| Autor: |
Arab HH; Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.; Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt., Fikry EM; Department of Pharmacology, Egyptian Drug Authority (EDA)-Formerly NODCAR, Giza 12654, Egypt., Alsufyani SE; Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia., Ashour AM; Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al Qura University, P.O. Box 13578, Makkah 21955, Saudi Arabia., El-Sheikh AAK; Basic Health Sciences Department, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia., Darwish HW; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia., Al-Hossaini AM; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia., Saad MA; Department of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman 4184, United Arab Emirates.; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt., Al-Shorbagy MY; Department of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman 4184, United Arab Emirates.; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt., Eid AH; Department of Pharmacology, Egyptian Drug Authority (EDA)-Formerly NODCAR, Giza 12654, Egypt. |
| Abstrakt: |
Cadmium (Cd) is a widespread environmental pollutant that triggers testicular dysfunction. Dapagliflozin is a selective sodium-glucose co-transporter-2 inhibitor with notable antioxidant and anti-apoptotic features. It has shown marked cardio-, reno-, hepato-, and neuroprotective effects. Yet, its effect on Cd-evoked testicular impairment has not been examined. Hence, the goal of the current study was to investigate the potential positive effect of dapagliflozin against Cd-induced testicular dysfunction in rats, with an emphasis on autophagy, apoptosis, and oxidative insult. Dapagliflozin (1 mg/kg/day) was given by oral gavage, and testicular dysfunction, impaired spermatogenesis, and biomolecular events were studied via immunohistochemistry, histopathology, and ELISA. The current findings demonstrated that dapagliflozin improved relative testicular weight, serum testosterone, and sperm count/motility and reduced sperm abnormalities, signifying mitigation of testicular impairment and spermatogenesis disruption. Moreover, dapagliflozin attenuated Cd-induced histological abnormalities and preserved testicular structure. The testicular function recovery was prompted by stimulating the cytoprotective SIRT1/Nrf2/HO-1 axis, lowering the testicular oxidative changes, and augmenting cellular antioxidants. As regards apoptosis, dapagliflozin counteracted the apoptotic machinery by downregulating the pro-apoptotic signals together with Bcl-2 upregulation. Meanwhile, dapagliflozin reactivated the impaired autophagy, as seen by a lowered accumulation of SQSTM-1/p62 and Beclin 1 upregulation. In the same context, the testicular AMPK/mTOR pathway was stimulated as evidenced by the increased p-AMPK (Ser487)/total AMPK ratio alongside the lowered p-mTOR (Ser2448)/total mTOR ratio. Together, the favorable mitigation of Cd-induced testicular impairment/disrupted spermatogenesis was driven by the antioxidant, anti-apoptotic, and pro-autophagic actions of dapagliflozin. Thus, it could serve as a tool for the management of Cd-evoked testicular dysfunction. |
