• Users Online: 86
  • Home
  • Print this page
  • Email this page

 Table of Contents  
Year : 2016  |  Volume : 6  |  Issue : 1  |  Page : 48-54

Hydrogen therapy: from mechanism to cerebral diseases

Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China

Date of Web Publication4-Apr-2016

Correspondence Address:
Gang Chen
Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province
Login to access the Email id

Source of Support: Funding: This work was supported by a grant from Suzhou Key Medical Center of China (No. Szzx201501), grants from the National Natural Science Foundation of China (No. 81571115, 81422013, and 81471196), a grant from the Scientific Department of Jiangsu Province of China (No. BL2014045), a grant from Suzhou Government of China (No. LCZX201301, SZS201413, and SYS201332), and A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions., Conflict of Interest: None

DOI: 10.4103/2045-9912.179346

Rights and Permissions

The medicinal value of hydrogen (H 2 ) was ignored prior to research illustrating that inhalation of 2% H 2 can significantly decrease the damage of cerebral ischemia/reperfusion caused by oxidative stress via selective elimination of hydroxyl freebase (OH) and peroxynitrite anion (ONOOˉ). Subsequently, there have been numerous experiments on H 2 . Most research and trials involving the mechanisms underlying H 2 therapy show the effects of antioxygenation, anti-inflammation, and anti-apoptosis. Among quantities of diseases related with H 2 therapy, the brain disease is a hotspot as brain tissue and cell damage are easier to be induced by oxidative stress and other stimulations. In this review, emphasis is on stroke, traumatic brain injuries, and degenerative diseases, such as Alzheimer's disease and Parkinson's disease. Taking into account the blood-brain barrier, penetrability, possible side effects, and the molecular properties of H 2 within a single comprehensive review should contribute to advancing both clinical and non-clinical research and therapies. A systematic introduction of H 2 therapy with regards to mechanisms and cerebral diseases both in animal and human subjects can make it easier to comprehend H 2 therapy and therefore provide the basis for further clinical strategy.

Keywords: hydrogen therapy; ingestion; oxidative stress; inflammation; apoptosis; cerebral diseases

How to cite this article:
Liu Cl, Zhang K, Chen G. Hydrogen therapy: from mechanism to cerebral diseases. Med Gas Res 2016;6:48-54

How to cite this URL:
Liu Cl, Zhang K, Chen G. Hydrogen therapy: from mechanism to cerebral diseases. Med Gas Res [serial online] 2016 [cited 2023 Mar 28];6:48-54. Available from: https://www.medgasres.com/text.asp?2016/6/1/48/179346

Cheng-lin Liu, Kai Zhang.
These authors contributed equally to this work.
H 2 : hydrogen; ·OH: hydroxyl freebase; ONOOˉ: peroxynitrite anion; BBB: blood brain barrier; IL-1β: interleukin 1 beta; TNF-α: tumor necrosis factor-alpha; DR: death receptors; TRAIL: TNF related apoptosis inducing ligand; TUNEL: Terminal-deoxynucleotidyl Transferase Mediated Nick End Labeling; NF-κB: Nuclear factor-κB; ERK 1/2: extracellular-regulated kinase1/2; DNA: deoxyribonucleic acid; ROS: reactive oxygen species; tMCAO: transient middle cerebral artery occlusion; pMCAO: persistent middle cerebral artery occlusion; 8-OhdG: 8-hydroxy-2-deoxyguanosine; MMP-9: matrix metalloproteinases-9; SAH: subarachnoid hemorrhage; ICH: intracerebral hemorrhage; Hb: hemoglobin; TBI: Traumatic brain injury; AD: Alzheimer′s disease; PD: Parkinson′s disease; SOD: superoxide dismutase; MDA: malondialdehyde; NHI: neonatal hypoxia-ischemia.
Author contributions
CLL and KZ were responsible for writing the manuscript. GC was responsible for drafting and revision of the manuscript. All authors read and approved the final manuscript.
Conflicts of interest
The authors declare no competing interests.

  Introduction Top

Hydrogen (H 2 ) therapy has been an intense subject of interest following the discovery of selective antioxygenation by Ohsawa in 2007 (Ohsawa et al., 2007). Currently, there are only a minority of antioxidants used in the clinical treatment of nervous system diseases and they are not very effective (Jang et al., 2009; Munakata et al., 2011). Combined with special natures and multiple manners of ingestion, H 2 is a strong prospect for clinical application (Ichihara et al., 2015). In our review, we discuss the advantages and disadvantages of H 2 therapy, its underlying mechanisms, and ingestion characteristics. Furthermore, we focus heavily on H 2 therapy's relative role in treating brain diseases, since cerebral cells and tissues are sensitive to oxidative stress and other relevant stimulation (Allen and Bayraktutan, 2009).

  Ingestion Characteristics Top

Under normal temperature and pressure, the solubility of H 2 is low and it cannot be largely absorbed by the body. Although humans and most mammals do not have endogenous cells that produce H 2 , a large number of anaerobic bacteria in the large intestine can produce H 2 by decomposing plant fibers and carbohydrates from polysaccharide fragments. Additionally, H 2 can be expelled by anus exhaust, intestinal flora metabolism, and the respiratory tract (Levitt, 1969; Sahakian et al., 2010).

Clinically, methods for ingestion of H 2 include oral intake of H 2 water, intravenous drip infusion of H 2 -rich saline, and inhalation of air containing 2-4% H 2 gas (Ono et al., 2011; Ishibashi et al., 2012, 2014, 2015; Sakai et al., 2014). Side effects related to the concentration of H 2 are often neglected, occasionally resulting in a lack or excess of H 2 administered to patients, and, potentially, toxic effects (Nakao et al., 2010a). Research reveals that concentrations of H 2 in tissue corresponds to its concentration in the administered water or gas, suggesting that it is important to consider the disease of interest when selecting the most efficient route of H 2 administration.

  Mechanisms Top


Free radicals are generated during metabolic processes. By breathing 2% H 2 , the free radical can be effectively removed, decreasing cerebral ischemia/reperfusion injury (Ohsawa et al., 2007). It was demonstrated at the cellular level that H 2 can selectively neutralize ĽOH and ONOOˉ, and therefore concluded that this selective antioxidant effect is the basis of H 2 therapy for cerebral ischemia/reperfusion injury. Additionally, a variety of animal experiments confirmed that H 2 has the capacity to improve the activity of antioxidant system, reducing damage to cells and tissues induced by oxidative stress (Xie et al., 2010; Wang et al., 2015). Other experiments showed improvement in the activity of antioxidant enzymes under H 2 inducement (Kawamura et al., 2010).

Anti-inflammation effect

Inflammation is a common pathological process accompanying most diseases, whereby activation of immunocytes and the release inflammatory cytokines are involved. This includes interleukin 1 beta (IL- 1β), IL- 6 and tumor necrosis factor-alpha (TNF-α). Animal experiments confirmed that ingestion of H 2 can decrease both the amount of inflammatory cytokines and immunocyte stimulation (Kawamura et al., 2010; (Kajiya et al., 2009; Liu et al., 2010; Wang et al., 2011b; Zhang et al., 2011). As a result, the degree of inflammation was alleviated through H 2 therapy.

Anti-apoptosis effect

According to recent studies, apoptosis can be triggered by intrinsic stimulation through the mitochondrial signaling pathway, or by extrinsic stimulation through cell surface death receptors (DR), such as TNFα, TNF-related apoptosis-inducing ligand (TRAIL) receptors, and Fas (CD95/APO1) (Adams, 2003; Green, 2005). In either case, activation of cysteine aspartyl proteases (caspases) is necessary, and therefore, we define apoptosis as a caspase-dependent manner of cell death. Research showed that the apoptosis of neurons in newborn rats induced by hypoxia and ischemia is inhibited if inhaling H 2 , as the ratio of Terminal-deoxynucleotidyl Transferase Mediated Nick End Labeling (TUNEL) staining positive cells and the activity of caspase-3 and caspase-12 of the hippocampus and cortex is decreased (Cai et al., 2008). Other animal studies discovered the anti-apoptosis effect of H 2 . For instance, in the case of spinal cord injury, apoptosis-related indicators decline if an intraperitoneal injection of H 2 -saturated saline is administered within a certain time period (Chen et al., 2010a).

Additional mechanisms

Nuclear factor-kappaB (NF-κB) is quick and widespread transcription factors in the cytoplasm that regulate expression of target genes, such as cytokines, chemokines, adhesion molecules, and oxidative stress-related enzymes. Studies based on specific animal models have demonstrated the inhibition of NF-κB with the introduction of H 2 (Wang et al., 2011a). H 2 can also control the activity of extracellular signal-regulated kinase, such as with the inhibition of phosphorylation of extracellular signal-regulated kinase1/2 (ERK 1/2) (Liu et al., 2010).

  Advantages and Disadvantages Top

Easy preparation, low cost, non-toxicity, powerful permeability, absence of residue, are characteristics that make H 2 a strong prospect for clinical application (Ichihara et al., 2015). H 2 's powerful permeability grants it accessibility to secondary organelles, such as mitochondria and nuclei, which are primary locations of deoxyribonucleic acid (DNA) and reactive oxygen species (ROS) damage (Ohsawa et al., 2007; Nakata et al., 2015). Additionally, H 2 can selectively remove hydroxyl free radicals and nitrous acid anions. Hypoergia between H 2 and other gases when in therapeutic concentration makes H 2 gas capable of combining with other gas therapies, such as anesthesia inhalation (Nakao et al., 2010b). Furthermore, there are many methods for ingestion of H 2 , such as oral intake of H 2 water, intravenous drip of H 2 -rich saline, and inhalation of air containing 2-4% H 2 gas (Zheng et al., 2009; Qian et al., 2010; Lin et al., 2011; Kurokawa et al., 2015). Having various means of ingestion produces multiplicity when faced with different diseases. Unfortunately, until 2011, clinical outcomes were poor, and the effects of H 2 on human subjects are often less remarkable than those seen in animal models (Ichihara et al., 2015).

The prominent effects of H 2 play an important role in a variety of clinical diseases and animal models, but unclear and unsolved conundrums remain (Katz et al., 2015). Research reported that levels of some biological enzymes, such as aspartate aminotransferase, alanine aminotransferase, γ-glutathione transferase and total bilirubin, declined upon ingestion of a certain amount of H 2 (Nakao et al., 2010a; Saitoh et al., 2010). These variations and interactions were also observed in clinical trials and do not exceed standard ranges.

Intuitive understanding of H 2 therapy was reached through the summary and visual representation of the above content ([Figure 1]).
Figure 1: Relevant features and mechanisms of hydrogen therapy.

Click here to view

Role in cerebral diseases


Stroke is a devastating illness second only to cardiac ischemia as a cause of death worldwide. Its main causes include cerebral vasospasm, obstacles in cerebral blood circulation, and the rupture of cerebral vessels. Oxidative stress and immunity are key elements of stroke pathobiology and are present from the stroke's early damaging stages, to the late post-ischemic tissue repair (Iadecola and Anrather, 2011; Behrouz, 2016; Sukumari-Ramesh et al., 2016). Strokes are divided into two categories: ischemic stroke and hemorrhagic stroke.

An ischemic stroke refers to local brain tissue damage caused by external or intracranial artery stenosis, or occlusion lesions sustained as a result of insufficient collateral circulation within the brain (Lyden and Zivin, 1993; Li et al., 2015). Studies show that cerebral ischemia and ischemia-reperfusion injuries contain more impact factors and mechanisms, and oxidative stress plays an important role (Allen and Bayraktutan, 2009; Hafez et al., 2014; Seifert and Pennypacker, 2014; Weaver and Liu, 2015).

One study on rats revealed that H 2 provides nerve protection in the transient middle cerebral artery occlusion (tMCAO) (Wardlaw et al., 2012). The volume of infarctus, malondialdehyde (a product of lipid oxidation) and 8-hydroxy-2-deoxyguanosine (8-OHdG, a product of DNA oxidation) declined after ingesting 2% H 2 . In the same experiment, researchers also confirmed that H 2 can act as an antioxidant and selectively remove ĽOH and ONOOˉ. Furthermore, its curative effects on cerebral ischemia/reperfusion injury were more significant than those of edaravone. H 2 also demonstrated an anti-inflammatory and anti-apoptotic effect. In addition, TNF-α and caspase-3 is inhibited after intraperitoneal injection of H 2 saline.

In clinical studies, upon ischemic stroke onset, 8.5-30% of patients suffer a hemorrhagic stroke (Wardlaw et al., 2012). Among patients in both the high sugar and tMCAO groups, due to its suppressive effects, this risk of brain hemorrhaging was decreased upon H 2 administration. After persistent inhalation of 2.9% H 2 for 2 hours, oxydic products and matrix metalloproteinases-9 (MMP-9) decreased, illustrating protection of the BBB (Chen et al., 2010b). Researchers speculated this effect contributed to the lower occurrence of hemorrhage accompanying cerebral infarction. Following intraperitoneal injection of H 2 saline, persistent middle cerebral artery occlusion (pMCAO) conformed to continuous ischemia of vessels, activity of antioxidant enzymes increased, and infarction areas were effectively reduced (Nagatani et al., 2012). In animals, small doses of H 2 can significantly reduce mortality in cases of ischemic strokes that target the entire brain. Another clinical trial on brain stem infarction revealed that cooperation of H 2 and edaravone can cut down recovery time significantly better than using edaravone alone.

A hemorrhagic stroke is defined as a cerebral hemorrhage following compression and necrosis of brain tissue (Chen et al., 2015). It is also known as a hemorrhagic cerebrovascular accident, which is generally divided into two categories: subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH). Hemorrhagic strokes are typically more dangerous than ischemic strokes (Engelhardt and Sorokin, 2009). Microglia and inflammatory cells are activated upon hemorrhage, producing free radicals. A series of changes, like the formation of hematoma, decomposition of hemoglobin (Hb), and Feton reactions can aggravate oxidative stress. In an ICH model for mice, inhalation of 2% H 2 for 1 hour reduced the degree of cerebral edema and improved neural function significantly, though only for 72 hours, suggesting that H 2 demonstrates only acute protection from ICH. This was speculated to be a due to neutrophil infiltration and microglial activation not peaking until after 72 hours, and antioxygenation of H 2 not persistent or sufficient at that time (Manaenko et al., 2011). Lastly, infiltration and activation of mastocytes play an important role in inflammatory responses during the initial stages of stroke. H 2 was shown to protect BBB and decrease cerebral edema by preventing activation of mastocytes.

Traumatic brain injury

Traumatic brain injury (TBI) is one of the leading causes of death and disability of young people, and recovering patients usually experience impairment in learning and memory (Chua et al., 2007). Experimentation on rats showed that TBI led to brain edema, dysfunction of the nervous system, and delays in remodeling (Zhang et al., 2014). Furthermore, oxidative stress was determined an important factor in pathological changes (Zhang et al., 2014). When TBI occurred in rats, in-drawing of 2% H 2 decreased oxidation products, increased antioxidant enzyme activity, improved cerebral edema, and decreased nervous system dysfunction (Ji et al., 2010). Other studies revealed the protective effects of H 2 -rich saline on hydraulic coup injury: malondialdehyde (an important antioxidant adjustment factor) declined, silent information regulators and brain-derived neurotrophic factors elevated (factors which mediate the synaptic plasticity associated with learning and memory). Additionally, Morris water maze tests also confirmed improved cognitive function following H 2 therapy (Hou et al., 2012).

Degenerative diseases

A neurodegenerative disease is characterized as the loss of cells in the brain and spinal cord, which are generally not renewable. As time progresses, neural deterioration is aggravated, leading to devastating and irreversible neural dysfunction. Neurodegenerative diseases are divided into two types: One impacting movement, such as cerebellar ataxia, and the other affecting memory and is related to dementia.

Alzheimer's disease (AD) is the most common neurological degenerative disease, in which glial cells and inflammation are activated and free radicals are produced, damaging neurons (Cupino and Zabel, 2014). One study found that drinking H 2 saline deterred the decline of age-related memory and learning ability (Gu et al., 2010). In that study, activation of cerebral 5-hydroxytryptamine and haemal antioxidant increased, resulting in a reduction of hippocampal neuron degeneration and improved scores on the Morris water maze test (Gu et al., 2010). In other AD models, NF-κB was combined with H 2 therapy (Guo et al., 2015).

Parkinson's disease (PD) is an age-related neurodegenerative disease characterized by neural degeneration in the substantia nigra and striatum. Administration of H 2 -rich saline for 6-hydroxydopamine-induced Parkinson's syndrome resulted in neural protection effects, and drinking H 2 saline yielded similar effects in 1-methyl-4-phenolic group-1, 2, 3, 6-4 hydrogen purineinduced PD (Gu et al., 2010).

Additional cerebral diseases

Acute carbon monoxide poisoning is a systemic disease mainly involving damage of the central nervous system and delayed encephalopathy. Investigations concluded that acute brain injury and delayed encephalopathy of carbon monoxide poisoning have a close relationship with oxidative stress, cell apoptosis and immune injuries (Kao and Nanagas, 2005). Related research showed that H 2 -rich saline improved activation of superoxide dismutase (SOD) in brain tissues and serum, and decreased malondialdehyde (MDA), therefore improving memory, learning, and environmental adaptation during acute carbon monoxide poisoning(Sun et al., 2011; Shen et al., 2013).

In recent years, mortality rate in premature births have increased, but effective treatments for neonatal hypoxia-ischemia (NHI) remain few. Antioxidant systems in newborns are immature and are more sensitive to free radical damage. H 2 therapy was shown useful in NHI treatment, as activity of caspase-3 and degree of cell apoptosis decreased, suggesting that H 2 offers neural protection by inhibiting apoptosis (Cai et al., 2008).

In order to facilitate simple comprehension, the relationships between H 2 therapy and the brain diseases discussed above is summarized through illustration ([Figure 2]).
Figure 2: Summary of the relationship between hydrogen therapy and brain diseases.

Click here to view

  Discussion Top

Due to the feasibility and effectiveness of H 2 therapy, H 2 is a strong prospect for clinical application. Until now, studies and clinical trials of H 2 were carried out internationally and involved the investigation of a variety of diseases. In this review, we simplify comprehension of H 2 therapy and provide the basis for further clinical strategy. It is important to note that underlying mechanisms, optimal concentration, and biological safety of H 2 are worthy of deeper investigation. Additionally, the interrelationships between effects such as antioxygenation, anti-inflammation, and anti-apoptosis, remain unclear. In conclusion, we recommend more research in both the individual and molecular levels in order to drive H 2 to become a more effective therapy in clinical settings.


H 2 : hydrogen; ĽOH: hydroxyl freebase; ONOOˉ: peroxynitrite anion; BBB: blood brain barrier; IL-1β: interleukin 1 beta; TNF-α: tumor necrosis factor-alpha; DR: death receptors; TRAIL: TNF related apoptosis inducing ligand; TUNEL: Terminal-deoxynucleotidyl Transferase Mediated Nick End Labeling; NF-κB: Nuclear factor-κB; ERK 1/2: extracellular-regulated kinase1/2; DNA: deoxyribonucleic acid; ROS: reactive oxygen species; tMCAO: transient middle cerebral artery occlusion; pMCAO: persistent middle cerebral artery occlusion; 8-OhdG: 8-hydroxy-2-deoxyguanosine; MMP-9: matrix metalloproteinases-9; SAH: subarachnoid hemorrhage; ICH: intracerebral hemorrhage; Hb: hemoglobin; TBI: Traumatic brain injury; AD: Alzheimer's disease; PD: Parkinson's disease; SOD: superoxide dismutase; MDA: malondialdehyde; NHI: neonatal hypoxia-ischemia.[57]

  References Top

Adams JM (2003) Ways of dying: multiple pathways to apoptosis. Genes Dev 17:2481-2495.  Back to cited text no. 1
Allen CL, Bayraktutan U (2009) Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int J Stroke 4:461-470.  Back to cited text no. 2
Behrouz R (2016) Re-exploring tumor necrosis factor alpha as a target for therapy in intracerebral hemorrhage. Transl Stroke Res 7:93-96.  Back to cited text no. 3
Cai J, Kang Z, Liu WW, Luo X, Qiang S, Zhang JH, Ohta S, Sun X, Xu W, Tao H, Li R (2008) Hydrogen therapy reduces apoptosis in neonatal hypoxia-ischemia rat model. Neurosci Lett 441:167-172.  Back to cited text no. 4
Chen C, Chen Q, Mao Y, Xu S, Xia C, Shi X, Zhang JH, Yuan H, Sun X (2010a) Hydrogen-rich saline protects against spinal cord injury in rats. Neurochem Res 35:1111-1118.  Back to cited text no. 5
Chen CH, Manaenko A, Zhan Y, Liu WW, Ostrowki RP, Tang J, Zhang JH (2010b) Hydrogen gas reduced acute hyperglycemia-enhanced hemorrhagic transformation in a focal ischemia rat model. Neuroscience 169:402-414.  Back to cited text no. 6
Chen S, Yang Q, Chen G, Zhang JH (2015) An update on inflammation in the acute phase of intracerebral hemorrhage. Transl Stroke Res 6:4-8.  Back to cited text no. 7
Chua KS, Ng YS, Yap SG, Bok CW (2007) A brief review of traumatic brain injury rehabilitation. Ann Acad Med Singapore 36:31-42.  Back to cited text no. 8
Cupino TL, Zabel MK (2014) Alzheimer's silent partner: cerebral amyloid angiopathy. Transl Stroke Res 5:330-337.  Back to cited text no. 9
Engelhardt B, Sorokin L (2009) The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol 31:497-511.  Back to cited text no. 10
Green DR (2005) Apoptotic pathways: ten minutes to dead. Cell 121:671-674.  Back to cited text no. 11
Gu Y, Huang CS, Inoue T, Yamashita T, Ishida T, Kang KM, Nakao A (2010) Drinking hydrogen water ameliorated cognitive impairment in senescence-accelerated mice. J Clin Biochem Nutr 46:269-276.  Back to cited text no. 12
Guo SX, Fang Q, You CG, Jin YY, Wang XG, Hu XL, Han CM (2015) Effects of hydrogen-rich saline on early acute kidney injury in severely burned rats by suppressing oxidative stress induced apoptosis and inflammation. J Transl Med 13:183.  Back to cited text no. 13
Hafez S, Coucha M, Bruno A, Fagan SC, Ergul A (2014) Hyperglycemia, acute ischemic stroke, and thrombolytic therapy. Transl Stroke Res 5:442-453.  Back to cited text no. 14
Hou Z, Luo W, Sun X, Hao S, Zhang Y, Xu F, Wang Z, Liu B (2012) Hydrogen-rich saline protects against oxidative damage and cognitive deficits after mild traumatic brain injury. Brain Res Bull 88:560-565.  Back to cited text no. 15
Iadecola C, Anrather J (2011) The immunology of stroke: from mechanisms to translation. Nat Med 17:796-808.  Back to cited text no. 16
Ichihara M, Sobue S, Ito M, Ito M, Hirayama M, Ohno K (2015) Beneficial biological effects and the underlying mechanisms of molecular hydrogen - comprehensive review of 321 original articles. Med Gas Res 5:12.  Back to cited text no. 17
Ishibashi T, Sato B, Rikitake M, Seo T, Kurokawa R, Hara Y, Naritomi Y, Hara H, Nagao T (2012) Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis: an open-label pilot study. Med Gas Res 2:27.  Back to cited text no. 18
Ishibashi T, Sato B, Shibata S, Sakai T, Hara Y, Naritomi Y, Koyanagi S, Hara H, Nagao T (2014) Therapeutic efficacy of infused molecular hydrogen in saline on rheumatoid arthritis: a randomized, double-blind, placebo-controlled pilot study. Int Immunopharmacol 21:468-473.  Back to cited text no. 19
Ishibashi T, Ichikawa M, Sato B, Shibata S, Hara Y, Naritomi Y, Okazaki K, Nakashima Y, Iwamoto Y, Koyanagi S, Hara H, Nagao T (2015) Improvement of psoriasis-associated arthritis and skin lesions by treatment with molecular hydrogen: A report of three cases. Mol Med Rep 12:2757-2764.  Back to cited text no. 20
Jang YG, Ilodigwe D, Macdonald RL (2009) Metaanalysis of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care 10:141-147.  Back to cited text no. 21
Ji X, Liu W, Xie K, Liu W, Qu Y, Chao X, Chen T, Zhou J, Fei Z (2010) Beneficial effects of hydrogen gas in a rat model of traumatic brain injury via reducing oxidative stress. Brain Res 1354:196-205.  Back to cited text no. 22
Kajiya M, Silva MJ, Sato K, Ouhara K, Kawai T (2009) Hydrogen mediates suppression of colon inflammation induced by dextran sodium sulfate. Biochem Biophys Res Commun 386:11-15.  Back to cited text no. 23
Kao LW, Nanagas KA (2005) Carbon monoxide poisoning. Med Clin North Am 89:1161-1194.  Back to cited text no. 24
Katz I, Murdock J, Palgen M, Pype J, Caillibotte G (2015) Pharmacokinetic analysis of the chronic administration of the inert gases Xe and Ar using a physiological based model. Med Gas Res 5:8.  Back to cited text no. 25
Kawamura T, Huang CS, Tochigi N, Lee S, Shigemura N, Billiar TR, Okumura M, Nakao A, Toyoda Y (2010) Inhaled hydrogen gas therapy for prevention of lung transplant-induced ischemia/reperfusion injury in rats. Transplantation 90:1344-1351.  Back to cited text no. 26
Kurokawa R, Seo T, Sato B, Hirano S, Sato F (2015) Convenient methods for ingestion of molecular hydrogen: drinking, injection, and inhalation. Med Gas Res 5:13.  Back to cited text no. 27
Levitt MD (1969) Production and excretion of hydrogen gas in man. N Engl J Med 281:122-127.  Back to cited text no. 28
Li XJ, Li CK, Wei LY, Lu N, Wang GH, Zhao HG, Li DL (2015) Hydrogen sulfide intervention in focal cerebral ischemia/reperfusion injury in rats. Neural Regen Res 10:932-937.  Back to cited text no. 29
Lin Y, Kashio A, Sakamoto T, Suzukawa K, Kakigi A, Yamasoba T (2011) Hydrogen in drinking water attenuates noise-induced hearing loss in guinea pigs. Neurosci Lett 487:12-16.  Back to cited text no. 30
Liu Q, Shen WF, Sun HY, Fan DF, Nakao A, Cai JM, Yan G, Zhou WP, Shen RX, Yang JM, Sun XJ (2010) Hydrogen-rich saline protects against liver injury in rats with obstructive jaundice. Liver Int 30:958-968.  Back to cited text no. 31
Lyden PD, Zivin JA (1993) Hemorrhagic transformation after cerebral ischemia: mechanisms and incidence. Cerebrovasc Brain Metab Rev 5:1-16.  Back to cited text no. 32
Manaenko A, Lekic T, Ma Q, Ostrowski RP, Zhang JH, Tang J (2011) Hydrogen inhalation is neuroprotective and improves functional outcomes in mice after intracerebral hemorrhage. Acta Neurochir Suppl 111:179-183.  Back to cited text no. 33
Munakata A, Ohkuma H, Shimamura N (2011) Effect of a free radical scavenger, edaravone, on free radical reactions: related signal transduction and cerebral vasospasm in the rabbit subarachnoid hemorrhage model. Acta Neurochir Suppl 110:17-22.  Back to cited text no. 34
Nagatani K, Wada K, Takeuchi S, Kobayashi H, Uozumi Y, Otani N, Fujita M, Tachibana S, Nawashiro H (2012) Effect of hydrogen gas on the survival rate of mice following global cerebral ischemia. Shock (Augusta, Ga) 37:645-652.  Back to cited text no. 35
Nakao A, Toyoda Y, Sharma P, Evans M, Guthrie N (2010a) Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome-an open label pilot study. J Clin Biochem Nutr 46:140-149.  Back to cited text no. 36
Nakao A, Kaczorowski DJ, Wang Y, Cardinal JS, Buchholz BM, Sugimoto R, Tobita K, Lee S, Toyoda Y, Billiar TR, McCurry KR (2010b) Amelioration of rat cardiac cold ischemia/reperfusion injury with inhaled hydrogen or carbon monoxide, or both. J Heart Lung Transplant 29:544-553.  Back to cited text no. 37
Nakata K, Yamashita N, Noda Y, Ohsawa I (2015) Stimulation of human damaged sperm motility with hydrogen molecule. Med Gas Res 5:2.  Back to cited text no. 38
Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, Katayama Y, Asoh S, Ohta S (2007) Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med 13:688-694.  Back to cited text no. 39
Ono H, Nishijima Y, Adachi N, Tachibana S, Chitoku S, Mukaihara S, Sakamoto M, Kudo Y, Nakazawa J, Kaneko K, Nawashiro H (2011) Improved brain MRI indices in the acute brain stem infarct sites treated with hydroxyl radical scavengers, Edaravone and hydrogen, as compared to Edaravone alone. A non-controlled study. Med Gas Res 1:12.  Back to cited text no. 40
Qian L, Cao F, Cui J, Huang Y, Zhou X, Liu S, Cai J (2010) Radioprotective effect of hydrogen in cultured cells and mice. Free Radic Res 44:275-282.  Back to cited text no. 41
Sahakian AB, Jee SR, Pimentel M (2010) Methane and the gastrointestinal tract. Dig Dis Sci 55:2135-2143.  Back to cited text no. 42
Saitoh Y, Harata Y, Mizuhashi F, Nakajima M, Miwa N (2010) Biological safety of neutral-pH hydrogen-enriched electrolyzed water upon mutagenicity, genotoxicity and subchronic oral toxicity. Toxicol Ind Health 26:203-216.  Back to cited text no. 43
Sakai T, Sato B, Hara K, Hara Y, Naritomi Y, Koyanagi S, Hara H, Nagao T, Ishibashi T (2014) Consumption of water containing over 3.5 mg of dissolved hydrogen could improve vascular endothelial function. Vasc Health Risk Manag 10:591-597.  Back to cited text no. 44
Seifert HA, Pennypacker KR (2014) Molecular and cellular immune responses to ischemic brain injury. Transl Stroke Res 5:543-553.  Back to cited text no. 45
Shen MH, Cai JM, Sun Q, Zhang DW, Huo ZL, He J, Sun XJ (2013) Neuroprotective effect of hydrogen-rich saline in acute carbon monoxide poisoning. CNS Neurosci 19:361-363.  Back to cited text no. 46
Sukumari-Ramesh S, Alleyne CH, Jr., Dhandapani KM (2016) The histone deacetylase inhibitor suberoylanilide hydroxamic acid (saha) confers acute neuroprotection after intracerebral hemorrhage in mice. Transl Stroke Res 7:141-148.  Back to cited text no. 47
Sun Q, Cai J, Zhou J, Tao H, Zhang JH, Zhang W, Sun XJ (2011) Hydrogen-rich saline reduces delayed neurologic sequelae in experimental carbon monoxide toxicity. Crit Care Med 39:765-769.  Back to cited text no. 48
Wang C, Li J, Liu Q, Yang R, Zhang JH, Cao YP, Sun XJ (2011a) Hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of JNK and NF-kappaB activation in a rat model of amyloid-beta-induced Alzheimer's disease. Neurosci Lett 491:127-132.  Back to cited text no. 49
Wang JL, Zhang QS, Zhu KD, Sun JF, Zhang ZP, Sun JW, Zhang KX (2015) Hydrogen-rich saline injection into the subarachnoid cavity within 2 weeks promotes recovery after acute spinal cord injury. Neural Regen Res 10:958-964.  Back to cited text no. 50
Wang Y, Jing L, Zhao XM, Han JJ, Xia ZL, Qin SC, Wu YP, Sun XJ (2011b) Protective effects of hydrogen-rich saline on monocrotaline-induced pulmonary hypertension in a rat model. Respir Res 12:26.  Back to cited text no. 51
Wardlaw JM, Murray V, Berge E, del Zoppo G, Sandercock P, Lindley RL, Cohen G (2012) Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet 379:2364-2372.  Back to cited text no. 52
Weaver J, Liu KJ (2015) Does normobaric hyperoxia increase oxidative stress in acute ischemic stroke? A critical review of the literature. Med Gas Res 5:11.  Back to cited text no. 53
Xie K, Yu Y, Pei Y, Hou L, Chen S, Xiong L, Wang G (2010) Protective effects of hydrogen gas on murine polymicrobial sepsis via reducing oxidative stress and HMGB1 release. Shock (Augusta, Ga) 34:90-97.  Back to cited text no. 54
Zhang Y, Sun Q, He B, Xiao J, Wang Z, Sun X (2011) Anti-inflammatory effect of hydrogen-rich saline in a rat model of regional myocardial ischemia and reperfusion. Int J Cardiol 148:91-95.  Back to cited text no. 55
Zhang YP, Cai J, Shields LB, Liu N, Xu XM, Shields CB (2014) Traumatic brain injury using mouse models. Transl Stroke Res 5:454-471.  Back to cited text no. 56
Zheng X, Mao Y, Cai J, Li Y, Liu W, Sun P, Zhang JH, Sun X, Yuan H (2009) Hydrogen-rich saline protects against intestinal ischemia/reperfusion injury in rats. Free Radic Res 43:478-484.  Back to cited text no. 57


  [Figure 1], [Figure 2]

This article has been cited by
1 Biomaterials tools to modulate the tumour microenvironment in immunotherapy
Yu Chao, Zhuang Liu
Nature Reviews Bioengineering. 2023;
[Pubmed] | [DOI]
2 Perioperative stroke: A perspective on challenges and opportunities for experimental treatment and diagnostic strategies
Xia Jin, Peiying Li, Dominik Michalski, Shen Li, Yueman Zhang, Jukka Jolkkonen, Lili Cui, Nadine Didwischus, Wei Xuan, Johannes Boltze
CNS Neuroscience & Therapeutics. 2022;
[Pubmed] | [DOI]
3 Hydrogen therapy after resuscitation improves myocardial injury involving inhibition of autophagy in an asphyxial rat model of cardiac arrest
Xiaohui Gong, Xinhui Fan, Xinxin Yin, Tonghui Xu, Jiaxin Li, Jialin Guo, Xiangkai Zhao, Shujian Wei, Qiuhuan Yuan, Jiali Wang, Xuchen Han, Yuguo Chen
Experimental and Therapeutic Medicine. 2022; 23(6)
[Pubmed] | [DOI]
4 Hydrogen-induced Neuroprotection in Neonatal Hypoxic-ischemic Encephalopathy
Ferenc Domoki
Current Pharmaceutical Design. 2021; 27(5): 687
[Pubmed] | [DOI]
5 Intracellular second messengers mediate stress inducible hormesis and Programmed Cell Death: A review
David R. Zhou,Rawan Eid,Katie A. Miller,Eric Boucher,Craig A. Mandato,Michael T. Greenwood
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2019; 1866(5): 773
[Pubmed] | [DOI]
Yu. A. Rakhmanin,Natalija A. Egorova,R. I. Mikhailova,I. N. Ryzhova,D. B. Kamenetskaya,M. G. Kochetkova
Hygiene and sanitation. 2019; 98(4): 359
[Pubmed] | [DOI]
7 Protective Role of Hydrogen Gas on Oxidative Damage and Apoptosis in Intestinal Porcine Epithelial Cells (IPEC-J2) Induced by Deoxynivalenol: A Preliminary Study
Xu Ji,Weijiang Zheng,Wen Yao
Toxins. 2019; 12(1): 5
[Pubmed] | [DOI]
8 2-(2-Benzofuranyl)-2-imidazoline treatment within 5 hours after cerebral ischemia/reperfusion protects the brain
Zheng Zhang,Jin-Long Yang,Lin-Lei Zhang,Zhen-Zhen Chen,Jia-Ou Chen,Yun-Gang Cao,Man Qu,Xin-Da Lin,Xun-Ming Ji,Zhao Han
Neural Regeneration Research. 2018; 13(12): 2111
[Pubmed] | [DOI]
9 The Role of Gaseous Molecules in Traumatic Brain Injury: An Updated Review
Xiaoru Che,Yuanjian Fang,Xiaoli Si,Jianfeng Wang,Xiaoming Hu,Cesar Reis,Sheng Chen
Frontiers in Neuroscience. 2018; 12
[Pubmed] | [DOI]
10 Hydrogen Gas Does Not Ameliorate Renal Ischemia Reperfusion Injury in a Preclinical Model
Sarah A. Hosgood,Tom Moore,Maria Qurashi,Tom Adams,Michael L. Nicholson
Artificial Organs. 2018;
[Pubmed] | [DOI]
11 Therapeutic Potentials of Synapses after Traumatic Brain Injury: A Comprehensive Review
Zunjia Wen,Dong Li,Meifen Shen,Gang Chen
Neural Plasticity. 2017; 2017: 1
[Pubmed] | [DOI]
12 Fermented Chinese formula Shuan-Tong-Ling attenuates ischemic stroke by inhibiting inflammation and apoptosis
Zhi-gang Mei,Ling-jing Tan,Jin-feng Wang,Xiao-li Li,Wei-feng Huang,Hua-jun Zhou
Neural Regeneration Research. 2017; 12(3): 425
[Pubmed] | [DOI]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Ingestion Charac...
Advantages and D...
Article Figures

 Article Access Statistics
    PDF Downloaded631    
    Comments [Add]    
    Cited by others 12    

Recommend this journal