Stroke is a leading cause of death and long-term disability, particularly in the elderly population [
19]. It is associated with a 30-day mortality rate of approximately 20% [
19]. The prevalence of stroke is expected to increase significantly as the global population of men and women - older than 65 years of age - increases continuously by an estimated 9 million people per year [
20]. Consequently, it is most essential to investigate novel and potentially effective therapeutics to improve the neurofunctional outcome in patients. The effects of hydrogen treatment for ischemic stroke have been evaluated in an experimental rodent model of transient middle cerebral artery occlusion (tMCAO) [
21]. This model exerts its damaging effect through focal ischemia and reperfusion, which generates acute oxidative stress to the affected brain regions. Under general anesthesia the rat's left middle cerebral artery (MCA) was occluded using a nylon monofilament with a distal silicon rubber tip. The treatment group inhaled 2% hydrogen gas during the entire procedure. Treated and control animals underwent neurological testing, and were sacrificed at 12 hours, 24 hours, 3 days, and 7 days post-surgery. Brains were then sectioned and stained with 2,3,5-triphenyltetrazolium chloride (TTC) to label the infarcted brain area, followed by volumetric computation of the infarct volume. Observed protective effects of hydrogen therapy included: decreased infarct volume, maintenance of body weight after surgery, and improved neurological function when compared to control animals. Liu et al. [
22] utilized the tMCAO model to evaluate neuroprotective effects of intraperitoneally administered hydrogen saline (1 ml/100 g body weight). The results showed that hydrogen saline significantly reduced infarct volume, brain edema, and neurological function when administered within a 6 hour time window after ischemia induction. Hydrogen saline reduced ROS, inflammation markers, as well as caspase 3 activity in the ischemic brain [
22]. Matchett et al. administered hydrogen gas (2.9%) to adult rats that were subjected to tMCAO [
23]. Hydrogen administration showed a tendency to reduce the infarction volume in the treatment group, when compared to control animals; however, neurological deficits were similar in both groups. Furthermore, Chen et al. [
24] reported that hydrogen gas effectively reduced acute hyperglycemia-enhanced hemorrhagic transformation after focal ischemia in the rat. Potential mechanisms on how hydrogen gas ameliorates hemorrhagic transformation remain to be investigated.
Oshawa et al. demonstrated that hydrogen selectively reduced ROS in neuronal tissue cultures [
21]. The effects were demonstrated via electron spin resonance signals in cells subjected to oxygen glucose deprivation followed by oxygen glucose reperfusion, which models cerebral ischemia-reperfusion in vitro [
21]. After reperfusion, fluoroscopy demonstrated an immediate decrease in hydroxyl radicals (OH
-), and an increase in neuronal survival at 24 hours, suggesting that hydrogen effectively protects neurons from oxidative stress-mediated cell death.
Hemorrhagic stroke is often more severe than ischemic stroke, and includes intracerebral hemorrhages (ICH) and subarachnoid hemorrhages (SAH). The mortality rates for ICH and SAH have been reported as 40% to 50%, and survivors are commonly affected by chronic morbidity [
25]. Furthermore, the aggregate lifetime cost of hemorrhagic stroke cases has been estimated as high as $5.6 to $6.0 billion per year [
26]. The effects of hydrogen administration in hemorrhagic stroke models have been previously reported. In a mouse model that implemented collagenase-induced ICH, hydrogen therapy was found to significantly reduce cerebral edema and neurological deficits at 24 hours after surgery; however, hydrogen post-treatment showed only a tendency to improve these outcomes at 72 hours after surgery [
27]. The authors conclude that hydrogen inhalation exerts an acute neuroprotective effect in mice subjected to experimental ICH. Similarly to these results, hydrogen treatment (2.9% for 2 hours) starting 1 hour after induction of experimental SAH (endovascular perforation method), ameliorated brain edema, reduced apoptosis, and improved neurological deficits at 24 hours, but not at 72 hours after surgery [
28]. The protective effects of hydrogen therapy were associated with the reduction of oxidative injury of lipids, proteins, and DNA.