BAICALEIN RELIEVES BRAIN INJURY VIA INHIBITING FERROPTOSIS AND ENDOPLASMIC RETICULUM STRESS IN A RAT MODEL OF CARDIAC ARREST

ABSTRACT: Background: Cardiac arrest (CA) is one of the leading causes of death worldwide. Endoplasmic reticulum (ER) stress and ferroptosis are proven pathological mechanisms implicated in neuronal damage. Baicalein, a ferroptosis Inhibitor, improved outcomes after traumatic brain injury. We aimed to explore the effects of baicalein on brain injury via ferroptosis and ER stress in a rat model of CA.Methods: Cardiac arrest models were established in Sprague-Dawley (SD) rats. The sham group (n = 6) was untreated with inducing ventricular fibrillation to cardiac arrest and cardiopulmonary resuscitation (CPR). Survival rats were randomly divided into five groups (n = 6). Ferroptosis inhibitor and ER stress agonist were administered separately and together in three groups. There was no drug intervention in the remaining group. The neurological deficit scores were recorded. Characteristics of ferroptosis were observed. And the associated protein of ferroptosis and ER stress were determined by Western blot. Cerebral ROS production was measured by using 2',7'-dichlorofluorescein diacetate as the oxidative fluorescent probe. Results: Baicalein treatment improved neurological outcomes and decreased neurocyte injuries compared with CPR group. The changes of ferroptosis, more specifically, iron content, glutathione peroxidase 4 (GPX4), reactive oxygen species (ROS), arachidonate 15-lipoxygenase (ALOX15) and mitochondrial characteristics, were observed in brain tissue after ROSC. ALOX15 was lower in baicalein group than in CPR group. The morphology and structure of mitochondria in baicalein group were better than in CPR group. The ER stress markers, glucose-regulated protein 78, activating Transcription Factor 4 and C/EBP homologous protein was lower in baicalein group compared with CPR group. ROS in tunicamycin group was higher than in CPR group. And ROS in baicalein +tunicamycin group was lower than in tunicamycin group. Conclusion: Ferroptosis and ER stress are both involved in brain injury after ROSC. Baicalein alleviates brain injury via suppressing the ferroptosis and ER stress, and reduces ROS partly through inhibiting ER stress. Baicalein is a potential drug to relieve brain injury after ROSC.