The Effects of Moderate-Intensity Continuous Training (MICT) and Berberine Supplementation (BB) on Ketamine-Induction Ferroptosis in Testicular Tissue of Wistar Rats: Emphasis on the Xc/GSH/GPX Signaling Pathway

Background and Objective: Long-term consumption of ketamine can result in adverse changes in biological tissues, including the testicles, as well as disruptions in the ferroptosis process. The primary strategy for addressing these effects involves discontinuing ketamine use and adopting nutritional interventions, supplementation, and exercise. Therefore, the present study aims to investigate the effects of ketamine withdrawal, ketamine withdrawal combined with moderate-intensity continuous training (MICT), ketamine withdrawal accompanied by berberine supplementation (BB), and ketamine withdrawal combined with the MICT+BB on certain indices related to testicular ferroptosis in Wistar rats following chronic exposure to ketamine.
Materials and Methods: In this experimental study, 36 rats were randomly assigned to six groups, each consisting of six rats: 1) control, 2) ketamine, 3) ketamine withdrawal, 4) ketamine withdrawal + BB, 5) ketamine withdrawal + MICT, and 6) ketamine withdrawal + BB + MICT. Rats in the intervention groups were administered ketamine at a dose of 100 mg per kilogram of body weight for 8 weeks. Following this period, ketamine injection was halted for all groups. Rats in the MICT groups exercised at an intensity of 65-70% of their maximum speed, while those in the BB supplementation groups received a dosage of 50 mg per kilogram of body weight for an additional 8 weeks. Levels of iron (Fe), glutathione (GSH), glutathione peroxidase (GPX), and malondialdehyde (MDA), as well as the expression of ferritin heavy chain (Fth), ferroportin (Fpn), iron-regulating transferrin receptor (Tfr1), and solute carrier family 7 member 11 (SLC7A11) were assessed. A one-way analysis of variance (ANOVA) was employed for intergroup comparisons, and Tukey's post hoc test was used to identify differences among groups.
Results: Ketamine administration resulted in increased levels of Fe, MDA, and Tfr1, while decreasing levels of GSH and GPX. In the ketamine withdrawal + BB and ketamine withdrawal + MICT groups, the levels of GPX, SLC7A11, GSH, and Fpn significantly increased, in contrast to the reductions in MDA and Tfr1. Ultimately, the combined group (ketamine withdrawal + BB + MICT) exhibited the most substantial improvement in these indices (p < 0.05).
Conclusion: In summary, ketamine appears to increase oxidative stress and induce ferroptosis in the testicular tissue. Conversely, MICT and BB supplementation, both independently and synergistically (MICT + BB), can significantly ameliorate oxidative stress and the indices of testicular ferroptosis in male Wistar rats following chronic ketamine exposure. Overall, the results suggest a certain degree of synergistic effect from the MICT + BB combination. However, both BB and MICT independently can also effectively reduce the damage caused by oxidative stress and testicular ferroptosis.