Hydrogen Era

Hydrogen Therapy

History of hydrogen therapy

A Brief History of H₂ as a Medical Gas

Although hydrogen therapy may seem as a new phenomenon in the medical field, animal trials evaluating hydrogen as a therapeutic agent since 1789, when Antoine Laurent Lavoisier exposed a type of pigs to hydrogen while investigating the properties of air. As such a newly discovered element, a century passed until further medical experiments with hydrogen were again documented. In 1888, a flurry of reports reported that insufflation, an application where hydrogen is delivered directly into body cavities, could assist with the diagnosis of visceral injury. However, researchers did not expand on these reports, and it would be another 150 years before hydrogen gas was considered as a therapeutic agent, when it was demonstrated that H₂ inhalation could be used as a physiological recovery aide for the deep-sea divers.

In 1944, Arne Zetterstrom was credited with creating Hydrox gas, a combination of hydrogen and oxygen (96% and 4%, respectively) that allowed deep-sea divers to traverse depths of up to 500m by preventing decompression sickness. The hydrogen–oxygen mixture can be compressed into cylinders, as the low concentration of oxygen renders the composition nonexplosive, making this method of hydrogen delivery valuable, particularly for exploration, industrial use, and submarine rescue scenarios. Despite the popularity and demonstrated efficacy of hydrogen as an inhalation treatment, further advances in medical research were not put forward until 1975, when Dole and colleagues realized that hyperbaric administration (95% H₂/8atm) of H₂ for periods of 10–14 days could reduce squamous cell carcinoma in murine models of disease. Even though this discovery was revolutionary, medical hydrogen research again subsided, and it was another thirteen years before another article in this field was published. Shirahata and colleagues describe hydrogen created from the electrolysis of water, could protect DNA from oxidative damage. In 2001, building upon the research conducted by Dole et al., Gharib and associates described a reduction in markers of liver disease resulting from chronic inflammation when utilizing hyperbaric administration of H₂ (0.7 MPa for two weeks). Once again, however, research into medical hydrogen lapsed and was not revived until 2007, when Ohsawa’s laboratory in the Department of Biochemistry and Cell Biology, Nippon Medical School, Japan, reported an antioxidant effect of H₂ in a rodent model of ischemia-reperfusion injury. Since Ohsawa’s discovery, there has been renewed interest in the effects of H₂ as an Aesculapian gas and research into this promising area of medicine is developing rapidly.

Basic Characteristics of H2:

H2 has two different characteristics

Molecular hydrogen is a colorless, odorless, and tasteless gas molecule with poor water solubility. It is considered inert in mammalian cells under physiological conditions. Molecular hydrogen can be broken down by some bacteria via enzymatic catalysis to provide energy and electrons. In addition, bacteria produce molecular hydrogen by anaerobic metabolism. Genes encoding the iron- or nickel-containing enzymes necessary to catalyze these reactions, such as hydrogenase, are lacking in mammals. However, molecular hydrogen is now recognized as a novel medically relevant gas with therapeutic potential. Ohsawa et al. (2007) reported that the inhalation of 2% molecular hydrogen results in the selective scavenging of hydroxyl free radical (·OH) and peroxynitrite anion (ONOO-), significantly improving oxidative stress injury caused by cerebral ischemia/reperfusion (I/R). This study prompted substantial interest in the medical value of molecular hydrogen, and many cellular, animal, and clinical trials and studies have since investigated its preventive and therapeutic effects. Molecular hydrogen can exert biological effects on almost all organs, including the brain, heart, lung, liver, and pancreas. It has a variety of biological functions, including roles in the regulation of oxidative stress and anti-inflammatory and anti-apoptotic effects.

Mechanism of Action of H2:

1. Anti-oxidation

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are by-products of energy metabolism during daily activities. ROS/RNS include superoxide anion (O2 -), ·OH, peroxyl (RO2·), alkoxyl (RO·), and nitric oxide (NO·) radicals. They play critical roles under normal conditions in immune defense, signaling processes, and the extraction of energy from organic molecules. However, if ROS and RNS production exceeds the antioxidant capacity of the body or if the antioxidant capacity of the body is decreased, oxidative stress occurs.

Acute oxidative stress often occurs during inflammation and I/R (e.g., cardiac arrest, myocardial and cerebral infarction, organ transplantation, and intraoperative hemostasis). Chronic ROS injury can occur in a variety of pathological conditions, such as malignant cancer, diabetes, chronic inflammatory diseases, atherosclerosis, and neurodegeneration, as well as in the process of aging. Humans have antioxidant defense systems to protect against free radical toxicity. Antioxidants are divided into enzymatic and non-enzymatic types. Enzymatic types include superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and non-enzymatic types include bilirubin, α‍-tocopherol (vitamin E), β‍-carotene, and uric acid.

The antioxidant effects of molecular hydrogen are primarily mediated by the following mechanisms:

(1) Molecular hydrogen has a lower molecular weight than other common antioxidants (e.g., SOD, CAT, and α‍-tocopherol). It can selectively react with strong oxidants and can easily penetrate biological membranes, such as nuclear and mitochondrial membranes, without affecting the metabolic redox reaction.

(2) By stimulating nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the basal and induces expression of many antioxidant enzymes and the proteasome, hydrogen can increase the expression of heme oxygenase-1 (HO-1). It also decreases ·ONOO-related gene expression and production and increases the activity of the antioxidant enzymes SOD, CAT, and myeloperoxidase (MPO).

(3) Molecular hydrogen can block the apoptosis signal-regulating kinase 1 (ASK1) signaling pathway and the downstream signaling molecule p38 mitogen-activated protein kinase (p38MAPK), thereby inhibiting nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and decreasing free radical production. Through these antioxidant effects, molecular hydrogen protects cells from lipid and fatty acid peroxidation.

2. Anti-inflammatory effects

The major mechanisms underlying the anti-inflammatory effects of molecular hydrogen are as follows:

(1) It inhibits the synthesis and release of the pro-inflammatory factors tumor necrosis factor-‍‍α (TNF-‍α), interleukin (IL)-‍‍‍1β, IL-6, nuclear factor-‍κB (NF-‍κB), and high-mobility group box 1 (HMGB-1); increases the expression of the anti-inflammatory factor IL-‍10; inhibits the release of chemokines, including keratinocyte-derived chemokine, macrophage inflammatory protein (MIP)-‍1α, MIP-2, and monocyte chemoattractant protein 1; and inhibits the release of intercellular cell adhesion molecule-1 (ICAM-1), granulocyte-macrophage colony-stimulating factor (GMCSF), and granulocyte colony-stimulating factor (G-CSF).

(2) It promotes macrophage phagocytosis at lesion sites and inhibits the recruitment of neutrophils and M1 macrophages to lesions.

(3) The anti-inflammatory effects of molecular hydrogen involve multiple signaling pathways. For example, the stimulation of the Nrf2/HO-1/HMGB-1 pathway mitigates endothelial dysfunction and lung injury caused by polymicrobial sepsis. The inhibition of p38MAPK and c-Jun N-terminal kinase (JNK) alleviates lipopolysaccharide (LPS)-induced ALI. The modulation of autophagy-related pathways, such as the mammalian target of rapamycin (mTOR)/transcription factor EB (TFEB) and phosphatase and tensin homolog (PTEN)‍-induced kinase 1 (PINK1)/Parkin pathways, mitigates ALI endothelial dysfunction and myocardial I/R injury.

3. Regulation of autophagy

In eukaryotic cells, catabolism is the degradation of intracellular components by the ubiquitin-proteasome system and lysosomes. Autophagy (particularly macro‍autophagy) is defined as a lysosome-dependent catabolic process for maintaining cellular homeostasis. However, when stress exceeds a critical duration or intensity threshold, it may have maladaptive effects, causing cell damage or even death. Emerging evidence suggests that hydrogen has dual roles in the modulation of autophagy (i.e., roles in both its promotion and inhibition).

4. Regulation of apoptosis

Apoptosis is a canonical form of programmed cell death that does not stimulate inflammatory responses. It is an evolutionarily conserved type of cell death with major effects on biological processes. The molecular mechanism underlying apoptosis involves the sequential activation of cysteine proteases, called caspases, and a series of pro-apoptotic and anti-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins. In various disease models and organs, molecular hydrogen plays a protective role by regulating apoptosis.

It can inhibit apoptosis by regulating apoptosis signaling pathways and apoptosis-related proteins, such as the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase-3β (GSK3β), ASK1/JNK, rat sarcoma (Ras)-extracellular signal-related kinase 1/2 (ERK1/2)-mitogen-activated protein kinase 1/2 (MEK1/2), and Akt pathways, and by suppressing the activation of caspase-3, -8, and -9 and the Bcl-2/Bcl-2-associated X (Bax) ratio. Molecular hydrogen also reduces the rate of apoptosis by reducing inflammation and oxidative damage and protects mitochondrial function. The inhibition of autophagy improves cell survival and inhibits apoptosis. For example, in an I/R myocardial injury model, PINK-mediated autophagy alleviates inflammation and apoptosis. Accordingly, there is crosstalk among molecular hydrogen, apoptosis, and autophagy.

5. Regulation of aging

Aging is a progressive loss of physiological function and is an unavoidable process ending in death. It is now considered a major factor underlying the development and progression of various diseases, such as COPD and idiopathic PF. Molecular hydrogen can decrease the expression of the aging-related proteins β‍-galactosidase, p53, and p21, suppress downregulation of sirtuin 3 (Sirt3) expression, and reduce oxidative stress damage, thereby extending cell survival. Research has shown that molecular hydrogen produced by intestinal bacteria in the body suppresses increased hydrogen peroxide (H₂O₂) by suppressing intracellular ·OH-mediated lipid peroxide formation and cellular senescence, thus contributing to the suppression of aging. Genomic instability is one of the primary hallmarks of the aging process. By reducing oxidative DNA damage, hydrogen can help maintain genomic stability. For example, in cigarette smoke (CS)‍-induced emphysema, hydrogen significantly decreased phosphorylated histone H2AX and 8-hydroxy-2′-deoxyguanosine (8-OHdG), which are markers of oxidative DNA damage. As a “philosophical molecule,” hydrogen may be used for the treatment of intractable diseases and aging.

Routes of H2 Administration:

Hydrogen gas has some special characteristics, such as its nonpolarity, small size, and low solubility (1.6 ppm (part per million, ×10-6)) under physiological conditions. Typical administration routes include the inhalation of hydrogen gas, oral intake of HRW, and injection of HRS. Inhalation is a simple method in which a ventilator circuit, facemask, or nasal cannula is used to administer hydrogen gas. The effects are rapid, and it can be used to treat acute oxidative stress. The oral intake of HRS, which is hydrogen dissolved in water, is a portable, safe, and convenient method for administration. Under normal atmospheric pressure and at room temperature, hydrogen can be dissolved in water up to 0.8 mmol/L (1.6 mg/L). The injection of HRS can provide highly accurate hydrogen doses. Either peritoneal or intravenous injection can be applied to provide a protective effect. In addition, intrathecal injection can produce neuro-protective effects. Its lack of polarity and easy cell penetration make hydrogen promising for the treatment of skin and eye diseases with topical formulations and eye drops.

The Safety of Hydrogen

The safety of hydrogen for humans is demonstrated by its application in Hydreliox, an exotic breathing gas mixture of 49% hydrogen, 50% helium and 1% oxygen, which is used for the prevention of decompression sickness and nitrogen narcosis during very deep technical diving. Also, no adverse effects have been found using drinking hydrogen water in a human study. A study showed that 20 subjects with potential metabolic syndrome consumed 1.5-2.0 l/day of H₂–saturated water for 8 weeks, the treated subjects showed significant improvements in liver and kidney function, which showed that H₂ had no toxic side effects on liver and kidney and may even protect liver and kidney function. Another study also showed that hemodialysis patients treated with dialysis solution with H₂ for 6 months had no adverse clinical signs or symptoms. All these studies are existed in the references section.

Contatc us Now

Below are some references and researchs that illustrate the extent of the positive therapeutic effect of hydrogen: