Nimesulide Inhibits MAPK/COX-2 Pathway, and Prevents Oxidative Stress, Inflammation, and Apoptosis in Testes of Cisplatin-Challenged Rats

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Amr A. Fouad
Hanaa M. Khalaf
Usama I. Akl
Manal I. Abdelghany


The potential testicular protective effect of nimesulide (NSE) was studied in cisplatin (CSP)-challenged rats. NSE therapy (10 mg/kg/day, p.o.) was applied for 15 days, and a single dose of CSP (7 mg/kg, i.p.) was administered on the 10th day. CSP significantly decreased the levels of serum testosterone, testicular reduced glutathione, and superoxide dismutase. CSP also significantly increased testicular malondialdehyde, nitric oxide, tumor necrosis factor-α, interleukin-1β, cyclooxygenase-2 (COX-2), prostaglandin E2, nuclear factor-κB p65, Bax, and caspase-3. NSE significantly ameliorated all the biochemical changes observed in CSP-challenged rats. Moreover, NSE significantly reduced the histopathological injury, and the expressions of phosphorylated c-Jun N-terminal kinase (p-JNK) and p38 mitogen-activated protein kinases (MAPKs) in testes of rats received CSP. It was concluded that NSE significantly blocked the CSP-induced acute testicular injury in rats through inhibition of MAPK/COX-2 signaling pathway, and by combating oxidative stress, inflammation, and apoptosis.

Nimesulide, cisplatin, MAPK, COX-2, testes

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How to Cite
Fouad, A. A., Khalaf, H. M., Akl, U. I., & Abdelghany, M. I. (2020). Nimesulide Inhibits MAPK/COX-2 Pathway, and Prevents Oxidative Stress, Inflammation, and Apoptosis in Testes of Cisplatin-Challenged Rats. Journal of Pharmaceutical Research International, 32(22), 35-43.
Original Research Article


Qi L, Luo Q, Zhang Y, Jia F, Zhao Y, Wang F. Advances in toxicological research of the anticancer drug cisplatin. Chem Res Toxicol. 2019;32:1469-86.

Ekinci Akdemir FN, Yildirim S, Kandemir FM, Aksu EH, Guler MC, Kiziltunc Ozmen H, et al. The antiapoptotic and antioxidant effects of eugenol against cisplatin-induced testicular damage in the experimental model. Andrologia. 2019;51:13353.

Kaushik S, Tomar A, Puthanmadhom Narayanan S, Nag TC, Arya DS, Bhatia J. Pitavastatin attenuates cisplatin-induced renal injury by targeting MAPK and apoptotic pathways. J Pharm Pharmacol. 2019;71:1072-81.

Ma ZN, Liu Z, Wang Z, Ren S, Tang S, Wang YP, et al. Supplementation of American ginseng berry extract mitigated cisplatin-evoked nephrotoxicity by suppressing ROS-mediated activation of MAPK and NF-κB signaling pathways. Food Chem Toxicol. 2017;110:62-73.

Kim IH, Kwon MJ, Jung JH, Nam TJ. Protein extracted from Porphyra yezoensis prevents cisplatin-induced nephrotoxicity by downregulating the MAPK and NF-κB pathways. Int J Mol Med. 2018;41:511-20.

Azab SS, Kamel I, Ismail NN, El Din Hosni H, El Fatah MA. The defensive role of taurine against gonadotoxicity and testicular apoptosis effects induced by cisplatin in rats. J Infect Chemother. 2020;26(1):51-57.

Kress HG, Baltov A, Basiński A, Berghea F, Castellsague J, Codreanu C, et al. Acute pain: a multifaceted challenge - the role of nimesulide. Curr Med Res Opin. 2016;32:23-36.

Arslan A, Ozcicek A, Suleyman B, Coban TA, Cimen FK, Nalkiran HS, et al. Effects of nimesulide on the small intestine mucositis induced by methotrexate in rats. Exp Anim. 2016;65:329-36.

Temp FR, Marafiga JR, Milanesi LH, Duarte T, Rambo LM, et al. Cyclooxygenase-2 inhibitors differentially attenuate pentylenetetrazol-induced seizures and increase of pro- and anti-inflammatory cytokine levels in the cerebral cortex and hippocampus of mice. Eur J Pharmacol. 2017;810:15-25.

Mittal R, Kumar A, Singh DP, Bishnoi M, Nag TC. Ameliorative potential of rutin in combination with nimesulide in STZ model of diabetic neuropathy: targeting Nrf2/HO-1/NF-kB and COX signalling pathway. Inflammopharmacology. 2018;26:755-68.

Afzal M, Bhardwaj DP, Khan R, Kazmi I, Saleem S, Al-Abbasi FA, et al. Antineoplastic influence of nimesulide in chemically induced hepatocellular carcinoma by inhibition of DNA synthesis. Inflammopharmacology. 2019;27:89-98.

Polat EC, Bozkurt AS, Keskin Cimen F, Gulaboglu M, Altuner D. The investigation of the protective effects of nimesulide on experimental testicular ischemia-reperfusion injury in rats. Rev Int Androl. 2020;18(2):55-62.

Köroğlu KM, Çevik Ö, Şener G, Ercan F. Apocynin alleviates cisplatin-induced testicular cytotoxicity by regulating oxidative stress and apoptosis in rats. Andrologia. 2019;51:13227.

Erpek S, Bilgin MD, Dikicioglu E, Karul A. The effects of low frequency electric field in rat testis. Rev Med Vet (Toulouse). 2007;158:206-11.

Johnsen SG. Testicular biopsy score count - a method for registration of spermatogenesis in human testes: normal values and results in 335 hypogonadal males. Horm Res Paediatr. 1970;1:2-25.

Fouad AA, Refaie MMM, Abdelghany MI. Naringenin palliates cisplatin and doxorubicin gonadal toxicity in male rats. Toxicol Mech Methods. 2019;29:67-73.

Tian M, Liu F, Liu H, Zhang Q, Li L, Hou X, et al. Grape seed procyanidins extract attenuates Cisplatin-induced oxidative stress and testosterone synthase inhibition in rat testes. Syst Biol Reprod Med. 2018;64:246-59.

Amin A, Abraham C, Hamza AA, Abdalla ZA, Al-Shamsi SB, Harethi SS, et al. A standardized extract of Ginkgo biloba neutralizes cisplatin-mediated reproductive toxicity in rats. J Biomed Biotechnol. 2012;2012:362049.

Sherif IO, Sabry D, Abdel-Aziz A, Sarhan OM. The role of mesenchymal stem cells in chemotherapy-induced gonadotoxicity. Stem Cell Res Ther. 2018;9:196.

Michel HE, Menze ET. Tetramethylpyrazine guards against cisplatin-induced nephrotoxicity in rats through inhibiting HMGB1/TLR4/NF-κB and activating Nrf2 and PPAR-γ signaling pathways. Eur J Pharmacol. 2019;857:172422.

Chen X, Wei W, Li Y, Huang J, Ci X. Hesperetin relieves cisplatin-induced acute kidney injury by mitigating oxidative stress, inflammation and apoptosis. Chem Biol Interact. 2019;308:269-78.

Kandeil MA, Mahmoud MO, Abdel-Razik AH, Gomaa SB. Thymoquinone and geraniol alleviate cisplatin-induced neurotoxicity in rats through downregulating the p38 MAPK/STAT-1 pathway and oxidative stress. Life Sci. 2019;228:145-51.

Yamaguchi K, Ishikawa T, Kondo Y, Fujisawa M. Cisplatin regulates Sertoli cell expression of transferrin and interleukins. Mol Cell Endocrinol. 2008;283:68-75.

Mohamed HE, Badawy MMM. Modulatory effect of zingerone against cisplatin or γ-irradiation induced hepatotoxicity by molecular targeting regulation. Appl Radiat Isot. 2019;154:108891.

Niranjan R, Rajasekar N, Nath C, Shukla R. The effect of guggulipid and nimesulide on MPTP-induced mediators of neuroinflammation in rat astrocytoma cells, C6. Chem Biol Interact. 2012;200:73-83.

Fekry E, Rahman AA, Awny MM, Makary S. Protective effect of mirtazapine versus ginger against cisplatin-induced testicular damage in adult male albino rats. Ultrastruct Pathol. 2019;43(1):66-79.

Jahan S, Munawar A, Razak S, Anam S, Ain QU, Ullah H, Afsar T, Abulmeaty M, Almajwal A. Ameliorative effects of rutin against cisplatin-induced reproductive toxicity in male rats. BMC Urol. 2018;18(1):107.

Aksu EH, Kandemir FM, Altun S, Küçükler S, Çomaklı S, Ömür AD. Ameliorative Effect of Carvacrol on Cisplatin-Induced Reproductive Damage in Male Rats. J Biochem Mol Toxicol. 2016;30(10):513-520.