Olmesartan attenuates doxorubicin-elicited testicular toxicity: The interaction between sirtuin-1, HMGB1/NLRP3 inflammasome/gasdermin D signaling, and AMPK/mTOR-driven autophagy.

BACKGROUND

In the recent years, there has been an increased incidence of testicular toxicity associated with doxorubicin (DOX) use in cancer therapy. The mechanisms of this adverse effect may include induction of oxidative stress with augmentation of the inflammatory and the apoptotic signals in the testicular tissues. The ongoing research is directed towards the exploration of new agents that are capable of overcoming this health problem. This study was a trial to evaluate the efficacy of Olmesartan as a protective agent against DOX-induced testicular dysfunction in male rats.

MATERIALS AND

METHODS

Forty adult male Sprague-Dawley rats were divided into control group, DOX-injected group, and three DOX-injected groups treated with olmesartan at 3 dose levels (1, 5, and 10 mg/kg/day). The effect of the different treatments was assessed at the biochemical and the morphological levels.

KEY FINDINGS: Olmesartan administered to DOX-treated rats induced dose-dependent restoration of the testicular weight and functions, normalization of the hormonal profile, augmentation of the antioxidant defenses, and potentiation of AMPK/mTOR-driven autophagy in comparison to rats treated with DOX alone. These effects were accompanied with a dose-dependent significant mitigation of the cellular events related to pyroptosis and inflammation and a significant amelioration of the testicular morphological changes induced by DOX.

SIGNIFICANCE: Olmesartan may represent a promising therapy for DOX-elicited testicular dysfunction, possibly via dose-dependent antioxidant, anti-pyroptotic, anti-inflammatory, and autophagy enhancing effects.