Molecular hydrogen is the smallest molecule that we can find in the nature. Its effectiveness has been discovered only like a decade ago through scientific research.

Hydrogen has numerous benefits and this is due to its anti-oxidant, anti-inflammatory, anti-apoptotic, anti-allergic and cytoprotective properties. You would probably wonder how this small molecule has all these properties. Scientists are still discovering new uses of hydrogen day by day. New research is piling up each day and you can find hundreds of studies done on treatment with hydrogen mostly in animal but increasingly also in human trials.

In this article we will talk about the cytoprotective effect of hydrogen.

The cell is the smallest building block of a living organism. If there is a dysfunction of the cells we can get serious diseases. The cells can get damaged due to various reasons.This could be due to trauma, oxidative stress, chemicals, burns, microorganism, radiation and others.

What is cytoprotection?

Cytoprotection means a process in which the cells are protected against harmful substances or stimuli. This process has been described mainly in the gastric mucosa. Gastric ulcer formation can be prevented by the use of a gastric cytoprotective agent such as prostaglandin. Similarly hydrogen can act as an agent that protects the cells against noxious stimuli.

How does hydrogen act as a cytoprotective agent?

Hydrogen can act at the cellular level unlike most other substances and hence is considered unique. It can even cross the blood brain barrier which separates the brain from the blood flow. It can even enter the sub cellular organisms such as mitochondria. Once hydrogen get to these ideal locations, it can exert its anti-oxidant, cytoprotective and anti-apoptotic properties.

It has been suggested that hydrogen can induce signalling mechanisms which results in generation of cytoprotective factors. According to Itoh et al. 2011, hydrogen acts as a signal modulator and affects the signal transduction. They proposed that hydrogen can inhibit the LPS/IFNγ-induced nitric oxide production in macrophages and this in turn will result in reduced inflammatory reactions ultimately protecting the cells. Although the full mechanism is still not clear, there are other researches which propose possible mechanisms. According to another research, hydrogen increases the anti-oxidant enzyme levels such as superoxide dismutase and catalase and thereby provides the cytoprotective effect.

Another proposed mechanism for hydrogen as a cytoprotective substance is preventing the action of caspase which is implicated in the cell death as described in the article about anti-apoptotic properties of hydrogen.

It is also proposed that molecular hydrogen binds to metal ions and affect the signal transduction by interacting with metalloproteins.

What are the instances of cytoprotective effect of hydrogen?

Since hydrogen is not toxic to the body even when used in higher concentrations, it can be considered quite safe to use. Since hydrogen can diffuse rapidly through membranes and exert its action with the added advantage of feasibility and relatively low cost, it can be applied to various disease treatments.

The cytoprotective effect of molecular hydrogen has been first published by Ohsawa et al. in 2007. This research was the first of its kind. They have studied the anti-oxidative effect on a rat model in which oxidative stress damage was induced in the brain by focal ischemia and reperfusion and also in cultured cells by three independent methodes . After a stroke, if the occlusion to the vessel is removed (reperfusion), the cells can get damaged by the sudden release of oxidative substances, it is the so called reperfusions injury. It has been shown here that hydrogen has potential as an antioxidant in preventive and therapeutic applications. This research has paved the pathway for many other researches to explore strategies of using hydrogen to prevent cell damages after ischemia.

Molecular hydrogen has also been able to protect the liver cells against damage from obstructive jaundice. In a rat model there was induced an obstructive jaundice. After 10 days the liver damage was evaluated microscopically and was controlling the liver enzyme levels (ASAT and ALAT) and the levels of mediators of inflammation (IL-1, IL-6, TNFa and others). Hydrogen-rich saline reduced levels of these markers and relieved morphological liver injury. Additionally it markedly increased the activities of anti-oxidant enzymes. It inhibits inflammation, oxidative stress and also modulates the so called ERK1/2 pathway and protects the cells from damage.

In liver transplantation an ischemia and reperfusion injury is critical for the survival of the graft. There is a formation of cytotoxic oxygen free radicals. Their effect can be neutralized by anti-oxidant properties of hydrogen. It protects the cells against reperfusion injury. That has been found in a study with pigs.

Ulcerative colitis is a disease in which ulcers are formed in the gut mucosa due to a genetic predisposition. It is associated with enhanced production of reactive oxygen species and altered angiogenesis. Administration of hydrogen by intraperitoneal injection once every 2 days for 2 weeks in a rat model was able to reduce the ulcers by preventing mucosal cell damage through its cytoprotective effects. Treatment with hydrogen-rich saline also reduced symptoms like weight loss and diarrhea.

Hydrogen inhalation was also effective in protecting neurones according to several studies. As hydrogen readily crosses the blood brain barrier, it can reach the neurones and improve the neurological outcome in diseases. Drinking hydrogen rich water has shown to be able to suppress the oxidative stress for dopiminergic neurones in the case of Parkinson’s disease in a mice model. The results have also been shown that hydrogen prevented cognitive impairment.

Recently, there was a pilot clinical trial initiated to study the effects of hydrogen water on the progression of Parkinson’s disease in Japanese patients. The trial was a randomized, placebo-controlled, double-blind, parallel-group trial studying. The participants drank one liter per day of hydrogenated water or placebo for 48 weeks. Examining the Unified Parkinson’s Disease Rating Scale scores there has been shown that the disease worsened in the group without hydrogen water application, whereas scores in the hydrogen water group improved. Though the numbers of the two groups were small and the duration of the trial was short, the difference between the hydrogen water group and placebo group was significant (p < 0.05).

After a cardiac arrest, when hydrogen rich saline was given at the start of hyperoxic cardiopulmonary resuscitation, it significantly improved brain and cardiac outcome in a rat model by protecting the cells from further damage.

Some patients have to be artificially ventilated for a long time due to coma and injuries. These people can develop lung injuries called acute ventilator induced lung injury. By administering hydrogen gas in a mice model, the incidence of this injury has been reduced via modulation of the nuclear factor-kappa B (NFκB) signaling pathway. The early activation of this pathway during hydrogen treatment was correlated with elevated levels of antiapoptotic proteins. Hydrogen inhalation increased oxygen tension, decreased lung edema and decreased the expression of proinflammatory mediators. The cytoprotective effects of hydrogen against apoptotic and inflammatory signaling pathway has been demonstrated.

Hydrogen applied as gas in a concentration or 3 % has also prolonged the in vitro replicative lifespan of bone marrow stromal cells and mesenchymal stem cells. This is important because stem cells are used in regenerative medicine in order to treat numerous diseases. The cytoprotective effect of hydrogen was initially thought to be due to anti-oxidant effect. However it was revealed that the 3% concentration they used did not reduce the hydroxyl radical levels although it effectively protected the cells. Therefore they suggested that an additional mechanism must be at play to protect the cells.

Due to these amazing effects of hydrogen, it will be used as a novel therapeutic agent in cardiovascular, metabolic, respiratory, neurological and cancer treatments. In emergency medicine, not only oxygen but also hydrogen (Browns gas) would be given at the same time in the future.

References

• Liu, Q., et al., Hydrogen-rich saline protects against liver injury in rats with obstructive jaundice. Liver International, 2010. 30(7): p. 958-968.
• Matsuno, N., et al., Beneficial effects of hydrogen gas on porcine liver reperfusion injury with use of total vascular exclusion and active venous bypass. Transplant Proc, 2014. 46(4): p. 1104-6.
• He, J., et al., Protective effects of hydrogen-rich saline on ulcerative colitis rat model. Journal of Surgical Research, 2013(0).
• Hayashida, K., et al., Hydrogen Inhalation During Normoxic Resuscitation Improves Neurological Outcome in a Rat Model of Cardiac Arrest, Independent of Targeted Temperature Management. Circulation, 2014
• Cui, Y., et al., Hydrogen-rich saline attenuates neuronal ischemia-reperfusion injury by protecting mitochondrial function in rats. J Surg Res, 2014.
• Ito, M., et al., Drinking hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamine-induced Parkinson’s disease in rats. Med Gas Res, 2012. 2(1): p. 15.