Common Epilepsy Drug May Harm the Ovary, but ATP Outperforms Melatonin in Rat Study

Lamotrigine is one of the most widely prescribed antiseizure medications in the world, taken daily by hundreds of thousands of women with epilepsy and bipolar disorder, many of them of reproductive age. A new study in rats now suggests that the drug, at high doses, can inflict measurable oxidative damage on the ovary, and that a surprising candidate may offer better protection than the antioxidant supplement most researchers would reach for first: adenosine triphosphate, or ATP, the very molecule cells use as their universal energy currency. The work, published in the Journal of Ovarian Research, compared exogenous ATP against melatonin and found the energy molecule came out ahead on nearly every measure of ovarian health.

The research team, led by Nesrin Yilmaz of Erzincan Binali Yıldırım University in Turkey together with colleagues across several Turkish institutions, set out to answer a question that had never been directly addressed. Previous studies had shown that lamotrigine can alter intracellular ATP levels in a dose-dependent manner, and that this energetic disturbance promotes the generation of reactive oxygen species, the unstable molecules that chew through lipids, proteins, and DNA. What remained unknown was whether the ovary, an organ exquisitely sensitive to oxidative stress because of its finite pool of follicles, suffers the same fate, and whether supplementing ATP from outside the cell could counteract the damage.

To find out, the investigators divided forty-two female Wistar albino rats into seven groups of six animals each. One group served as a healthy control. A second received a low oral dose of lamotrigine, ten milligrams per kilogram of body weight, roughly comparable to standard therapeutic exposure. A third received a high oral dose of thirty milligrams per kilogram. The remaining four groups received either ATP at five milligrams per kilogram intraperitoneally or melatonin at ten milligrams per kilogram orally, each paired with either the low or the high lamotrigine dose. Crucially, both protective agents were administered one hour before lamotrigine every day for thirty days, a pre-treatment design intended to ensure that the antioxidants were already on board when the drug hit the tissue.

At the end of the thirty-day period, the researchers assembled an unusually comprehensive picture of ovarian health. They quantified oxidant and antioxidant biomarkers in ovarian tissue, measured serum levels of anti-Mullerian hormone, or AMH, a widely used clinical marker of the ovarian follicle reserve, graded histopathological injury under the microscope, and deployed a double-immunofluorescence technique to visualize, cell by cell, the accumulation of 8-hydroxy-2′-deoxyguanosine, a signature of oxidative DNA damage, along with dityrosine, a marker of protein oxidation, and the inflammatory enzymes cyclooxygenase-1 and cyclooxygenase-2.

The results drew a sharp line between the two doses. Low-dose lamotrigine produced no detectable oxidative, histopathological, or immunofluorescence alterations at all, a reassuring finding for patients on standard regimens, at least in this animal model. High-dose lamotrigine, by contrast, told a very different story. Oxidant markers climbed significantly, antioxidant defenses fell, and serum AMH dropped, all accompanied by severe follicular degeneration visible in the tissue sections. The immunofluorescence work added molecular texture to the damage: pronounced immunopositivity for 8-OHdG and dityrosine signaled that both DNA and proteins had taken an oxidative beating, while cyclooxygenase-2, the inducible inflammatory enzyme, lit up strongly even as cyclooxygenase-1, its constitutive counterpart, was suppressed.

That COX-1/COX-2 imbalance is more than a technical footnote. Cyclooxygenase enzymes convert arachidonic acid into prostaglandins that participate in ovulation, luteal function, and inflammatory signaling within the ovary. A simultaneous rise in the inducible COX-2 and fall in the constitutive COX-1 suggests a shift from homeostatic prostaglandin production toward an inflammatory program, the kind of shift that can disrupt follicular development and impair the delicate hormonal crosstalk between the ovary and the rest of the reproductive axis. Combined with the decline in AMH, which reflects a shrinking or damaged follicle pool, the picture is one of genuine reproductive vulnerability, not merely incidental biochemical noise.

The most striking result, however, concerned the two protective strategies. When ATP was given before high-dose lamotrigine, it attenuated the oxidant surge, restored antioxidant levels, preserved AMH, reduced histopathological injury, and dampened the abnormal 8-OHdG, dityrosine, and COX-2 immunopositivity more effectively than melatonin did. This is a noteworthy result precisely because melatonin is something of a benchmark in oxidative-stress research, a hormone with a long track record of protecting reproductive tissues in animal models. For ATP to outperform it suggests that the mechanism of lamotrigine-induced injury is not simply an excess of free radicals but something more fundamental: a collapse of cellular energy homeostasis that melatonin, however capable a radical scavenger, cannot fully correct.

The authors propose that exogenous ATP works by restoring cellular energy balance and modulating inflammatory signaling, thereby addressing the injury at its energetic root rather than mopping up radicals downstream. The idea has an elegant logic. If lamotrigine perturbs intracellular ATP levels and that perturbation drives reactive oxygen species generation, then replenishing ATP supplies the cell with the resources it needs to run its own antioxidant machinery, including the energy-dependent repair enzymes that excise oxidized DNA bases and refold or degrade damaged proteins. In this framing, melatonin treats the symptom while ATP treats the cause, which would explain the superior outcomes across the biochemical, histological, and immunofluorescence readouts.

Several caveats deserve emphasis before anyone extrapolates these findings to the clinic. The study was conducted in rats over thirty days, with doses and routes of administration that do not map one-to-one onto human pharmacology. The high lamotrigine dose of thirty milligrams per kilogram exceeds typical human therapeutic exposure on a body-weight basis, and the ATP was delivered intraperitoneally, raising questions about how exogenous ATP would reach ovarian tissue in patients. The pre-treatment design, in which protection was given an hour before the drug, also differs from the real-world scenario in which a patient is already taking lamotrigine before any protective agent is considered. Whether ATP remains protective when given alongside or after the drug is unknown.

Even so, the study opens a genuinely novel therapeutic direction. If the findings hold up in translational work, cellular bioenergetic restoration could become an adjunctive strategy for protecting the ovary during chronic high-dose lamotrigine exposure, and perhaps during other drug treatments known to disturb cellular energy metabolism. For the many young women who must take antiseizure medications for years, the prospect of a fertility-sparing intervention is compelling. The Turkish team’s demonstration that a molecule as fundamental as ATP can shield the ovary more effectively than a celebrated antioxidant reframes drug-induced reproductive injury as, at least in part, an energy problem, and energy problems may have energy solutions. Further studies in larger animal models and, eventually, carefully designed clinical trials will determine whether this laboratory insight can be translated into a practical therapy for patients.

Subject of Research: The protective effects of exogenous adenosine triphosphate against lamotrigine-induced oxidative ovarian injury in rats

Article Title: 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

Article References: Yilmaz, N., Paltaci, S. I., Yavuzer, B., Sarigul, C., Ozkaraca, M., Gungor, A., Suleyman, B., Mammadov, R., & Suleyman, H. (2026). 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. Journal of Ovarian Research. https://doi.org/10.1186/s13048-026-02273-w

Image Credits: AI Generated

DOI: 10.1186/s13048-026-02273-w

Keywords: lamotrigine, adenosine triphosphate, melatonin, oxidative stress, ovary, ovarian injury, anti-Mullerian hormone, 8-OHdG, dityrosine, cyclooxygenase, rats, reproductive toxicology