Ratlarda diklofenak ile indüklenen kardiyotoksisite üzerine krisinin etkilerinin oksidatif stres, endoplazmik retikulum stresi ve apoptoz belirteçleri ile değerlendirilmesi

Year 2022, Volume: 15 Issue: 2, 151 - 160, 30.06.2022

Cihan Gür , Özge Kandemir , Fatih Mehmet Kandemir

https://doi.org/10.30607/kvj.1062346

Abstract

Diklofenak (DF), steroid olmayan anti-inflamatuar ilaçlar arasındadır ve yüksek dozlarda kalp dahil çeşitli dokularda toksik etkiler göstermektedir. Krisin (KRS) antioksidan ve anti-apoptotik gibi birçok yararlı etkiye sahiptir. Sunulan çalışmada DF ile indüklenen kardiyotoksisite üzerine KRS’nin etkileri araştırılmıştır. Bu amaçla Sprague Dawley ratlara DF ve/veya KRS uygulamaları yapıldıktan sonra kalp dokularında oksidatif stres, endoplazmik retikulum stresi ve apoptoz belirteçleri ve serum CK-MB seviyeleri analiz edildi. Elde edilen veriler DF ile indüklenen oksidatif stresin KRS uygulamasından sonra SOD, CAT ve GPx enzimlerinin ekspresyonlarının tetiklenmesi ve GSH seviyelerinin artması ile hafiflediğini ve MDA seviyelerinde azalma meydana geldiğini göstermektedir. Ayrıca ER stres belirteçleri olan ve DF’nin indüklediği ATF-6, PERK, IRE1 ve GRP78 ekspresyonlarının KRS tedavisinden sonra aşağı yönlü düzenlendiği belirlendi. ER stresi ile bağlantılı olarak KRS’nin Bax ve Kaspaz-3 ekspresyonlarını baskıladığı ve Bcl-2 ekspresyonunu arttırdığı da elde edilen veriler arasındadır. Ayrıca kalp hasarının önemli bir göstergesi olan CK-MB seviyelerinin KRS uygulamasından sonra azaldığı görüldü. Sonuç olarak DF’nin neden olduğu kardiyotoksisiteye karşı KRS’nin önemli bir koruma sağladığı tespit edildi.

Keywords

Diklofenak, endoplazmik retikulum stresi, kardiyotoksisite, krisin, oksidatif stres

Evaluation of the Effects of Chrysin on Diclofenac-Induced Cardiotoxicity in Rats by the Markers of Oxidative Stress, Endoplasmic Reticulum Stress and Apoptosis

Abstract

Diclofenac (DF) is among non-steroidal anti-inflammatory drugs and in high doses it has toxic effects on various tissues, including the heart. Chrysin (CRS) has many beneficial effects such as antioxidant and anti-apoptotic. In the present study, the effects of CRS on DF-induced cardiotoxicity were investigated. For this purpose, after DF and/or CRS treatments were applied to Sprague Dawley rats, the markers of oxidative stress, endoplasmic reticulum stress and apoptosis in heart tissues and serum CK-MB levels were analyzed. The data obtained displayed that oxidative stress induced by DF was alleviated by triggering the expression of SOD, CAT and GPx enzymes and increasing GSH levels after CRS administration, and a decrease in MDA levels occurred. It was also determined that the expressions of ATF-6, PERK, IRE1 and GRP78, which are ER stress markers and induced by DF, were downregulated after CRS treatment. Additionally, CRS suppressed Bax and Caspase-3 expressions and increased Bcl-2 expression in connection with ER stress. Another finding of this study demonstrated that CK-MB levels, which are an important indicator of heart damage, decreased after CRS administration. As a result, CRS provided a significant protection against cardiotoxicity caused by DF.

Keywords

Cardiotoxicity, chrysin, diclofenac, endoplasmic reticulum stress, oxidative stress

References

• Abdulmajeed N, Alnahdi H, Ayas N, Mohamed A. Amelioration of cardiotoxic impacts of diclofenac sodium by vitamin B complex. Eur Rev Med Pharmacol Sci. 2015; 19: 671-681.
• Adeyemi WJ, Olayaki LA. Diclofenac–induced hepatotoxicity: Low dose of omega-3 fatty acids have more protective effects. Toxicol Rep. 2018; 5: 90-95.
• Aja PM, Izekwe FI, Famurewa AC, Ekpono EU, Nwite FE, Igwenyi IO, Awoke JN, Ani OG, Aloke C, Obasi NA. Hesperidin protects against cadmium-induced pancreatitis by modulating insulin secretion, redox imbalance and iNOS/NF-ĸB signaling in rats. Life Sci. 2020; 259: 118268.
• Aksu EH, Kandemir FM, Küçükler S, Mahamadu A. Improvement in colistin‐induced reproductive damage, apoptosis, and autophagy in testes via reducing oxidative stress by chrysin. J Biochem Mol Toxicol. 2018; 32: e22201.
• AL‐Megrin WA, Alomar S, Alkhuriji AF, Metwally DM, Mohamed SK, Kassab RB, Abdel Moneim AE, El‐Khadragy MF. Luteolin protects against testicular injury induced by lead acetate by activating the Nrf2/HO‐1 pathway. IUBMB life. 2020; 72: 1787-1798.
• Alabi QK, Akomolafe RO. Kolaviron diminishes diclofenac-induced liver and kidney toxicity in wistar rats via suppressing inflammatory events, upregulating antioxidant defenses, and improving hematological indices. Dose-Response. 2020; 18: 1559325819899256.
• Ansari MA, Raish M, Ahmad A, Alkharfy KM, Ahmad SF, Attia SM, Alsaad AM, Bakheet SA. Sinapic acid ameliorate cadmium-induced nephrotoxicity: In vivo possible involvement of oxidative stress, apoptosis, and inflammation via NF-κB downregulation. Environ Toxicol Pharmacol. 2017; 51: 100-107.
• Arafa MH, Mohammad NS, Atteia HH. Rho-Kinase inhibitors ameliorate diclofenac-induced cardiotoxicity in chloroquine-treated adjuvant arthritic rats. Life sci. 2020; 254: 117605.
• Aycan İÖ, Elpek Ö, Akkaya B, Kıraç E, Tuzcu H, Kaya S, Coşkunfırat N, Aslan M. Diclofenac induced gastrointestinal and renal toxicity is alleviated by thymoquinone treatment. Food Chem Toxicol. 2018; 118: 795-804.
• Celik H, Kucukler S, Ozdemir S, Comakli S, Gur C, Kandemir FM, Yardim A. Lycopene protects against central and peripheral neuropathy by inhibiting oxaliplatin-induced ATF-6 pathway, apoptosis, inflammation and oxidative stress in brains and sciatic tissues of rats. Neurotoxicology. 2020; 80: 29-40.
• Çelik H, Kucukler S, Çomaklı S, Caglayan C, Özdemir S, Yardım A, Karaman M, Kandemir FM. Neuroprotective effect of chrysin on isoniazid-induced neurotoxicity via suppression of oxidative stress, inflammation and apoptosis in rats. Neurotoxicology. 2020; 81: 197-208.
• Deng H, Kuang P, Cui H, Chen L, Luo Q, Fang J, Zuo Z, Deng J, Wang X, Zhao L. Sodium fluoride (NaF) induces the splenic apoptosis via endoplasmic reticulum (ER) stress pathway in vivo and in vitro. Aging (Albany NY). 2016; 8: 3552.
• Eldutar E, Kandemir FM, Kucukler S, Caglayan C. Restorative effects of Chrysin pretreatment on oxidant–antioxidant status, inflammatory cytokine production, and apoptotic and autophagic markers in acute paracetamol‐induced hepatotoxicity in rats: an experimental and biochemical study. J Biochem Mol Toxicol. 2017; 31: e21960.
• Foufelle F, Fromenty B. Role of endoplasmic reticulum stress in drug‐induced toxicity. Pharmacol res perspect. 2016; 4: e00211.
• Geng X, Shao H, Zhang Z, Ng JC, Peng C. Malathion-induced testicular toxicity is associated with spermatogenic apoptosis and alterations in testicular enzymes and hormone levels in male Wistar rats. Environ Toxicol Pharmacol. 2015; 39: 659-667.
• Ghosh R, Goswami SK, Feitoza LFB, Hammock B, Gomes AV. Diclofenac induces proteasome and mitochondrial dysfunction in murine cardiomyocytes and hearts. Int J Cardiol. 2016; 223: 923-935.
• Gur C, Kandemir FM, Darendelioglu E, Caglayan C, Kucukler S, Kandemir O, Ileriturk M. Morin protects against acrylamide-induced neurotoxicity in rats: an investigation into different signal pathways. Environ Toxicol Pharmacol. 2021a; 1-12.
• Gur C, Kandemir O, Kandemir FM. Investigation of the effects of hesperidin administration on abamectin‐induced testicular toxicity in rats through oxidative stress, endoplasmic reticulum stress, inflammation, apoptosis, autophagy, and JAK2/STAT3 pathways. Environ Toxicol. 2021b.
• Gür C, Kandemir F, Genç A. Bortezomib ile Kalp Hasarı Oluşturulan Ratlarda Berberinin Oksidatif ve Nitrozatif Stres Üzerine Etkisi. Türk Doğa ve Fen Dergisi. 2020; 9: 118-126.
• Hanedan B, Ozkaraca M, Kirbas A, Kandemir FM, Aktas MS, Kilic K, Comakli S, Kucukler S, Bilgili A. Investigation of the effects of hesperidin and chrysin on renal injury induced by colistin in rats. Biomed Pharmacother. 2018; 108: 1607-1616.
• Ileriturk M, Benzer F, Aksu EH, Yildirim S, Kandemir FM, Dogan T, Dortbudak MB, Genc A. Chrysin protects against testicular toxicity caused by lead acetate in rats with its antioxidant, anti‐inflammatory, and antiapoptotic properties. J Food Biochem. 2021; 45: e13593.
• İleritürk M, Doğan T, Kandemir O. Investigation of the effect of berberine with arginase activity and oxidantantioxidant parameters on bortezomib-induced spleen injury in rats. Kocatepe Vet J. 2021; 14: 6-15.
• Jiang CC, Yang F, Thorne RF, Zhu BK, Hersey P, Zhang XD. Human melanoma cells under endoplasmic reticulum stress acquire resistance to microtubule-targeting drugs through XBP-1-mediated activation of Akt. Neoplasia. 2009; 11: 436-447.
• Kandemir FM, Kucukler S, Caglayan C, Gur C, Batil AA, Gülçin İ. Therapeutic effects of silymarin and naringin on methotrexate‐induced nephrotoxicity in rats: Biochemical evaluation of anti‐inflammatory, antiapoptotic, and antiautophagic properties. J Food Biochem. 2017; 41: e12398.
• Kandemir FM, Yıldırım S, Kucukler S, Caglayan C, Darendelioğlu E, Dortbudak MB. Protective effects of morin against acrylamide-induced hepatotoxicity and nephrotoxicity: A multi-biomarker approach. Food Chem Toxicol. 2020; 138: 111190.
• Kandemir FM, Yildirim S, Kucukler S, Caglayan C, Mahamadu A, Dortbudak MB. Therapeutic efficacy of zingerone against vancomycin-induced oxidative stress, inflammation, apoptosis and aquaporin 1 permeability in rat kidney. Biomed Pharmacother. 2018; 105: 981-991.
• Kucukler S, Benzer F, Yildirim S, Gur C, Kandemir FM, Bengu AS, Ayna A, Caglayan C, Dortbudak MB. Protective effects of chrysin against oxidative stress and inflammation induced by lead acetate in rat kidneys: a biochemical and histopathological approach. Biol Trace Elem Res. 2021; 199: 1501-1514.
• Kuzu M, Kandemir FM, Yıldırım S, Çağlayan C, Küçükler S. Attenuation of sodium arsenite-induced cardiotoxicity and neurotoxicity with the antioxidant, anti-inflammatory, and antiapoptotic effects of hesperidin. Environ Toxicol Pharmacol. 2021; 28: 10818-10831.
• Küçükler S, Kandemir FM, Yıldırım S. Protective effect of chrysin on indomethacin induced gastric ulcer in rats: role of multi-pathway regulation. Biotech Histochem. 2022; 1-14.
• Liu W, Yang B, Wu L, Zou W, Pan X, Zou T, Liu F, Xia L, Wang X, Zhang D. Involvement of NRF2 in perfluorooctanoic acid-induced testicular damage in male mice. Biol Reprod. 2015; 93(2): 41, 41-47.
• Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. methods. 2001; 25: 402-408.
• Oda SS, Derbalah AE. Impact of diclofenac sodium on tilmicosin-induced acute cardiotoxicity in rats (tilmicosin and diclofenac cardiotoxicity). Cardiovasc Toxicol. 2018; 18: 63-75.
• Owumi SE, Aliyu‐Banjo NO, Odunola OA. Selenium attenuates diclofenac‐induced testicular and epididymal toxicity in rats. Andrologia. 2020; 52: e13669.
• Placer ZA, Cushman LL, Johnson BC. Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem. 1966; 16: 359-364.
• Prince SE. Diclofenac-induced renal toxicity in female Wistar albino rats is protected by the pre-treatment of aqueous leaves extract of Madhuca longifolia through suppression of inflammation, oxidative stress and cytokine formation. Biomed Pharmacother. 2018; 98: 45-51.
• Radwan OK, Alzahrani YA, Kassab RB. Neuroprotective efficiency of Mangifera indica leaves extract on cadmium-induced cortical damage in rats. Metab Brain Dis. 2018; 33: 1121-1130.
• Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem. 1968; 25: 192-205.
• Semis HS, Gur C, Ileriturk M, Kandemir FM, Kaynar O. Evaluation of Therapeutic Effects of Quercetin Against Achilles Tendinopathy in Rats via Oxidative Stress, Inflammation, Apoptosis, Autophagy, and Metalloproteinases. Am J Sports Med. 2021a; 03635465211059821.
• Semis HS, Gur C, Ileriturk M, Kaynar O, Kandemir FM. Investigation of the anti-inflammatory effects of caffeic acid phenethyl ester in a model of λ-Carrageenan–induced paw edema in rats. Hum Exp Toxicol. 2021b; 40: S721-S738.
• Semis HS, Kandemir FM, Kaynar O, Dogan T, Arikan SM. The protective effects of hesperidin against paclitaxel-induced peripheral neuropathy in rats. Life Sci. 2021c; 287: 120104.
• Taslimi P, Kandemir FM, Demir Y, İleritürk M, Temel Y, Caglayan C, Gulçin İ. The antidiabetic and anticholinergic effects of chrysin on cyclophosphamide‐induced multiple organ toxicity in rats: Pharmacological evaluation of some metabolic enzyme activities. J Biochem Mol Toxicol. 2019; 33: e22313.
• Temel Y, Kucukler S, Yıldırım S, Caglayan C, Kandemir FM. Protective effect of chrysin on cyclophosphamide-induced hepatotoxicity and nephrotoxicity via the inhibition of oxidative stress, inflammation, and apoptosis. Naunyn Schmiedebergs Arch Pharmacol. 2020; 393: 325-337.
• Yardim A, Kandemir FM, Ozdemir S, Kucukler S, Comakli S, Gur C, Celik H. Quercetin provides protection against the peripheral nerve damage caused by vincristine in rats by suppressing caspase 3, NF-κB, ATF-6 pathways and activating Nrf2, Akt pathways. Neurotoxicology. 2020; 81: 137-146.
• Yardım A, Kucukler S, Özdemir S, Çomaklı S, Caglayan C, Kandemir FM, Çelik H. Silymarin alleviates docetaxel-induced central and peripheral neurotoxicity by reducing oxidative stress, inflammation and apoptosis in rats. Gene. 2021; 769: 145239.
• Yesildag K, Gur C, Ileriturk M, Kandemir FM. Evaluation of oxidative stress, inflammation, apoptosis, oxidative DNA damage and metalloproteinases in the lungs of rats treated with cadmium and carvacrol. Mol Biol Rep. 2021; 1-11.