Ligustrazine hydrochloride Prevents Ferroptosis by Activating the NRF2 Signaling Pathway in a High-Altitude Cerebral Edema Rat Model

High-altitude cerebral edema (HACE) is a disorder caused by low pressure and hypoxia at high altitudes. Nevertheless, as of now, there is still a scarcity of safe and effective prevention and treatment methods. The active component of <i>Ligusticum</i> Chuanxiong, namely <i>Ligustrazine hydrochloride</i> (LH), has shown potential in the prevention and treatment of HACE due to its anti-inflammatory, antioxidant, and neuroprotective effects in nervous system disorders. Consequently, the potential protective effect of LH on HACE and its mechanism still need to be further explored. Prior to modeling, 90 male Sprague-Dawley rats were pretreated with different doses of drugs, including LH (100 mg/kg and 50 mg/kg), dexamethasone (4 mg/kg), and ML385 (30 mg/kg). Subsequently, the pretreated rats were placed in a low-pressure anoxic chamber simulating a plateau environment to establish the rat HACE model. The effects and mechanisms of LH on HACE rats were further elucidated through determination of brain water content, HE staining, ELISA, immunofluorescence, molecular docking, molecular dynamics simulation, western blot, and other techniques. The results showed, first of all, that LH pretreatment can effectively reduce brain water content; down-regulate the expression of AQP4, HIF-1α, and VEGF proteins; and alleviate damage to brain tissue and nerve cells. Secondly, compared with the HACE group, LH pretreatment can significantly reduce MDA levels and increase GSH and SOD levels. Additionally, LH decreased the levels of inflammatory factors IL-1β, IL-6, and TNF-α; reduced total iron content in brain tissue; increased the expression of ferroptosis-related proteins such as SLC7A11, GPX4, and FTH1; and alleviated ferroptosis occurrence. Molecular docking and molecular dynamics simulations show that LH has a strong binding affinity for NRF2 signaling. Western blot analysis further confirmed that LH promotes the translocation of NRF2 from the cytoplasm to the nucleus and activates the NRF2 signaling pathway to exert an antioxidant effect. The NRF2 inhibitor ML385 can reverse the anti-oxidative stress effect of LH and its protective effect on HACE rat brain tissue. In summary, LH may have a protective effect on HACE rats by activating the NRF2 signaling pathway, inhibiting ferroptosis, and resisting oxidative stress.