Abstract
Ovarian torsion is a gynecological emergency that leads to serious outcomes. Nicorandil (NIC) is an ATP-sensitive potassium (KATP) channel activator that protects the heart from ischemia. The current study aimed to investigate the role and mechanism of action of NIC in ovarian ischemia-reperfusion (OIR) and possible KATP participation. Twenty-four female albino rats were classified into 4 groups: sham control, OIR, OIR + NIC, OIR + NIC+ glibenclamide (GLB) groups. Serum anti-Müllerian hormone (AMH), ovarian malondialdehyde (MDA), total nitrites (NOx) contents, and superoxide dismutase (SOD) activity were evaluated. Bax and Bcl2 mRNA were also assessed. Histological and immunohistochemical (anti-COX-2 and anti CD68) studies were done. The OIR non-treated group showed histopathological ovarian injury with decreased AMH level. Ovarian MDA, NOx, and Bax mRNA and the expression of COX-2 and CD68 were increased; however, SOD activity and Bcl2 mRNA level were decreased by OIR. NIC significantly ameliorated the histopathological ovarian injury with the restoration of AMH level. NIC significantly corrected oxidative stress and apoptotic biomarkers with decreased COX-2 and CD68 immunostaining. GLB co-administration significantly decreased the protection afforded by NIC. These results imply that NIC has a protective role against OIR via antioxidant, anti-inflammatory, and anti-apoptotic effects and such protection relies, at least partially, on the KATP channel.
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References
Abdel-Gaber SA, Mohammed RK, Refaie MM (2018) Mechanism mediating the protective effect of diacerein in ischemia-reperfusion-induced testicular injury in rats. Life Sci 209:57–62
Abdel-Gaber SA, Geddawy A, Moussa RA (2019) The hepatoprotective effect of sitagliptin against hepatic ischemia reperfusion-induced injury in rats involves Nrf-2/HO-1 pathway. Pharmacol Rep 71:1044–1049. https://doi.org/10.1016/j.pharep.2019.06.006
Abdel-Raheem IT, Taye A, Abouzied MM (2013) Cardioprotective effects of nicorandil, a mitochondrial potassium channel opener against doxorubicin-induced cardiotoxicity in rats. Basic Clin Pharmacol Toxicol 113:158–166. https://doi.org/10.1111/bcpt.12078
Abdelzaher WY, Bahaa HA, Toni NDM, Sanad AS (2018) Mechanisms underlying the protective effect of montelukast in prevention of endometrial hyperplasia in female rats. Int Immunopharmacol 62:326–333. https://doi.org/10.1016/j.intimp.2018.07.008
Abramov AY, Scorziello A, Duchen MR (2007) Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci 27:1129–1138. https://doi.org/10.1523/jneurosci.4468-06.2007
Ahmed SM, Abdelzaher WY (2016) Zafirlukast alleviates ovarian histological and biochemical alterations induced by ischemia–reperfusion in rats. Kasr Al Ainy Med J 22:129
Akao M, Teshima Y, Marban E (2002) Antiapoptotic effect of nicorandil mediated by mitochondrial atp-sensitive potassium channels in cultured cardiac myocytes. J Am Coll Cardiol 40:803–810
Asfour V, Varma R, Menon P (2015) Clinical risk factors for ovarian torsion. J Obstet Gynaecol 35(7):721–725. https://doi.org/10.3109/01443615
Balsak D, Togrul C, Ekinci C et al (2015) Effects of melatonin on ischemia-reperfusion injury in rat ovary: histopathologic and immunohistochemical study. Open J Obstet Gynecol 05(11):639–645
Bancroft JD, Layton C (2013) The hematoxylins and eosin (7th Edition). In: Suvarna SK, Layton C, Bancroft JD (Eds) Bancroft’s theory and practice of histological techniques, 10. Elsevier, Edinburgh, 173–186
BAŞ H, KARA Ö, Kara M, Pandir D (2013) Protective effect of vardenafil on ischemia–reperfusion injury in rat ovary. Turk J Med Sci 43:684–689
Beyazit F, Buyuk B, Turkon H, Elmas S, Uzun M (2019) Adalimumab mitigates ovarian ischemia-reperfusion injury in rats by regulating oxidative stress, apoptosis and resolution of inflammation. J Obstet Gynaecol Res 45:358–367. https://doi.org/10.1111/jog.13846
Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol 52:302–310. https://doi.org/10.1016/s0076-6879(78)52032-6
Chowdhury UR, Bahler CK, Hann CR, Chang M, Resch ZT, Romero MF, Fautsch MP (2011) ATP-sensitive potassium (KATP) channel activation decreases intraocular pressure in the anterior chamber of the eye. Invest Ophthalmol Vis Sci 52:6435–6442. https://doi.org/10.1167/iovs.11-7523
Côté S (1993) Current protocol for light microscopy immunocytochemistry. Immunohistochemistry II:148–167
Cure MC et al (2016) The protective effect of adalimumab on renal injury in a model of abdominal aorta cross-clamping. Adv Clin Exp Med 25:219–226. https://doi.org/10.17219/acem/33250
Eken MK, Ersoy GS, Kaygusuz EI, Devranoğlu B, Takır M, Çilingir ÖT, Çevik Ö (2019) Etanercept protects ovarian reserve against ischemia/reperfusion injury in a rat model. Arch Med Sci. https://doi.org/10.5114/aoms.2017.72406
El-Kashef DH (2018) Nicorandil ameliorates pulmonary inflammation and fibrosis in a rat model of silicosis. Int Immunopharmacol 64:289–297. https://doi.org/10.1016/j.intimp.2018.09.017
Elshazly SM (2015) Ameliorative effect of nicorandil on high fat diet induced non-alcoholic fatty liver disease in rats. Eur J Pharmacol 748:123–132. https://doi.org/10.1016/j.ejphar.2014.12.017
El-Sheikh AA, Morsy MA, Hamouda AH (2016) Protective mechanisms of thymoquinone on methotrexate-induced intestinal toxicity in rats. Pharmacogn Mag 12:S76–S81. https://doi.org/10.4103/0973-1296.176106
Eser A, Hizli D, Haltas H, Namuslu M, Kosus A, Kosus N, Kafali H (2015) Effects of curcumin on ovarian ischemia-reperfusion injury in a rat model. Biomed Rep 3:807–813. https://doi.org/10.3892/br.2015.515
Finkernagel F et al (2016) The transcriptional signature of human ovarian carcinoma macrophages is associated with extracellular matrix reorganization. Oncotarget 7:75339–75352. https://doi.org/10.18632/oncotarget.12180
Franco L, Talamini G (2009) Cross-talk between inducible nitric oxide synthase and cyclooxygenase in Helicobacter-pylori-induced gastritis. Med Princ Pract 18:477–481
Freeman EW, Sammel MD, Lin H, Gracia CR (2012) Anti-mullerian hormone as a predictor of time to menopause in late reproductive age women. J Clin Endocrinol Metab 97:1673–1680. https://doi.org/10.1210/jc.2011-3032
Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 126:131–138
Hafez HMMZ, Abdel-Ghany H, Zenhom NM, Khalaf MA, Elhussieny M (2017) Nicorandil mitigates renal oxidative damage, apoptotic, and fibrotic changes induced by cyclosporine-A in rats. Egypt J Basic Clin Pharmacol 7:25–36. https://doi.org/10.32527/2017/101423
Horinaka S, Kobayashi N, Higashi T, Hara K, Hara S, Matsuoka H (2001) Nicorandil enhances cardiac endothelial nitric oxide synthase expression via activation of adenosine triphosphate-sensitive K channel in rat. J Cardiovasc Pharmacol 38:200–210
Huang C, Hong MK, Ding DC (2017) A review of ovary torsion. Ci Ji Yi Xue Za Zhi 29:143–147. https://doi.org/10.4103/tcmj.tcmj_55_17
Huchon C, Fauconnier A (2010) Adnexal torsion: a literature review. Eur J Obstet Gynecol Reprod Biol 150:8–12. https://doi.org/10.1016/j.ejogrb.2010.02.006
Jafari A, Pourrazi H, Nikookheslat S, Baradaran B (2015) Effect of exercise training on Bcl-2 and bax gene expression in the rat heart. Gene Cell Tissue 2(4):e60174
Karamese SA, Toktay E, Unal D, Selli J, Karamese M, Malkoc I (2015) The protective effects of beta-carotene against ischemia/reperfusion injury in rat ovarian tissue. Acta Histochem 117:790–797. https://doi.org/10.1016/j.acthis.2015.07.006
Keskin Kurt R et al (2015) Zofenopril attenuates injury induced by ischemia-reperfusion on rat ovary. J Obstet Gynaecol Res 41:926–931. https://doi.org/10.1111/jog.12658
Kumar D, Singla SK, Puri V, Puri S (2015) The restrained expression of NF-kB in renal tissue ameliorates folic acid induced acute kidney injury in mice. PLoS One 10:e115947. https://doi.org/10.1371/journal.pone.0115947
Marklund S, Marklund G (1974) Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47:469–474
Ozlem K, Birkan Y, Mustafa K, Emin K (2018) Protective effect of Vaccinium myrtillus on ischemia- reperfusion injury in rat ovary. Taiwan J Obstet Gynecol 57:836–841. https://doi.org/10.1016/j.tjog.2018.10.012
Patel S, Patel N, Patel V (2017) Anti-fibrotic potential of nicorandil in the treatment of bleomycin induced pulmonary fibrosis. J Young Pharm 9:376–380
Prieto-Moure B, Lloris-Carsí JM, Barrios-Pitarque C, Toledo-Pereyra LH, Lajara-Romance JM, Berda-Antolí M, Lloris-Cejalvo JM, Cejalvo-Lapeña D (2016) Pharmacology of ischemia-reperfusion. Translational Research Considerations. J Investig Surg 29:234–249. https://doi.org/10.3109/08941939.2015.1119219
Refaie MMM, El-Hussieny M (2018) Protective effect of pioglitazone on ovarian ischemia reperfusion injury of female rats via modulation of peroxisome proliferator activated receptor gamma and heme-oxygenase 1. Int Immunopharmacol 62:7–14. https://doi.org/10.1016/j.intimp.2018.06.037
Sahnoun Z, Jamoussi K, Zeghal KM (1998) Free radicals and antioxidants: physiology, human pathology and therapeutic aspects (part II). Therapie 53:315–339
Sayar I, Bicer S, Gursul C, Gürbüzel M, Peker K, Işik A (2016) Protective effects of ellagic acid and ozone on rat ovaries with an ischemia/reperfusion injury. J Obstet Gynaecol Res 42:52–58
Soyman Z, Kelekçi S, Sal V, Şevket O, Bayındır N, Uzun H (2017) Effects of apigenin on experimental ischemia/reperfusion injury in the rat ovary. Balkan Med J 34:444–449. https://doi.org/10.4274/balkanmedj.2016.1386
Su Q, Li L, Zhao J, Sun Y, Yang H (2017) Effects of nicorandil on PI3K/Akt signaling pathway and its anti-apoptotic mechanisms in coronary microembolization in rats. Oncotarget 8:99347–99358. https://doi.org/10.18632/oncotarget.19966
Taira N (1989) Nicorandil as a hybrid between nitrates and potassium channel activators. Am J Cardiol 63:18j–24j
Tamura Y, Tanabe K, Kitagawa W, Uchida S, Schreiner GF, Johnson RJ, Nakagawa T (2012) Nicorandil, a K(atp) channel opener, alleviates chronic renal injury by targeting podocytes and macrophages. Am J Physiol Ren Physiol 303:F339–F349. https://doi.org/10.1152/ajprenal.00158.2012
Tas Hekimoglu A, Toprak G, Akkoc H, Evliyaoglu O, Tas T, Kelle I, Colpan L (2014) Protective effect of 3-aminobenzamide, an inhibitor of poly (ADP-ribose) polymerase in distant liver injury induced by renal ischemia-reperfusion in rats. Eur Rev Med Pharmacol Sci 18:34–38
Tokgoz VY, Sipahi M, Keskin O, Guvendi GF, Takir S (2018) Protective effects of vitamin D on ischemia-reperfusion injury of the ovary in a rat model. Iran J Basic Med Sci 21:593–599. https://doi.org/10.22038/ijbms.2018.26914.6581
Tuncer AA, Bozkurt MF, Koken T, Dogan N, Pektas MK, Baskin Embleton D (2016) The protective effects of alpha-lipoic acid and coenzyme Q10 combination on ovarian ischemia-reperfusion injury: an experimental study. Adv Med 2016:3415046. https://doi.org/10.1155/2016/3415046
VanGuilder HD, Vrana KE, Freeman WM (2008) Twenty-five years of quantitative PCR for gene expression analysis. Biotechniques 44:619–626. https://doi.org/10.2144/000112776
Wimmer I, Zrzavy T, Lassmann H (2018) Neuroinflammatory responses in experimental and human stroke lesions. J Neuroimmunol 323:10–18
Wu RJ, Van der Hoek KH, Ryan NK, Norman RJ, Robker RL (2004) Macrophage contributions to ovarian function. Hum Reprod Update 10:119–133. https://doi.org/10.1093/humupd/dmh011
Wu H, Ye M, Yang J, Ding J, Yang J, Dong W, Wang X (2015) Nicorandil protects the heart from ischemia/reperfusion injury by attenuating endoplasmic reticulum response-induced apoptosis through PI3K/Akt signaling pathway. Cell Physiol Biochem 35:2320–2332. https://doi.org/10.1159/000374035
Yamazaki H et al (2011) The effect of nicorandil on ischemia-reperfusion injury in a porcine total hepatic vascular exclusion model. J Surg Res 167:49–55. https://doi.org/10.1016/j.jss.2009.09.049
Zhang M, Zhang H, Liu C, Li X, Ling M, Wang Z, Xing Y (2018) Myocardial protective effects of nicorandil on rats with type 2 diabetic cardiomyopathy. Med Sci Monit Basic Res 24:141–145. https://doi.org/10.12659/msmbr.910974
Acknowledgments
The authors would like to thank Dr Nagwa Mohammed Zynhom, Lecturer of biochemistry, Biochemistry Department, Faculty of Medicine, Minia University, Egypt, for her kind help and support in the PCR determination part.
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SA, MA, and WY conceived and designed research. SA conducted experiments. WY wrote the manuscript. SM performed and wrote the part of histopathology, immunohistochemistry. MA revised the manuscript. All authors read and approved the manuscript.
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The experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and the protocol was approved by the Faculty of Medicine, Minia University Ethics Committee, for the Care and Use of Laboratory Animals.
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Abdel-Gaber, S.AW., Atta, M., Abdel-Hafez, S.M.N. et al. Ameliorative effect of nicorandil in ovarian ischemia-reperfusion–induced injury in rats: role of potassium channel. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1599–1610 (2020). https://doi.org/10.1007/s00210-020-01854-w
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DOI: https://doi.org/10.1007/s00210-020-01854-w