Betaine Alleviates Favipiravir-induced Ovarian and Uterine Toxicity by Regulating Oxidative, Inflammatory, Cellular Death, Steroidogenic, Hormonal, and Histopathological Changes

This study aims to evaluate the protective effects of betaine (BTN), an antioxidant agent, against ovarian and uterine toxicity caused by favipiravir (FVP), an antiviral agent, through multifaceted damage pathways. A total of 28 Wistar rats were divided into four experimental groups: Control, BTN (250 mg/kg), FVP (200 mg/kg), and FVP + BTN. At the end of the 10-day protocol, blood samples were collected along with ovarian and uterine tissue samples. Subsequently, the samples were subjected to biochemical analysis, qRT-PCR analysis, histological evaluation, and immunohistochemical studies. These methods assessed oxidative stress, inflammatory, apoptotic, and autophagic responses, hormonal changes, and overall tissue damage. FVP administration significantly increased oxidative stress (MDA, p < 0.001), inflammation (NF-κB, TNF-α, IL-1β, p < 0.001), apoptosis (Caspase-3, Bax, p < 0.001), and autophagy (Beclin-1, LC3A, p < 0.001); while decreasing antioxidant levels, Bcl-2, and steroidogenesis genes (CYP11A1, CYP17A1, CYP19A1, p < 0.001), and reducing serum AMH, E2, FSH, and LH values (p < 0.001). When BTN was administered concomitantly, most of these changes were reversed, antioxidant and hormonal balance were significantly restored, and the increases in oxidative, inflammatory, and apoptotic markers were reduced (p < 0.05–0.001). Histologically, betaine preserved tissue integrity by mitigating ovarian and uterine damage caused by FVP (p < 0.05). FVP caused multifaceted oxidative, inflammatory, apoptotic, and hormonal damage in ovarian and uterine tissues, while BTN significantly reduced these effects, preserving tissue integrity and function.