PMID- 32621855 OWN - NLM STAT- MEDLINE DCOM- 20220308 LR - 20220308 IS - 1873-1708 (Electronic) IS - 0890-6238 (Linking) VI - 96 DP - 2020 Sep TI - Tadalafil alleviates cisplatin-induced reproductive toxicity through the activation of the Nrf2/HO-1 pathway and the inhibition of oxidative stress and apoptosis in male rats. PG - 165-174 LID - S0890-6238(20)30174-X [pii] LID - 10.1016/j.reprotox.2020.06.015 [doi] AB - Male reproductive toxicity is a well-known adverse effect of cisplatin (CIS), an important antineoplastic agent used to control several types of cancers. Tadalafil (TDF), is a long-acting phosphodiesterase-5 (PDE5) inhibitor commonly used as treatment for erectile dysfunction. The aim of this work was to study the possible protective effect of TDF against CIS-induced testicular toxicity in rats and the possible involvement of Nrf2/HO-1 pathway, which demonstrates antioxidant and inflammatory activities utilizing zinc protoporphyrin-IX (ZnPP) as HO-1 inhibitor. Results revealed that TDF attenuated the CIS-induced disturbances in sperm count and activities, normalized the serum testosterone level, improved the CIS-induced changes in epididymal and testicular weights and restored the normal structure of testicular tissues. In addition, TDF upregulated the gene expression levels of Nrf2 and HO-1 and the activity of HO-1 whereas, it reduced the CIS-induced changes in testicular oxidative stress markers and the levels of in fl ammatory mediators (TNF-alpha and iNOS). Furthermore, TDF antagonized the CIS-induced increase in testicular gene expression of apoptotic markers caspase-3 and Bax, and the decrease in Bcl-2. However, ZnPP co-administration signi fi cantly attenuated all TDF-mediated improvements in CIS-induced testicular toxicity, biochemical changes, and apoptosis. In conclusion, TDF exerts a protective effect against CIS-induced reproductive toxicity in males, through different mechanisms, besides its inhibitory action to PDE5, possibly mediated by the upregulation of Nrf2/HO-1, along with its antioxidant, anti-inflammatory, and anti-apoptotic effects. Hence, the use of TDF represents a promising therapeutic approach to protect the male reproductive system from the harmful toxic effects of CIS. CI - Copyright (c) 2020 Elsevier Inc. All rights reserved. FAU - Abdel-Wahab, Basel A AU - Abdel-Wahab BA AD - Department of Pharmacology, College of Pharmacy, Najran University, Najran, P.O. 1988, Saudi Arabia; Department of Medical Pharmacology, College of Medicine, Assiut University, Assiut, Egypt. Electronic address: basel_post@msn.com. FAU - Alkahtani, Saad Ahmad AU - Alkahtani SA AD - Department of Clinical Pharmacy, College of Pharmacy, Najran University, Najran, P.O. 1988, Saudi Arabia. FAU - Elagab, Ehab A M AU - Elagab EAM AD - Department of Pathology, College of Medicine, Najran University, Najran, P.O. 1988, Saudi Arabia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200701 PL - United States TA - Reprod Toxicol JT - Reproductive toxicology (Elmsford, N.Y.) JID - 8803591 RN - 0 (Antineoplastic Agents) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Nfe2l2 protein, rat) RN - 0 (Phosphodiesterase 5 Inhibitors) RN - 0 (Protective Agents) RN - 0 (Tumor Necrosis Factor-alpha) RN - 3XMK78S47O (Testosterone) RN - 742SXX0ICT (Tadalafil) RN - EC 1.14.14.18 (Heme Oxygenase (Decyclizing)) RN - EC 1.14.14.18 (Hmox1 protein, rat) RN - Q20Q21Q62J (Cisplatin) SB - IM MH - Animals MH - Antineoplastic Agents/*toxicity MH - Apoptosis/drug effects MH - Cisplatin/*toxicity MH - Heme Oxygenase (Decyclizing)/genetics/metabolism MH - Male MH - NF-E2-Related Factor 2/genetics MH - Oxidative Stress/drug effects MH - Phosphodiesterase 5 Inhibitors/*pharmacology MH - Protective Agents/*pharmacology MH - Rats, Wistar MH - Signal Transduction/drug effects MH - Tadalafil/*pharmacology MH - Testis/*drug effects/metabolism MH - Testosterone/blood MH - Tumor Necrosis Factor-alpha/metabolism OTO - NOTNLM OT - Apoptosis OT - Cisplatin-induced testicular toxicity OT - Heme oxygenase-1 OT - Nrf2/HO-1 OT - Oxidative stress OT - Tadalafil OT - Zinc protoporphyrin EDAT- 2020/07/06 06:00 MHDA- 2022/03/09 06:00 CRDT- 2020/07/05 06:00 PHST- 2020/02/04 00:00 [received] PHST- 2020/06/25 00:00 [revised] PHST- 2020/06/27 00:00 [accepted] PHST- 2020/07/06 06:00 [pubmed] PHST- 2022/03/09 06:00 [medline] PHST- 2020/07/05 06:00 [entrez] AID - S0890-6238(20)30174-X [pii] AID - 10.1016/j.reprotox.2020.06.015 [doi] PST - ppublish SO - Reprod Toxicol. 2020 Sep;96:165-174. doi: 10.1016/j.reprotox.2020.06.015. Epub 2020 Jul 1.