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.

Remimazolam Improves the Markers of Postresuscitation Cerebral Injury in a Swine Model of Cardiac Arrest

“…After successful CPR, postresuscitation cerebral injury is mainly attributed to various types of pathologic damage (6,23,24). Among which, the release and accumulation of proinflammatory factors, and the imbalance between oxidant and antioxidant molecules can result in direct neural injury and even cell death, and both of them have become two classic pathways of cerebral pathologic damage after resuscitation (25,26).…”

Combination of Hyperoxygenation and Targeted Temperature Management Improves Functional Outcomes of Post Cardiac Arrest Syndrome Irrespective of Causes of Arrest in Rats

“…Anesthesia was induced by intraperitoneal injection of 2% pentobarbital (45 mg/kg), and additional doses of pentobarbital (10 mg/kg) would be injected intravenously at approximately 1-hour intervals for maintenance of anesthesia. The agent and dosage usage was applied based on the literature of CA/cardiopulmonary resuscitation (CPR) rat models and our previous animal studies (14)(15)(16)(17). Anesthetized animals were placed in the supine position, and then subcutaneous electroencephalogram (EEG) needles were inserted into the surfaces of the skull to monitor the EEG signal.…”

Inflammatory responses involved in post-cardiac arrest brain injury: mechanisms, regulation, and therapeutic potential

“…Ferroptosis, an iron-dependent cell death characterized by accumulation of free iron, lipid peroxidation, and plasma membrane damage [99], occurs in the brain after CA. Ferroptosis-related proteins [e.g., glutathione peroxidase 4 (GPX4) and acyl-coenzyme A synthetase long-chain family member 4 (ACSL4)] increased after resuscitation [100], accompanied by elevated ROS production [101]. The inhibition of ferroptosis via baicalein treatment relieved brain injury after ROSC [101].…”

“…Ferroptosis-related proteins [e.g., glutathione peroxidase 4 (GPX4) and acyl-coenzyme A synthetase long-chain family member 4 (ACSL4)] increased after resuscitation [100], accompanied by elevated ROS production [101]. The inhibition of ferroptosis via baicalein treatment relieved brain injury after ROSC [101]. Ferroptosis causes the release of DAMPs, which alert immune cells [99].…”