Melatonin Attenuates Spinal Cord Injury by Regulating Ferroptosis Through the Nrf2/HO-1/GPX4 Pathway

Spinal cord injury (SCI) is one of the most devastating and catastrophic types of injury, with high rates of mortality and disability. Ferroptosis has become the target of many major incurable human diseases. By inhibiting ferroptosis, melatonin (MT) can reduce the damage in various organs, but the protective effect of MT on SCI has not been reported yet. The modified Ellen's method was used to establish an SCI rat model. The protective effect of MT on spinal cord neurons and the recovery of motor function were observed. In in vitro experiments, an oxygen-glucose deprivation/reoxygenation (OGD/R) model was established by using mouse hippocampal neuron (HT22) cells to simulate spinal cord ischemia-reperfusion injury. A ferroptosis model directly induced by Erastin was also used. The nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML 385 was used to further detect the mechanism through which MT inhibits ferroptosis and protects neuronal cells. Our study demonstrates that in rats, melatonin can promote the recovery of behavior and injured tissue after SCI. Under the electron microscope, MT inhibited neuron ferroptosis, rescued damaged mitochondria, and partially restored the mitochondrial structure. ML385, an Nrf2 inhibitor, reversed the effects of MT. Overall, MT may alleviate early SCI by inhibiting ferroptosis through activating the Nrf2/heme oxygenase-1(HO-1)/glutathione peroxidase 4 (GPX 4) pathway.