Abstract
BACKGROUND: Depakine (valproic acid) is an antiepileptic medication that is commonly used as a first-line treatment for a variety of seizures in both adults and children. However, it can result in testicular toxicity by increasing oxidative stress inflammation. Melatonin (MLT) has antioxidant, anti-inflammatory, and anti-apoptotic potential. Therefore, the present study investigated the impact of MLT on depakine-induced testicular damage in rats. METHODS: Four groups of male Wistar rats were formed, each of 5 animals: Group 1 was the control group; Group 2 was the MLT-treated group, receiving 20 mg MLT/kg BW; Group 3 was the depakine group, receiving 45 mg/kg; and Group 4 was the MLT + depakine treatment group, which received MLT and depakine for 14 days. Drug treatments were by gavage and daily. RESULTS: Coadministration of MLT and depakine significantly (P < 0.001) improved the levels of testosterone and the expression of androgen receptors in the testes, explaining the improvement of sperm count, motility, and abnormalities. Similarly, spermatogenic cell depletion and shrinkage of seminiferous tubules were prevented by MLT + depakine treatment. Moreover, the testicles of rats given MLT + depakine had common histological architecture of seminiferous tubules, perimeter, and diameter, indicating melatonin's anti-reproductive disruption. The combined treatment with MLT and dapakine resulted in the normalization of hematological parameters, including erythrocyte, platelet, and leukocyte counts; hematocrit content; mean cellular volume; mean cellular hemoglobin; and mean cellular hemoglobin concentration to levels comparable to the control group. These effects were associated with the enhancement of nuclear factor erythroid 2-related factor-2 and glutathione levels. Moreover, reactive oxygen species and malondialdehyde formation were decreased in the testis compared to the depakine-treated rats, indicating improvement in the redox status in the testis. The improvement of redox balance caused a remarkable regression of apoptotic regulating proteins (Bax, Bcl-2, and caspase-3) in the testis and downregulated inflammatory cytokines and chemokines (NF-κB, TNF-α, IL-6, ICAM-1, and MCP-1), indicating protection of spermatogenic cell viability. CONCLUSIONS: The combination treatment with MLT and depakine sustained male reproductive status, which can be attributable to the integrated antioxidant, anti-inflammatory, and antiapoptotic properties of MLT. These results may contribute to increase the clinical utility of depakine as a successful choice for neurological disorders.