Melatonin (Mel) has neuroprotective effects; however, its roles in hypoxic-ischemic brain damage (HIBD) and the underlying mechanisms remain unknown. We aimed to explore its roles and mechanisms in a HIBD rat model. We found that exogenous Mel treatment ameliorated HIBD-induced pathological changes, inhibited neuronal ferroptosis, and promoted hippocampal neuronal survival. Moreover, Mel improved the learning and memory abilities of the HIBD rats. Further, we found that glutathione peroxidase 4 (Gpx4) inhibition with RSL3, Akt inhibition with LY29400, and nuclear factor erythroid-2-related factor 2 (Nrf2) inhibition with ML385 abolished the Mel protective effects in HIBD. Our findings indicate that exogenous Mel treatment has a protective effect on HIBD via the Akt/Nrf2/Gpx4 pathway.

褪黑激素 (Mel) 具有神经保护作用；然而，其在缺氧缺血性脑损伤 (HIBD) 中的作用及其潜在机制仍然未知。我们旨在探索其在 HIBD 大鼠模型中的作用和机制。我们发现外源性 Mel 治疗改善了 HIBD 诱导的病理变化，抑制了神经元铁死亡，并促进了海马神经元存活。此外，Mel 提高了 HIBD 大鼠的学习和记忆能力。此外，我们发现 RSL3 对谷胱甘肽过氧化物酶 4 (Gpx4) 的抑制、LY29400 对 Akt 的抑制以及 ML385 对核因子 erythroid-2 相关因子 2 (Nrf2) 的抑制消除了 HIBD 中的 Mel 保护作用。我们的研究结果表明，外源性 Mel 治疗通过 Akt/Nrf2/Gpx4 途径对 HIBD 具有保护作用。