The immunomodulatory effect of chicoric acid on cyclophosphamide-mediated gonadal dysfunction in male rats: Cross-talk between sirtuin-1, HMGB1/RAGE/TLR4 axis, and PI3K/Akt/mTOR signaling.

Cyclophosphamide (CP) is an alkylating agent that has been widely used in cancer therapy and in the treatment protocols of autoimmune disorders. However, the increased incidence of CP-induced testicular dysfunction represents a major limitation of its therapeutic use. The contributing factors to these deleterious effects include interference with the antioxidant defenses, potentiation of the inflammatory events, and abrogation of autophagy in the testicular tissues. Till now, there is no single agent that can completely overcome this health problem. This work tried to explore the possible role of chicoric acid in the alleviation of CP-induced testicular toxicity in a rat model. Fifty adult male Wistar rats were randomly assigned into control group, CP alone group, and 3 CP groups that were treated with three different doses of chicoric acid (25, 50, and 100 mg/kg/day). The harvested seminal fluid, blood, and tissue specimens were processed and evaluated at both the biochemical and pathological levels. Chicoric acid dose-dependently restored the weight and functions of the testis to approximate the normal values, abrogated the changes in the hormonal profile induced by CP, augmented the antioxidant defense mechanisms, and modulated autophagy in the testicular tissues when compared to animals treated with CP alone. These changes were dose-dependently reflected in the histopathological and electron microscopic picture of the testicular tissues. In conclusion, the antioxidant, anti-inflammatory, autophagy-inducing, and antiapoptotic properties of chicoric acid may make it a promising candidate for the mitigation of CP-induced gonadal dysfunction in male Wistar rats.