Exploring the mechanism of carbamazepine decreasing testosterone levels based on cAMP/PKA/CREB pathway.

The aim of this study was to explore the molecular mechanisms underlying carbamazepine (CBZ)-induced testicular toxicity and testosterone reduction in rats. For this purpose, Sprague-Dawley (SD) rats were intervened with 200 mg/kg CBZ for 12 weeks, and R2C cells were exposed to CBZ at concentrations of 0.5, 1 and 1.5 mM for 24 h. HE, Tunel, ELISA, immunofluorescence staining, RT-qPCR, and western blot were used to reveal the effects of CBZ on spermatozoa quality, testicular tissue structure, testosterone level and testosterone synthesis-related enzymes in rats. The results showed that CBZ significantly damaged the testicular tissue structure of rats, induced cell apoptosis, down-regulated the gene and protein expression levels of testosterone synthesis-related enzymes (STAR, TSPO, 17β-HSD and 3β-HSD), inhibited the expression of related proteins in the cAMP/PKA/CREB signalling pathway, and suppressed testosterone levels. In addition, the use of Db-cAMP (a PKA activator) significantly upregulated the protein expressions of PKA and p-CREB, evidently alleviated the CBZ-induced decrease in testosterone levels. In conclusion, CBZ induced testosterone resynthesis by inhibiting the cAMP/PKA/CREB pathway, affecting the expression of steroid synthesis-related enzymes and reducing testosterone levels.