Mechanistic Protective Effect of Cilostazol in Cisplatin-Induced Testicular Damage via Regulation of Oxidative Stress and TNF-α/NF-κB/Caspase-3 Pathways

Int J Mol Sci. 2023 Aug 10;24(16):12651. doi: 10.3390/ijms241612651.

Abstract

Despite being a potent anticancer drug, cisplatin has limited applicability due to its adverse effects, such as testicular damage. Consequently, reducing its toxicity becomes necessary. In this study, a selective phosphodiesterase-3 inhibitor, cilostazol, which is used to treat intermittent claudication, was examined for its ability to abrogate cisplatin-induced testicular toxicity. Its ameliorative effect was compared to that of two phosphodiesterase inhibitors, tadalafil and pentoxifylline. The study also focused on the possible mechanisms involved in the proposed protective effect. Cisplatin-treated rats showed a significant decrease in sperm number and motility, serum testosterone, and testicular glutathione levels, as well as a significant elevation in malondialdehyde, total nitrite levels, and the protein expression of tumor necrosis factor-alpha, nuclear factor-kappa β, and caspase-3. These outcomes were confirmed by marked testicular architecture deterioration. Contrary to this, cilostazol, in a dose-dependent manner, showed potential protection against testicular toxicity, reversed the disrupted testicular function, and improved histological alterations through rebalancing of oxidative stress, inflammation, and apoptosis. In addition, cilostazol exerted a more pronounced protective effect in comparison to tadalafil and pentoxifylline. In conclusion, cilostazol ameliorates cisplatin-induced testicular impairment through alteration of oxidative stress, inflammation, and apoptotic pathways, offering a promising treatment for cisplatin-induced testicular damage.

Keywords: cilostazol; cisplatin; pentoxifylline; tadalafil; testicular damage.

MeSH terms

  • Animals
  • Caspase 3
  • Cilostazol / pharmacology
  • Cisplatin / toxicity
  • Inflammation
  • Male
  • NF-kappa B*
  • Oxidative Stress
  • Pentoxifylline* / pharmacology
  • Phosphodiesterase 3 Inhibitors
  • Rats
  • Semen
  • Tadalafil
  • Tumor Necrosis Factor-alpha

Substances

  • NF-kappa B
  • Cilostazol
  • Tumor Necrosis Factor-alpha
  • Cisplatin
  • Caspase 3
  • Pentoxifylline
  • Tadalafil
  • Phosphodiesterase 3 Inhibitors

Grants and funding

The authors declare that no funds, grants, and other support were received during the preparation of this manuscript. The publication fee will partially be covered by the Terry Fox Foundation fund (# 21S103) and the Zayed Center for Health Sciences fund (# 31R184/12R043) for A.A.