Table 1.

Neuroprotective effects of molecular hydrogen in experimental post-ischemic brain injury.

Ischemia	Animal	Strain	Treatment	Benefits	References
Focal	Mice	C57B/L	Inhalation of 66.7% hydrogen/33.3% oxygen for 90 min post-ischemia.	Inhibition of microglial activity and regulation of microglial phenotype. Improvement of neurological outcome.	[19,68]
Global	Mice	C57BL/6J	Inhalation hydrogen (1.3%), oxygen (30%), and nitrogen (68.7%). 45 min of ischemia and 180 min of reperfusion, and 3 h/d, from 1 to 3 days post-ischemia.	Improved survival. Attenuation of neuronal injury, autophagy and brain edema.	[77]
Global	Rat	Wistar	2.1% hydrogen supplemented by room air ventilation for 4 h after ischemia.	Reduction changes of prooxidant enzyme and gap junction protein levels.	[90]
Global	Rat	Sprague-Dawley	Hydrogen-rich saline (5 mL/kg) was injected immediately post-ischemia.	Significant improvement of surviving cells. Reduction tissue damage, the degree of mitochondrial swelling, and the loss of mitochondrial membrane potential but also preservation the mitochondrial cytochrome c content.	[91]
Global	Rat	Sprague-Dawley	I.V. hydrogen-rich saline (1 mL/kg, 4 mL/kg, or 6 mL/kg), HRS was given before hypoxia and during reoxygenation.	Inhibition of hippocampus endoplasmic reticulum stress and microvascular endothelial cells apoptosis via PI3K/Akt/GSK3β signaling pathway.	[92]
Global	Rat	Sprague-Dawley	Hydrogen-rich saline 5 mL/kg was intraperitoneally injected immediately and 6 h post-ischemia.	Significant improvement survival rate and neurological function. The beneficial effects associated with decreased levels of oxidative products, as well as the increased levels of antioxidant enzymes and accompanied by the increased activity of glucose-regulated protein 78, the decreased activity of cysteinyl aspartate specific proteinase-12 (caspase-12).	[93]
Global	Rat	Wistar	Inhalation of 2% hydrogen started immediately at the end of ischemia and lasted for 3 h.	Attenuation of cognitive impairment. Decreased pyramidal neuronal death in CA1 region of hippocampus.	[78]
Global	Rat	Sprague-Dawley	Hydrogen-rich saline was administered i.v. at 1 min before end of ischemia, followed by injections at 6 and 12 h post-ischemia.	Improves survival and neurological outcome.	[8]
Focal	Rat	Sprague-Dawley	6 mL/kg i.p. per rat before and after ischemia.	Reduction brain infarct volume and improvement of neurological function. Prevention the ischemia-induced reduction of parvalbumin and hippocalcin levels and also reduced the glutamate toxicity-induced death of neurons. Attenuation the glutamate toxicity-induced by elevate in intracellular calcium.	[84]
Focal	Rat	Sprague-Dawley	0.5 mL/kg/day saturated hydrogen saline (0.6 mmol/L) i.p. 3 days prior to ischemia and immediately during 24 h of reperfusion.	Significantly reduction the number of apoptotic cells, and the protein expression of p38 MAPK and caspase-3. These effects may be associated with the p38MAPK signaling pathway.	[88]
Focal	Rat	Sprague-Dawley	Hydrogen saline was injected i.p. (1 mL/100 g body weight) at designed time points 0, 3 or 6 h after reperfusion onset.	Reduction 8-hydroxyl-2′-deoxyguanosine, malondidehyde, interleukin-1β, tumor necrosis factor-α, and suppressed caspase 3 activity in ischemic brain.	[87]
Global	Rabbit	White	Before ischemia i.p. injection of hydrogen low dose (10 mL/kg) or high dose (20 mL/kg).	Improvement survival and neurological outcomes, reduction of neuronal damage and inhibition of neuronal apoptosis. Reduction indicators of oxidative stress in the blood and the hippocampus and increased activity of antioxidant enzyme.	[83]
Global	Swine	Yorkshire	Inhalation of hydrogen (2.40%) for a 24-h period during and after the ischemic injury.	Reduced neurological injury.	[94]