Potential application of hydrogen in traumatic and surgical brain injury, stroke and neonatal hypoxia-ischemia

Traumatic brain injury (TBI) and cerebral vascular events can be devastating; yet there are few treatments proven to ameliorate the brain damage and overall outcome in patients. An ideal neuroprotectant would be non-toxic, easily administered, permeable at the blood-brain barrier (BBB), and offer protection at all stages of injury, including prophylaxis. Hydrogen sulfide (H2S) has shown some of these properties [1,2]. Its mechanisms may be related to the attenuation of reactive oxygen species (ROS) [3], or to its role as a neuromodulator [4]; however, the use of H2S is controversial because of its toxicity [5] and gasotransmitter functions [6].Hydrogen is the most abundant element in the universe [7]. Room air concentrations of hydrogen gas higher than 4% (normal air content = 0.000055%) are explosive, and could cause asphyxiation [8]. Therapeutically relevant dosages of hydrogen, as used in the following animal studies (range 2%-2.9%), appear to be well tolerated. Furthermore, 3% hydrogen gas has been safely and regularly used for human deep-sea divers without any adverse events [9].Currently, to our knowledge, there are no FDA approved therapeutic regimens involving hydrogen gas or dissolved hydrogen. We sought to analyze recent available data regarding the use of hydrogen as a neuroprotectant.Trauma is the leading cause of death in Americans younger than 45 years of age, and traumatic brain injury (TBI) accounts for over 50% of this mortality [10]. Out of the 1.5 million Americans who sustain a TBI each year, 230,000 are hospitalized, 80,000 to 90,000 remain with long-term disabilities, 50,000 die, and the estimated annual cost exceeds $60 billion [11-13]. To investigate whether hydrogen (H2) exerts abilities to ameliorate the outcome after TBI, Ji et al. administered 2% H2 to rats, which were also subjected to experimental TBI [14]. TBI-challenged rats, that did not inhale H2, presented with significantly greater brain edema, blood-brain barrier (BBB) permeabili