Metformin and Sildenafil Attenuate Inflammation and Suppress Apoptosis After Ischemia/Reperfusion Injuries in Rat Urinary Bladder
2
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
Purpose: Although metformin and sildenafil can protect various organs against ischemia/reperfusion (I/R) injuries, their effects and mechanisms of action in bladder I/R injuries remain unknown. This study investigated the effects and mechanisms of action of metformin and sildenafil against bladder I/R insults in rats. Methods: One hundred male Sprague-Dawley rats were randomly divided into 5 groups, each of which contained 20 rats: a sham-operated group, a bladder I/R group, and bladder I/R groups treated with metformin, sildenafil, or both agents. Ischemia was induced by clamping the bilateral common iliac arteries with atraumatic vascular clamps for 2 hours, followed by reperfusion for 7 days. During this period, rats were injected once daily with 4-mg/kg metformin and/or 1-mg/kg sildenafil. Results: I/R injuries induced increased malondialdehyde levels and myeloperoxidase activity and decreased superoxide dismutase activity. These changes were attenuated by treatment with metformin and/or sildenafil. The I/R group had significantly higher Jun N-terminal kinase, p38 mitogen-activated protein kinase (MAPK), Bax, caspase-3, and nuclear factor-kappa B (NF-κB) levels, and lower extracellular signal-regulated kinase, and Bcl-2 levels in the bladder than the sham-operated group; these changes were significantly ameliorated by metformin and/or sildenafil treatment. No differences in the levels of these markers were observed between rats coadministered metformin and sildenafil and those treated with either agent alone. Conclusions: Metformin and sildenafil protected the rat bladder against I/R injuries. This effect may have been due to the inhibition of reactive oxygen species production through MAPK, Bax, and Bcl-2 activation, and the restoration of inflammation through NF-κB inhibition. However, the combination of metformin and sildenafil was not more effective than either agent alone.
Abstract
Purpose: Although metformin and sildenafil can protect various organs against ischemia/reperfusion (I/R) injuries, their effects and mechanisms of action in bladder I/R injuries remain unknown. This study investigated the effects and mechanisms of action of metformin and sildenafil against bladder I/R insults in rats. Methods: One hundred male Sprague-Dawley rats were randomly divided into 5 groups, each of which contained 20 rats: a sham-operated group, a bladder I/R group, and bladder I/R groups treated with metformin, sildenafil, or both agents. Ischemia was induced by clamping the bilateral common iliac arteries with atraumatic vascular clamps for 2 hours, followed by reperfusion for 7 days. During this period, rats were injected once daily with 4-mg/kg metformin and/or 1-mg/kg sildenafil. Results: I/R injuries induced increased malondialdehyde levels and myeloperoxidase activity and decreased superoxide dismutase activity. These changes were attenuated by treatment with metformin and/or sildenafil. The I/R group had significantly higher Jun N-terminal kinase, p38 mitogen-activated protein kinase (MAPK), Bax, caspase-3, and nuclear factor-kappa B (NF-κB) levels, and lower extracellular signal-regulated kinase, and Bcl-2 levels in the bladder than the sham-operated group; these changes were significantly ameliorated by metformin and/or sildenafil treatment. No differences in the levels of these markers were observed between rats coadministered metformin and sildenafil and those treated with either agent alone. Conclusions: Metformin and sildenafil protected the rat bladder against I/R injuries. This effect may have been due to the inhibition of reactive oxygen species production through MAPK, Bax, and Bcl-2 activation, and the restoration of inflammation through NF-κB inhibition. However, the combination of metformin and sildenafil was not more effective than either agent alone.
참고문헌 (34)
- 서준교, "Comprehensive Review of Effective Application of Questionnaires for Clinical Research on Lower Urinary Tract Symptoms With Translation and Cultural Adaptation to the Korean Language", International Neurourology Journal, 24(4), pp.313~323 (2020), 대한배뇨장애요실금학회[DOI]
- 김도경, "Alpha-1 Adrenergic Receptor Blockers for the Treatment of Lower Urinary Tract Symptoms in Women: A Systematic Review and Meta-Analysis", International Neurourology Journal, 23(1), pp.56~68 (2019), 대한배뇨장애요실금학회[DOI]
- Bratslavsky G, "Reperfusion injury of the rat bladder is worse than ischemia", J Urol, 170, pp.2086~2090 (2003)
- Masuda H, "Reactive oxygen species mediate detrusor overactivity via sensitization of afferent pathway in the bladder of anaesthetized rats", BJU Int, 101, pp.775~780 (2008)
- Liochev SI, "Reactive oxygen species and the free radical theory of aging", Free Radic Biol Med, 60, pp.1~4 (2013)
- Mirmiranpour H, "Comparative effects of pioglitazone and metformin on oxidative stress markers in newly diagnosed type 2diabetes patients : a randomized clinical trial", J Diabetes Complications, 27, pp.501~507 (2013)
- Zhou G, "Role of AMP-activated protein kinase in mechanism of metformin action", J Clin Invest, 108, pp.1167~1174 (2001)
- Ling S, "Metformin potentiateds the effet of arsenic trioxide suppressing intrahepatic cholangiocarcinoma: roles of p38 MAPK, ERK3, and mTORC 1", J Hematol Oncol, 10, pp.59~ (2017)
- Yuan J, "The MAPK and AMPK signalings : interplay and implication in targeted cancer therapy", J Hematol Oncol, 13, pp.113~ (2020)
- Nesti L, "Metformin effects on the heart and the cardiovascular system : a review of experimental and clinical data", Nutr Metab Cardiovasc Dis, 27, pp.657~669 (2017)
- Wang ZS, "Metformin attenuated the inflammation after renal ischemia", reperfusion and suppressed apoptosis of renal tubular epithelial cell in rats, 2015, pp.30, 617~623
- Reffelmann T, "Phosphodiesterase 5 inhibitors : are they cardio-protective", Cardiovasc Res, 83, pp.204~212 (2009)
- Sohotnik R, "Phosphodiesterase-5 inhibition attenuates early renal ischemiareperfusioninduced acute kidney injury : assessment by quantitative measurement of urinary NGAL and KIM-1", Am J Physiol Renal Physiol, 304, pp.1099~1104 (2013)
- Morsy MA, "Sildenafil ameliorates gentamicin-induced nephrotoxicity in rats : role of iNOS and eNOS", J Toxicol, 2014, pp.489382~ (2014)
- Gotoh D, "Tadalafil, a phosphodiesterase type 5 inhibitor, improves bladder blood supply and restores the initial phase of lower urinary tract dysfunction in diabetic rats", Neurourol Urodyn, 37, pp.666~672 (2018)
- Tzanavari T, "Metformin protects against infection-induced myocardial dysfunction", Metabolism, 65, pp.1447~1458 (2016)
- Ozgur BC, "The effect of sildenafil and udenafil on testicular damage following ischemia-reperfusion injury in rats", J Urol, 192, pp.1272~1277 (2014)
- Durak I, "A methodological approach to superoxide dismutase(SOD)activity assay based on inhibition of nitroblue tetrazolium(NBT)reduction", Clin Chim Acta, 214, pp.103~104 (1993)
- Wasowicz W, "Optimized steps in fluorometric determination of thiobarbituric acid reactive substances in serum : importance of extraction pH and influence of sample preservation and storage", Clin Chem, 39, pp.2522~2526 (1993)
- Yang CH, "Dexmedetomidine-ketamine combination mitigates acute lung injury in haemorrhagic shock rats", Resuscitation, 80, pp.1204~1210 (2009)
- Levin RM, "Effects of ganoderma lucidum shell-broken spore on oxidative stress of the rabbit urinary bladder using an in vivo model of ischemia", reperfusion, 2017, pp.435, 25~35
- Rosen P, "Metformin delays the manifestation of diabetes and vascular dysfunction in Goto-Kakizaki rats by reduction of mitochondrial oxidative stress", Diabetes Metab Res Rev, 22, pp.323~330 (2006)
- Taheri N, "Study the ef fects of metformin on renal function and structure after unilateral ischemia-reperfusion in rat", Res Pharm Sci, 7, pp.77~ (2012)
- Sung JY, "Metformin-induced AMP-activated protein kinase activation regulates phenylephrine-mediated contraction of rat aorta", Biochem Biophys Res Commun, 421, pp.599~604 (2012)
- Scheepe JR, "Influence of sildenafil on blood oxgen saturation of the obstructed bladder", BMC Urol, 14, pp.44~ (2014)
- H oxidase induced by the thromboxane A2 mimetic, U46619, in corpus cavernosal smooth muscle cells, "BJU Int", 2005, 423~427
- Plotnikov A, "The MAPK cascades:Signaling components, nuclear roles and mechanisms of nuclear translocation", Biochim Biophys Acta, 1813, pp.1619~1633 (2011)
- Son Y, "Reactive oxygen species in the activation of MAP kinases", Methods Enzymol, 528, pp.27~48 (2013)
- McCubrey JA, "Reactive oxygen speciesinduced activation of the MAP kinase signaling pathways", Antioxid Redox Signal, 8, pp.1775~1789 (2006)
- Muhammad Shahid, "Pioglitazone Alters the Proteomes of Normal Bladder Epithelial Cells but Shows No Tumorigenic Effects", International Neurourology Journal, 24(1), pp.29~40 (2020), 대한배뇨장애요실금학회[DOI]
- 신말순, "Long-term Surgical and Chemical Castration Deteriorates Memory Function Through Downregulation of PKA", CREB, MEK, pp.ERK Pathways in Hippocampus, International Neurourology Journal[DOI]
- Choi YH, "Pharmacokinetic interaction between DA-8159, a new erectogenic, and metformin in rats: competitive inhibition of metabolism via hepatic CYP3A1", 2, 2008, pp.153, 1568~1578
- 노정호, "Polydeoxyribonucleotide Ameliorates Inflammation and Apoptosis in Achilles Tendon-Injury Rats", International Neurourology Journal, 24, pp.79~87 (2020), 대한배뇨장애요실금학회[DOI]
- Hattori Y, "Metformin inhibits cytokine-induced neclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells", Hypertension, 47, pp.1183~1188 (2006)