Chronoefficacy of alpha-lipoic acid in combination with nifedipine and glimepiride attenuates testicular toxicity in diabetic rats

Background: Knowledge of chronopharmacology and disease rhythms may provide additional therapeutic options for diabetic complications. The present research investigates the effect of chronomodulated alpha-lipoic acid/ nifedipine/ glimepiride combination in oxidative stress-mediated testicular toxicity in diabetic rats. A total of seven rat groups were used for the following study. Methods: A group of non-diabetic rats and a group of diabetic rats were treated with 1 mL/kg of water to serve as normal and diabetic controls respectively. All other groups were diabetic and received 10 mg/kg glimepiride at 20:00h. Additionally, groups four to seven were treated with 20 mg/kg nifedipine at 08:00h while groups five to seven received additional treatments with alpha-lipoic acid (ALA) at 08:00h, 14:00h and 20:00h respectively. Rats were euthanized after four weeks of oral treatment and the epididymis and testis were excised for assessment of fertility markers. Serum testosterone and relative testes weights were measured. The right testes were preserved in phosphate buffer for cholesterol and antioxidant assay while the left testes were fixed in formalin for histological studies. Results: All rat groups treated with ALA showed significantly (p ≤ 0.01) better prognostic values for all markers assessed compared to the diabetic control group. Those treated with ALA at 20:00h showed better prognosis (p ≤ 0.05) than treatment at other time points, showing values similar to the normal. Conclusion: Time-dependent triple therapy with alpha-lipoic acid, nifedipine and glimepiride mitigates oxidative stress-mediated testicular injury in diabetic rats and its clinical benefits may be explored using equivalent circadian timing in men.