Dose-dependent therapeutic effects of liposomal nano-curcumin on ovarian toxicity induced by chronic environmental diclofenac exposure via Bcl-2 upregulation and IL-6 modulation in female Wistar rats

An emerging but poorly understood risk to female reproductive health is the pervasiveness of non-steroidal anti-inflammatory drugs (NSAIDs) as environmental contaminants, especially the pseudo-persistent medication diclofenac. This study examined the effectiveness of liposomal nano-curcumin (NC), a bioactive nanocarrier with strong anti-inflammatory and antioxidant qualities, in treating (therapeutic model) ovarian toxicity in adult female Wistar rats brought on by long-term exposure to an environmental concentration of diclofenac (609.12 μg/L in drinking water). Based on an average water intake of 12.5 mL/100g body weight, this exposure translates to a systemic dose of approximately 76.14 μg/kg/day. Following the cessation of a 100-day exposure period, rats were treated with NC (5 and 20 mg/kg, IP) for 21 days. Thirty animals were divided into six groups (n=5) at random: diclofenac (DIC), NC5 (5 mg/kg), NC20 (20 mg/kg), control, DIC+NC5, and DIC+NC20. In addition to causing significant ovarian damage, such as follicular atresia, stromal hyperplasia, and a decreased healthy/atretic follicle ratio, diclofenac exposure also markedly increased relative ovarian weight. These effects were accompanied by downregulation of the anti-apoptotic protein Bcl2. Only a partial histological recovery was obtained with low-dose NC (5 mg/kg). Compared to animals exposed to diclofenac, high-dose NC (20 mg/kg) showed remarkable restorative efficacy, notably increasing primary and developing follicle populations, decreasing atresia, restoring ovarian cytoarchitecture, and significantly upregulating Bcl-2 expression while modulating IL-6 levels. These results offer the first proof that liposomal nano-curcumin, by means of coordinated modulation of follicular survival pathways and inflammatory mediators, represents a promising therapeutic approach for reducing reproductive toxicity caused by environmental pharmaceutical contamination.