Dexmedetomidine alleviates ferroptosis caused by traumatic brain injury via the NRF2/HO-1/GPX4 pathway

Emerging evidence suggests that TBI triggers ferroptosis, and dexmedetomidine (Dex) has a neuroprotective effect. This study aimed to explore the underlying mechanism of function of Dex in ferroptosisi after TBI. TBI model was established using the modified Feeney's weight drop injury method. Our experiment included the assessment of lesion volume by hematoxylin and eosin (HE) staining, the evaluation of the expression levels of ferroptosis-related proteins NRF2, HO-1, GPX4, FPN1, and TRFC by Western blotting (WB), the morphological changes via transmission electron microscopy (TEM), the increase in reactive oxygen species (ROS) through the measurement of malondialdehyde (MDA), the expression of HO-1 and GPX4 in the hippocampal tissues by immunofluorescence staining (IF), the behavioral assay by the Morris water maze (MWM) test and the open field test (OFT). Dex could alleviate the cognitive impairment in TBI mice and reduce ferroptosis after TBI. Dex could promote the nuclear translocation of NRF2 and enhance the expression of downstream HO-1, xCT, and GPX4, thereby inhibiting ferroptosis of neuronal cells. In addition, ML385 inhibited the expression of NRF2 and then reversed the neuroprotective effect of Dex. Dex alleviates ferroptosis and oxidative stress responses after TBI in mice through the NRF2/HO-1/GPX4 pathway, thus relieving the cognitive impairment in mice after TBI.