Constructing Mg-Based Hydrogen Container for Mitochondrial Dysfunction and Neuronal Ferroptosis in TCAR-Induced Cerebral Ischemia/Reperfusion Injury

Mitochondrial dysfunction and Reactive Oxygen Species (ROS) overexpression are crucial factors inducing neuronal Ferroptosis in cerebral ischemia/reperfusion injury (CIRI). Some therapeutics like RNAs and anti-oxidation drugs have been developed to regulate the functions of mitochondria, but are hardly delivered into brain effectively due to the blood-brain barrier (BBB). H₂ has recently been verified able to overcome the BBB efficiently and has a unique wide-spectrum anti-oxidation/anti-inflammation effect, but sustainable, high-amount, and safe delivery of H₂ into brain is still challenging currently. Herein, we develop an innovative H₂ administration method of intraperitoneal injection of magnesium hydride microparticles (MgH₂) with a high payload of hydrogen and a sustained hydrolytic H₂ production behavior, achieving persistent and high-dose supply of H₂ into the blood system as well as in the brain. In addition, we establish a novel CIRI rabbit model induced by transcarotid artery revascularization (TCAR), which leads to oxidative stress and subsequent Ferroptosis in the brain's hippocampus. In this CIRI model, MgH₂ treatment eliminates intracellular ROS, inhibits neuronal Ferroptosis, and recovers mitochondrial dysfunction by stabilizing mitochondrial membrane potential, regulating mitobiogenesis, promoting neuronal energy metabolism, and activating the anti-oxidative pathway. All these findings demonstrate that MgH₂ treatment provides a potential strategy for CIRI.