It was first reported in 2007 that inhaled hydrogen gas has antioxidant and antiapoptotic properties that protect the brain against I/R injury and stroke. In an in vitro study, researchers demonstrated that hydrogen functions as a scavenger of ·OH. Then in a neonatal hypoxia–ischemia rat model, we found that 2% hydrogen gas or HRS therapy reduced apoptosis [
3,
4]. However, another group has reported that 2.9% hydrogen gas therapy does not ameliorate moderate-to-severe ischemic damage in a neonatal hypoxia–ischemia rat model [
5], although they did find that hydrogen gas reduced infarction and hemorrhage and improved neurologic function in a rat model of middle cerebral artery occlusion. Inhalation of hydrogen gas ameliorated intracerebral hemorrhage in mice [
6], and hydrogen saline protected against brain injury from experimental subarachnoid hemorrhage [
7] and spinal cord I/R injury [
8]. It has been reported that HRS attenuated neuronal I/R injury by preserving mitochondrial function [
9]. Hong and colleagues concluded that hydrogen can protect against neurologic damage and apoptosis early in brain injury following subarachnoid hemorrhage through the Akt/hGSK3β signaling pathway [
10]. Also, we found that hydrogen saline decreased 8-hydroxyl-2'-deoxyguanosine (8-OHdG), reduced malondialdehyde (MDA), interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) and suppressed caspase-3 activity in the ischemic brain [
11]. Hyperglycemia is one of the major factors contributing to hemorrhage after ischemic stroke. Chen et al. found that the protective effect of hydrogen in the rat brain is accompanied by a reduction in oxidative stress and blood glucose levels after dextrose injection [
12]. In addition, hydrogen-rich pure water has been reported to prevent superoxide formation in brain slices from vitamin C depleted SMP30/GNL-knockout mice during hypoxia–re-oxygenation [
13]. In a model of perinatal asphyxia in newborn pigs, ventilation with 2.1% hydrogen-supplemented room air significantly preserved cerebrovascular reactivity to hypercapnia and reduced neuronal injury induced by asphyxia–re-ventilation [
14]. Interestingly, our group found that lactulose, which is used in the treatment of constipation and hepatic encephalopathy, ameliorated cerebral I/R injury by inducing hydrogen [
15]. Finally, it has been reported that drinking hydrogen-rich water ameliorated cognitive impairment in mice with accelerated senescence [
16].