ATP mitigates high-dose lamotrigine-induced oxidative ovarian injury in rats more effectively than melatonin: insights from biochemical parameters, histopathology, and 8-OHdG, dityrosine, and COX-1/COX-2 double immunofluorescence

Lamotrigine has been shown to alter intracellular adenosine triphosphate (ATP) levels depending on the administered dose, thereby promoting reactive oxygen species (ROS) generation and oxidative tissue injury. However, its ovarian effects and the protective role of exogenous ATP remain unexplored. This study investigated the ovarian effects of low- and high-dose lamotrigine and compared exogenous ATP and melatonin, a well-established antioxidant, in lamotrigine-induced oxidative ovarian injury. Forty-two female Wistar albino rats were allocated into seven groups ( n = 6): healthy control, low-dose lamotrigine (10 mg/kg, oral), high-dose lamotrigine (30 mg/kg, oral), and combination groups receiving ATP (5 mg/kg, intraperitoneal) or melatonin (10 mg/kg, oral) with either lamotrigine dose. Both agents were administered one hour prior to lamotrigine daily for 30 days. Ovarian oxidant and antioxidant biomarkers were quantified. Serum anti-Mullerian hormone (AMH) was measured. Histopathological injury and double-immunofluorescence immunopositivity for 8-hydroxy-2′-deoxyguanosine [8-OHdG], dityrosine, cyclooxygenase-1 [COX-1], and cyclooxygenase-2 [COX-2] were graded semiquantitatively. Low-dose lamotrigine produced no detectable oxidative, histopathological, or immunofluorescence alterations. High-dose lamotrigine significantly elevated oxidant markers and reduced antioxidant levels and AMH, accompanied by severe follicular degeneration and pronounced 8-OHdG, dityrosine, and COX-2 immunopositivity with concurrent COX-1 suppression. ATP pre-administration more effectively attenuated these alterations than melatonin. ATP mitigates high-dose lamotrigine-induced oxidative ovarian injury more effectively than melatonin, likely by restoring cellular energy homeostasis and modulating inflammatory signaling. These findings support further translational investigation of ATP-mediated ovarian protection during chronic high-dose lamotrigine exposure and highlight cellular bioenergetic restoration as a potential adjunctive therapeutic strategy.