Magnesium hydride microparticles represent a novel therapeutic approach for cerebral ischemia/reperfusion injury by enabling sustained, high-dose hydrogen delivery across the blood-brain barrier to suppress neuronal ferroptosis and restore mitochondrial function. The treatment effectively reduces reactive oxygen species, stabilizes mitochondrial membrane potential, and promotes neuronal energy metabolism, demonstrating significant neuroprotective potential in TCAR-induced cerebral injury models. This innovative hydrogen administration method addresses previous delivery challenges and offers a promising strategy for managing acute ischemic stroke and related cerebrovascular complications.
Plain-Language Summary
This study tested a new way to deliver hydrogen gas to the brain using magnesium hydride microparticles (tiny particles that slowly release hydrogen) in rabbits with a type of brain injury caused by temporarily blocking blood flow to the brain. The researchers found that this hydrogen delivery method reduced harmful molecules called reactive oxygen species, protected brain cells from a type of damage called ferroptosis, and restored normal function to mitochondria (the energy-producing parts of cells).
Abstract
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.
