Pioglitazone abrogates testicular damage induced by testicular torsion/detorsion in rats

Document Type : Original Article


Department of Pharmacology, Faculty of Medicine, Zagazig University, Egypt


Objective(s): Testicular torsion/detorsion (T/D) is a well-known cause for infertility. Pioglitazone is an agonist of peroxisome proliferator activated receptor-gamma (PPAR-γ). Previous studies have shown that pioglitazone has anti-inflammatory, antioxidant and antiapoptotic properties. The present study hypothesized that pioglitazone may be protective against the testicular T/D tissue insults, and the possible pathophysiological mechanisms involved in this effect were also investigated.
Materials and Methods: Rats were randomly divided into four groups: sham group, T/D group where testicular torsion was performed for 4 hr followed by 4 hr of detorsion and two pioglitazone-treated groups (1 mg/kg and 3 mg/kg, by single intraperitoneal injection 30 min prior to detorsion). At the end of reperfusion period, blood, ipsilateral and contralateral testicular tissue samples were obtained for biochemical and histopathological examination.
Results: Pioglitazone reduced oxidative tissue damages, inflammatory mediators, and apoptotic markers and enhanced the total antioxidant status, and AMP-activated protein kinase level. Moreover, pioglitazone improved spermatogenesis evidenced by increased Johnsen’s score and reversed the histopathological damages induced by testicular T/D. The effects of pioglitazone were higher with the dose of 3 mg/kg.
Conclusion: Pioglitazone exhibited a protective effect against the deleterious actions of testicular T/D. This beneficial potential of pioglitazone may be attributed to its antioxidant, anti-inflammatory and antiapoptotic properties, which was more obvious with the dose of 3 mg/kg. Pioglitazone may be a promising therapy for testicular T/D.


Main Subjects

Arevalo M K, Sheth KR, Menon VS, Ostrov L, Henns H, Singla N, et al. Straight to the Operating Room: An Emergent Surgery Track for Acute Testicular Torsion Transfers. J Pediatr 2018;192:178-183.
Ghasemnejad-Berenji M, Ghazi-Khansari M, Yazdani I, Saravi SSS, Nobakht M, Abdollahi A, et al. Rapamycin protects testes against germ cell apoptosis and oxidative stress induced by testicular ischemia-reperfusion. Iran J Basic Med Sci 2017; 8, 905-911.
Parlaktas BS, Atilgan D, Ozyurt H, Gencten Y, Akbas A, Erdemir F, et al. The biochemical effects of ischemia-reperfusion injury in the ipsilateral and contralateral testes of rats and the protective role of melatonin. Asian J Androl 2014; 2: 314-318.
Kanter M. Protective effects of melatonin on testicular torsion/detorsion-induced ischemia-reperfusion injury in rats. Exp Mol Pathol 2010; 3: 314-320.
Taati M, Moghadasi M, Dezfoulian O, Asadian P, Zendehdel M. Effects of Ghrelin on germ cell apoptosis and proinflammatory cytokines production in Ischemia-reperfusion of the rat testis. Iran J Reprod Med 2015; 2: 85-92.
Bonato JM, Bassani TB, Milani H, Vital MABF, de Olivera RMW. Pioglitazone reduces mortality, prevents depressive-like behavior, and impacts hippocampal neurogenesis in the 6-OHDA model of Parkinson’s disease in rats. Exp Neurol 2017; 300: 188-200.
Sekulic-Jablanovic M, Petkovic V, Wright M B, Kucharaya k, Huerzeler N, Levano S ,et al. Effects of peroxisome proliferator activated receptors (PPAR)-γ and -α agonists on cochlear protection from oxidative stress. PLoS One 2017; 11: e0188596.
Cao Z.1, Ye P, Long C, Chen K, Li X, Wang H. Effect of pioglitazone a peroxisome proliferator-activated receptor gamma agonist, on ischemia-reperfusion injury in rats. Pharmacology 2007; 3: 184-192.
Avlan D, Erdouğan K., Cimen B, Dusmez Apa D, Cinel I, Aksoyek S. The protective effect of selenium on ipsilateral and contralateral testes in testicular reperfusion injury.  Pediatr Surg Int 2005; 21: 274 - 278.
Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem 1988; 3:497-500.
Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem 2005; 12: 1103-1111.
Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 2004; 4:277-285.
Johnsen S G. Testicular biopsy score count - method for registration of spermatogenesis in human testes: normal values and results in 335 hypogonadal males. Hormones 1970; 1:2-25.
Sukhotnik I, Miselevich I, Lurie M, Nativ O, Coran AG, MMogilner JG. The time relationship between ipsilateral testicular ischemia and germ cell apoptosis in the contralateral testis in rat. Pediatr Surg Int 2005; 217: 512-516.
Tsounapi  P, Saito M, Dimitriadis F, Shimizu S, Kinoshita Y, Shomori K, et al. Protective effect of sivelestat, a neutrophil elastase inhibitor, on ipsilateral and contralateral testes after unilateral testicular ischaemia- reperfusion injury in rats. BJU Int 2011; 107: 329-336.
Filho DW, Torres MA, Bordin AL, Crezcynski-Pasa TB, Boveris A. Spermatic cord torsion, reactive oxygen and nitrogen species and ischemia-reperfusion injury. Mol Aspects 2004; 1-2:199-210.
Oral A, Halici Z, Bayir Y, opcu A, Un H, Bilgin AO, et al. Effect of oral zinc administration on long – term ipsilateral and contralateral testes damage after experimental testis ischemia reperfusion. Andrologia 2017; 49. doi: 10.1111/and.12673.
Somi M H, Hajipour B, Asl N A, Estakhri R, Azar AN, Zade MN, et al. Pioglitazone attenuates ischemia/reperfusion-induced liver injury in rats. Transplant Proc 2009; 41: 4105-4109.
Surapaneni KM, Jainu M. Comparative effect of pioglitazone, quercetin and hydroxy citric acid on the status of lipid peroxidation and antioxidants in experimental non-alcoholic steatohepatitis. J Physiol Pharmacol 2014; 65: 67-74.
Ragab D, Abdallah D M, El-Abhar H S. Cilostazol renoprotective effect: modulation of PPAR-γ, NGAL, KIM-1 and IL-18 underlies its novel effect in a model of ischemia-reperfusion. PloS One 2014; 9, e 95313.
Un H, Bayir, Y, Halici Z, Akpinar E, Karakus E, Oral A, et al. The Effects of RAAS inhibition in rate limiting step by aliskiren on testicular torsion injury in rats. J Urol 2015; 194:828-833
Gupta G, Krishna G, Chellappan D K, Gubbiyappa KS, Candasamy M, Duma K. Protective effect of pioglitazone, a PPARγ agonist against acetaminophen-induced hepatotoxicity in rats. Mol Cell Biochem 2014; 393: 223-228.
Gumieniczek A, Hopkała H, Roliński J, Bojarska-Junak, A. Interleukin-6 and oxidative stress in plasma of alloxan-induced diabetic rabbits after pioglitazone treatment. Immunopharmacol Immunotoxicol 2006; 28: 81-91.
Collino M, Aragno M, Mastrocola R, Gallicchio M, Rosa AC, Dianzani C, et al. Modulation of the oxidative stress and inflammatory response by PPAR-gamma agonists in the hippocampus of rats exposed to cerebral ischemia/reperfusion.. Eur J Pharmacol 2006; 530:70-80.
Garcia-Ruiz I, Solis-Munoz P, Fernandez-Moreira D, Muñoz-Yagüe T, Solís-Herruzo JA. Pioglitazone leads to an inactivation and disassembly of complex I of the mitochondrial respiratory chain. BMC Biol 2013; 11: 88-102.
Takada S, Hirabayashi K, Kinugawa S, Yokota T, Matsushima S, Suga T, et al. Pioglitazone ameliorates the lowered exercise capacity and impaired mitochondrial function of the skeletal muscle in type 2 diabetic mice. Eur J Pharmacol 2014; 5; 740:690-696.
Fröde TS, Buss Zda S, dos Reis, G O, Medeiros YS. Evidence of anti-inflammatory effects of pioglitazone in the murine pleurisy model induced by carrageenan. Int Immunopharmacol 2009; 9:1394-1400.
El-Sahar A E , Safar M M, Zaki, H F, Attia AS, Ain-Shoka AA. Neuroprotective effects of pioglitazone against transient cerebral ischemic reperfusion injury in diabetic rats: Modulation of antioxidant, anti-inflammatory, and anti-apoptotic biomarkers. Pharmacol Rep 2015; 67: 901- 906.
Han J, Wang D, Ye L, Li P, Hao W, Chen X, et al. Rosmarinic acid protects against inflammation and cardiomyocyte apoptosis during myocardial ischemia/reperfusion injury by activating peroxisome proliferator-activated receptor gamma. Front Pharmacol 2017; 8: 456-466.
Gerdprasert O, O’Bryan MK, Nikolic-Paterson D J, Sebire K, de Kretser DM, Hedger MP. Expression of monocyte chemoattractant protein-1 and macrophage colony-stimulating factor in normal and inflamed rat testis. Mol Hum Reprod 2002; 8:518-524.
Al-Maghrebi M, Renno W M, Al-Ajmi N. Epigallocatechin-3-gallate inhibits apoptosis and protects testicular seminiferous tubules from ischemia/reperfusion-induced inflammation. Biochem Biophys Res Commun 2012; 420: 434-439.
Ito H, Nakano A, Kinoshita M, Matsumori A. Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, attenuates myocardial ischemia/reperfusion injury in a rat model. Lab Invest 2003; 83: 1715-1721.
Matsutani T, Tamura K, Kutsukake M, Matsuda A, Tachikawa E, Uchida E. Impact of pioglitazone on macrophage dynamics in adipose tissues of cecal ligation and puncture-treated mice. Biol Pharm Bull 2017; 5: 638- 644.
Kuru karabas M, Ayhan M, Guney E, Serter M, Meteoglu I. The effect of pioglitazone on antioxidant levels and renal histopathology in streptozotocin-induced diabetic rats. ISRN Endocrinol 2013; 9:858690.
Shaha C, Tripathi R, Mishra D P. Male germ cell apoptosis: regulation and biology. Philos Trans R Soc Lond B Biol Sci 2010; 365: 1501–1515.
Kitazumi I, Tsukahara M, Regulation of DNA fragmentation: the role of caspases and phosphorylation. FEBS J 2011; 278: 427-444.
Turner T T, Bang H J, Lysiak J L. The molecular pathology of experimental testicular torsion suggests adjunct therapy to surgical repair. J Urol 2004; 172: 2574-2578.
Hu H, Zou C, Xi X, Shi Z, Wang G, Huang X. Protective effects of pioglitazone on renal ischemia-reperfusion injury in mice. J Surg Res 2012; 178: 460 - 465.
Hao M, Zhu S, Hu L, Zhu H, Wu X, Li Q. Myocardial ischemic postconditioning promotes autophagy against ischemia reperfusion injury via the activation of the nNOS/AMPK/mTOR Pathway. Int J Mole Sci 2017; 18: pii: E614.
Zhang M, Yang D, Gong X, Ge P, Dai J, Lin L, et al. Protective benefits of AMP-activated protein kinase in hepatic ischemia-reperfusion injury. Am J Transl Res 2017; 9:823-829.
Chen BL, Wang LT, Huang KH, Wang CC, Chiang CK, Liu SH. Quercetin attenuates renal ischemia/reperfusion injury via an activation of AMP-activated protein kinase-regulated autophagy pathway. J Nutr Biochem 2014; 25:1226-1234.
Craig PM, Moyes C, LeMoine CM R. Sensing and responding to energetic stress: Evolution of the AMPK network. Comp Biochem Physiol B Biochem Mol Biol 2017; 17:30161-30166.
Peralta C, Bartrons R, Serafin A, Blázquez C, Guzmán M, Prats N, et al. Adenosine monophosphate-activated protein kinase mediates the protective effects of ischemic preconditioning on hepatic ischemia-reperfusion injury in the rat. Hepatology 2001; 34: 1164 –1173.
Yun H, Park S, Kim MJ, Yang WK, Im DU, Yang KR, et al. AMP-activated protein kinase mediates the antioxidant effects of resveratrol through regulation of the transcription factor FoxO1. FEBS J 2014; 281: 4421- 4438.
Song P, Zou M H. Regulation of NAD (P) H oxidases by AMPK in cardiovascular systems.  Free Radic Biol 2012; 52: 1607-1619.
Tian Y, Chen T, Wu Y, Yang L, Wang L, Fan X, et al. Pioglitazone stabilizes atherosclerotic plaque by regulating the Th17/Treg balance in AMPK-dependent mechanisms. Cardiovasc Diabetol 2017; 16:140-148.
Zhang J, ZhangY, Xiao F, Liu Y, Wang J, Gao H, et al. The peroxisome proliferator-activated receptor γ agonist pioglitazone prevents NF-κB activation in cisplatin nephrotoxicity through the reduction of p65 acetylation via the AMPK-SIRT1/p300 pathway. Biochem Pharmacol 2016; 101: 100-111.
Matsuura N, Asano C, Nagasawa K, Ito S, Sano Y, Minagawa Y, et al. Effects of pioglitazone on cardiac and adipose tissue pathology in rats with metabolic syndrome. Int J Cardiol 2015; 179:360-369.