Neuroprotective Effects of Molecular Hydrogen: A Critical Review

Molecular hydrogen (H₂) is a physiologically inert gas. However, during the last 10 years, increasing evidence has revealed its biological functions under pathological conditions. More specifically, H₂ has protective effects against a variety of diseases, particularly nervous system disorders, which include ischemia/reperfusion injury, traumatic injury, subarachnoid hemorrhage, neuropathic pain, neurodegenerative diseases, cognitive dysfunction induced by surgery and anesthesia, anxiety, and depression. In addition, H₂ plays protective roles mainly through anti-oxidation, anti-inflammation, anti-apoptosis, the regulation of autophagy, and preservation of mitochondrial function and the blood-brain barrier. Further, H₂ is easy to use and has neuroprotective effects with no major side-effects, indicating that H₂ administration is a potential therapeutic strategy in clinical settings. Here we summarize the H₂ donors and their pharmacokinetics. Meanwhile, we review the effectiveness and safety of H₂ in the treatment of various nervous system diseases based on preclinical and clinical studies, leading to the conclusion that H₂ can be a simple and effective clinical therapy for CNS diseases such as ischemia-reperfusion brain injury, Parkinson's disease, and diseases characterized by cognitive dysfunction. The potential mechanisms involved in the neuroprotective effect of H₂ are also analyzed.