Naringenin protects against L-NAME-induced preeclampsia and fetal developmental abnormalities via modulation of inflammation, eNOS/NO signaling, AKT/mTOR pathway, and restoring endothelial function.

Preeclampsia considered as multi-organ disorder involving systemic inflammation and endothelial dysfunction. Our work was designed to investigate the protective role of Naringenin (NGN) against Nω-nitro-l-arginine methyl ester (L-NAME)-induced placental damage and congenital abnormalities in a rat model of preeclampsia. Forty-five adult female albino rats (weighing 160-180 g) were randomly allocated into nine groups (n = 6 per group) and treated for a duration of 18 days. Group 1 served as the untreated control, while Group 2 received 10% DMSO as a vehicle control. Group 3 was administered L-NAME (50 mg/kg, i.p.) from 13 to 18th day of gestation to induce preeclampsia and served as the positive control. Groups 4-6 received NGN alone at doses of 10, 25, and 50 mg/kg, p.o, respectively from 10 to 18th day of gestation. Groups 7-9 received NGN at the same doses, followed one hour later by L-NAME from day 13 to 18. Fetal developmental parameters and skeletal abnormalities were evaluated on gestational day 20. Placental inflammatory markers (TNF-α, IL-1β, TGF-β), signaling proteins (AKT and mTOR), and nitric oxide metabolites (NOx) were quantified using ELISA. Endothelial nitric oxide synthase (eNOS) expression was assessed by immunohistochemistry. Pre-treatment of L-NAME-administered dams with NGN reduced fetal death and resorption rates, elevated NO levels and eNOS expression, and significantly suppressed placental inflammatory markers (TNF-α, IL-1β, TGF-β). These effects were linked to the activation of the AKT/mTOR signaling cascade. Histopathological analysis of the placenta, liver, and kidney confirmed the biochemical findings. Furthermore, NGN alleviated intrauterine growth restriction by increasing fetal weight and length, and provided protection against L-NAME-induced morphological and skeletal deformities. The protective effects of NGN against L-NAME-induced preeclampsia appear to be dose-dependent and primarily mediated through the modulation of inflammation and endothelial dysfunction, suggesting a promising approach for combating preeclampsia.