The purpose of this study was to determine whether quercetin may counteract the negative effects of levetiracetam on rat reproductive capabilities by examining its influence on a few reproductive parameters following levetiracetam administration. Twenty (20) experimental rats were employed, with five (n = 5) animals per treatment group. Rats in group 1 received saline (10 mL/kg, p.o.) which served as control. Quercetin (20 mg/kg, p.o./day) was given to groups 2 and 4 for 28 days starting from 29 to 56 days, respectively. However, animals in groups 3–4 received LEV (300 mg/kg) once daily for 56 days with a 30-minute break in between treatments. All rats had their serum sex hormone levels, sperm characteristics, testicular antioxidant capability, and levels of oxido-inflammatory/apoptotic mediators evaluated. Additionally, the expression of proteins associated to BTB, autophagy, stress response was examined in rat testes. LEV increased sperm morphological defects and decreased sperm motility, sperm viability, sperm count body weight and testes weight, MDA and 8OHdG levels in the testis of LEV-treated rats were elevated, while antioxidant enzyme expression was concurrently decreased. Additionally, it reduced the levels of serum gonadotropins, testosterone, mitochondrial membrane potential, and cytochrome C liberation into the cytosol from the mitochondria. Caspase-3 and Caspase-9 activity increased. While Bcl-2, Cx-43, Nrf2, HO-1, mTOR, and Atg-7 levels were lowered, NOX-1, TNF-α, NF-kß, IL-1ß, and tDFI levels increased. Histopathological scoring provided further support for the decreased spermatogenesis. In contrast to all of these gonadotoxic effects of LEV, improvements in LEV-induced gonadal damage were seen through upregulation of Nrf2/ HO-1, Cx-43/NOX-1, mTOR/Atg-7 expression and attenuation of hypogonadism, poor sperm quality, mitochondria-mediated apoptosis, and oxidative inflammation due to quercetin post-treatment. The modulation of Nrf2/HO-1, /mTOR/Atg-7 and Cx-43/NOX-1 levels and the inhibition of mitochondria-mediated apoptosis and oxido-inflammation in LEV-induced gonadotoxicity in rats suggest that quercetin may hold promise as a possible therapeutic treatment.
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