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.