Hydrogen is Emerging as a Medical Gas (Part 2)

Antioxidant-Like Effect

It was initially suggested that the beneficial effect of hydrogen was due to an antioxidant as hydrogen selectively neutralized cytotoxic hydroxyl radicals ¹ in vitro. However, although H2 reduces *OH radicals ², as has been shown in various systems ^{1, 4, 5}, it may not occur via direct scavenging, and it also cannot fully explain all the benefits of hydrogen ⁶. For example, in a double-blinded placebo controlled trial in rheumatoid arthritis ³, hydrogen had a residual effect that continued improving the disease symptoms for four weeks after hydrogen administration was terminated ³. Many cell studies also show that pre-treatment with hydrogen has marked beneficial effects even when the assault (e.g. toxin, radiation, injury, etc.) is administered long after all the hydrogen has dissipated out of the system ^{7, 8, 9}. Additionally, the rate constants of hydrogen against the hydroxyl radical are relatively slow (4.2 x 107 M-1 sec-1) ², and the concentration of hydrogen at the cellular level is also quite low (micromolar levels), thus making it unlikely that H2 could effectively compete with the numerous other nucleophilic targets of the cell ¹⁰. Lastly, if the mechanism were primarily associated with scavenging of hydroxyl radicals, then we should see a greater effect from inhalation compared to drinking, but this is not always the case ^{11, 12}. In short, we consider it inaccurate or at least incomplete to claim that the benefits of hydrogen are due to its acting directly as a powerful antioxidant. Indeed, hydrogen is selective because it is a very weak antioxidant and thus does not neutralize important ROS or disturb important biological signaling molecules. Nevertheless, a metabolic tracer study ¹³ using deuterium gas demonstrated that, under physiological conditions, deuterium gas is oxidized, and the oxidation rate of hydrogen increases with an increasing amount of oxidative stress ¹⁴, but the physicochemical mechanism for this may still not be direct radical scavenging ¹³. However, not all studies show that hydrogen is oxidized via mammalian tissues ¹⁵, and it has also been reported that deuterium gas did not exert a therapeutic effect in the model studied whereas 1H did (unpublished data).

NRF2 Pathway

Unlike conventional antioxidants ¹⁶, hydrogen does have the ability to reduce excessive oxidative stress ⁶, but only under conditions where the cell is experiencing abnormally high levels of oxidative stress that would be harmful and not hormetic.

One mechanism that hydrogen uses to protect against oxidative damage is by the activation of the Nrf2-Keap1 system and subsequent induction of the antioxidant response element (ARE) pathway, which leads to the production of various cyto-protective proteins like glutathione, catalase, superoxide dismutase, glutathione per-oxidase, heme-1 oxygenase, etc. ^{17, 18, 19}. In some disease models, the benefits of hydrogen are negated by using Nrf2 gene knockouts ^{20, 21}, Nrf2 genetic silencing using iRNA ²², or pharmacologically blocking the Nrf2 pathway ^{23, 24}. Importantly, hydrogen only activates the Nrf2 pathway when there is an assault (e.g. toxin, injury, etc.) ²³ as opposed to constituently acting as a promoter, which could be harmful ^{25, 26}. The method that hydrogen activates the Nrf2 pathway remains unclear ¹⁷.

Cell Modulation

Besides the potential scavenging of hydroxyl radicals and/or activation of the Nrf2 pathway, hydrogen may ameliorate oxidative stress via a cell modulating effect ¹⁷ and reduce the formation of free radicals ²⁷, such as down regulating the NADPH oxidase system ²⁸. The various cell modulating effects of hydrogen are responsible for mediating the anti-inflammatory, anti-allergy, and anti-obesity effects of hydrogen. Hydrogen has been shown to downregulate pro-inflammatory cytokines (e.g. IL-1, IL-6, IL-8, etc.) ²⁹, attenuate the activation of TNF-a ³, NF-?B ³⁰, NFAT ^{12, 31}, NLRP3 ^{32, 33}, HMGB1 ³⁴, and other inflammatory mediators ¹⁷. Additionally, hydrogen has beneficial effects on obesity and metabolism by increasing the expression of FGF21 ³⁵, PGC-1a ³⁶, PPARa ³⁶, and more. ³⁷. Additional 2nd messenger molecules or transcription factors affected by hydrogen include ghrelin ³⁸, JNK-1 ²⁸, ERK1/2 ³⁹, PKC ⁴⁰, GSK ⁴¹, TXNIP ³², STAT3 ⁴², ASK1 ⁴³, MEK ⁴⁴, SIRT1 ⁴⁵, and many more. Over 200 bio-molecules are altered by hydrogen administration including over 1000 gene expressions.

However, the primary targets and master regulators responsible for these changes are still elusive ²⁹. There are many feedback systems and loops to consider, which makes it difficult to determine if we are detecting the cause or the effect of hydrogen administration.

The exact mechanism of how hydrogen modulates signal transduction, gene expression, and protein phosphorylation is still being investigated ¹⁷. A recent publication ⁴⁶ in Scientific Reports provides good evidence to suggest that one of the mechanisms through which hydrogen accomplishes the various cell-modulating effects is by modifying lipid per-oxidation in the cell membrane. In cultured cells, at biologically relevant concentrations, hydrogen suppressed the free radical chain reaction-dependent per-oxidation and recovered Ca²⁺-induced gene expressions, as determined by comprehensive micro-array analysis (see figure 6) ⁴⁶.

Scientific Recognition of Hydrogen

Although the primary targets or exact biochemical mechanisms of hydrogen are still not fully understood, the therapeutic effect in cells, tissues, animals, humans and even plants ⁴⁷ is becoming widely accepted due to the now over 500 peer-reviewed articles and the 1,600 researchers on the medical effects of hydrogen. The quality of the publications is also improving with an average impact factor (IF) of the journals publishing hydrogen is about 3. The table below shows a few of the studies published in the higher IF journals, which range from six to 27.

Future Directions

The goal of the Molecular Hydrogen Institute (MHI) is to help advance the research, education, and awareness of hydrogen as a therapeutic medical gas. It is uncommon to find a treatment that has both a high therapeutic potential and a high safety profile; hydrogen appears to fit this combination ⁶. Some researchers become interested in hydrogen simply due to its unforeseen ability to have a biological effect; with the realization that hydrogen is both safe and effective, a moral obligation develops to advance the research, education, and awareness of hydrogen as a medical gas.

Source: Molecular Hydrogen Institute