on retinal inflammation and oxidative stress in experimental diabetic retinopathy. Oxid Med Cell Longev 2016; 2016: 3528274.
[http://dx.doi.org/10.1155/2016/3528274] [PMID: 27143993]
[http://dx.doi.org/10.1155/2016/3528274] [PMID: 27143993]
[53]
ATAŞ M. Citirik M. SÖNMEZ K, ÇELİKER Ü. The protective effect of melatonin on the retinas of rats with streptozotocin-induced diabetes mellitus. Turkiye Klinikleri J Med Sci 2011; 31(2): 375-9.
[http://dx.doi.org/10.5336/medsci.2009-16017]
[http://dx.doi.org/10.5336/medsci.2009-16017]
[54]
Nikkhah H, Ahmadieh H, Ramezani A, et al. Safe dose of intravitreal imatinib and its effect on laser-induced choroidal neovascularization: a rat-model experiment. Int J Retina Vitreous 2015; 1(1): 16.
[http://dx.doi.org/10.1186/s40942-015-0017-4] [PMID: 27847609]
[http://dx.doi.org/10.1186/s40942-015-0017-4] [PMID: 27847609]
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