Molecular hydrogen is the smallest molecule we can find in nature. Its effectiveness was only discovered about a decade ago through scientific research.
Hydrogen has numerous benefits and this is due to its antioxidant, 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 for hydrogen day by day. Every day there are new research results and you can find hundreds of studies that have been done on the treatment with hydrogen, mostly in animal studies, but increasingly in human studies.
In this article we will talk about the cytoprotective effect of hydrogen.
The cell is the smallest building block of a living organism. If the cells malfunction, serious diseases can result. Cells can be damaged for a variety of reasons, including trauma, oxidative stress, chemicals, burns, microorganisms, radiation and others.
What is cytoprotection?
Cytoprotection is a process by which cells are protected from harmful substances or stimuli. This process has been described primarily in the gastric mucosa. The formation of gastric ulcers can be prevented by using a cytoprotective agent for the stomach such as prostaglandin. Similarly, hydrogen can act as an agent that protects cells from noxious stimuli.
How does hydrogen act as a cytoprotective agent?
Hydrogen, unlike most other substances, can act at the cellular level and is therefore considered unique. It can even cross the blood-brain barrier that separates the brain from the bloodstream. It can even enter the subcellular organisms such as the mitochondria. Once hydrogen reaches these ideal locations, it can exert its antioxidant, cytoprotective and anti-apoptotic properties.
It has been suggested that hydrogen can induce signalling mechanisms that lead to the formation of cytoprotective factors. According to Itoh et al. 2011, hydrogen acts as a signal modulator and influences signal transduction. They proposed that hydrogen can inhibit LPS/IFNγ-induced nitric oxide production in macrophages, which in turn leads to reduced inflammatory responses that ultimately protect cells. Although the full mechanism is not yet clear, there is other research that suggests possible mechanisms. According to another study, hydrogen increases the levels of antioxidant enzymes such as superoxide dismutase and catalase, thus providing the cytoprotective effect.
Another proposed mechanism for hydrogen as a cytoprotective substance is the prevention of the action of caspase, which is involved in cell death, as described in the article on the anti-apoptotic properties of hydrogen.
It is also proposed that molecular hydrogen binds to metal ions and affects signal transduction by interacting with metalloproteins.
What are the cases of the cytoprotective effect of hydrogen?
Since hydrogen is not toxic to the body even in higher concentrations, it can be considered quite safe to use. Since hydrogen can diffuse rapidly through membranes and exerts its effects with the added advantage of feasibility and relatively low cost, it can be used in various disease treatments.
The cytoprotective effect of molecular hydrogen was first published by Ohsawa et al. in 2007. This research was the first of its kind. They investigated the antioxidant effect in a rat model in which oxidative stress damage was induced in the brain by focal ischaemia and reperfusion, and in cultured cells using three independent methods. After a stroke, when the occlusion of the vessel is removed (reperfusion), the cells can be damaged by the sudden release of oxidative substances, this is the so-called reperfusion injury. Here, hydrogen has been shown to have potential as an antioxidant for preventive and therapeutic applications. This research has paved the way for much other research exploring strategies to use hydrogen to prevent cell damage after ischaemia.
Molecular hydrogen was also able to protect liver cells from damage caused by obstructive jaundice. In a rat model, obstructive jaundice was induced. After 10 days, liver damage was evaluated microscopically and liver enzyme levels (ASAT and ALAT) and levels of inflammatory mediators (IL-1, IL-6, TNFa and others) were monitored. The hydrogen-rich saline reduced the levels of these markers and alleviated the morphological liver damage. In addition, it significantly increased the activities of antioxidant enzymes. It inhibits inflammation, oxidative stress and also modulates the so-called ERK1/2 pathway, protecting cells from damage.
In liver transplantation, ischaemia and reperfusion injury is critical for graft survival. This results in the formation of cytotoxic oxygen free radicals. Their effect can be neutralised by the antioxidant properties of hydrogen. It protects the cells from reperfusion injuries. This was found in a study with pigs.
Ulcerative colitis is a disease in which ulcers form in the intestinal mucosa due to a genetic predisposition. It is associated with increased 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 ulcers by preventing mucosal cell damage through its cytoprotective effects. Treatment with saline containing hydrogen also reduced symptoms such as weight loss and diarrhoea.
Hydrogen inhalation also protected nerve cells, according to several studies. Because hydrogen can easily cross the blood-brain barrier, it can reach neurons and improve neurological outcomes in disease. Drinking hydrogen-rich water was able to suppress oxidative stress for dopinergic neurons in Parkinson's disease in a mouse model. Hydrogen has also been shown to prevent cognitive impairment.
Recently, a pilot clinical trial was initiated to investigate the effects of hydrogen water on the progression of Parkinson's disease in Japanese patients. The study was a randomised, placebo-controlled, double-blind trial with parallel groups. Participants drank one litre per day of hydrated water or placebo for 48 weeks. Examination of the Unified Parkinson's Disease Rating Scale scores showed that the disease worsened in the group without hydrogen water use, while the scores improved in the hydrogen water group. Although the number of the two groups was small and the duration of the study was short, the difference between the hydrogen water group and the placebo group was significant (p < 0.05).
When hydrogen-rich saline was given after cardiac arrest at the start of hyperoxic cardiopulmonary resuscitation, it significantly improved brain and heart outcomes in a rat model by protecting cells from further damage.
Some patients need to be artificially ventilated for a long period of time due to coma and injury. These people can develop lung injuries called acute ventilator-induced lung injury. Administration of hydrogen gas in a mouse model reduced the incidence of this injury via modulation of the nuclear factor-kappa B (NFκB) signalling pathway. Early activation of this pathway during hydrogen treatment was correlated with increased levels of anti-apoptotic proteins. Hydrogen inhalation increased oxygen tension, decreased pulmonary oedema and reduced the expression of proinflammatory mediators. The cytoprotective effect of hydrogen against apoptotic and inflammatory signalling pathways was demonstrated.
Hydrogen as a gas at a concentration of 3% also prolonged the in vitro replication lifespan of bone marrow stromal cells and mesenchymal stem cells. This is important because stem cells are used in regenerative medicine to treat many diseases. The cytoprotective effect of hydrogen was initially attributed to an antioxidant effect. However, it was found that the 3% concentration they used did not reduce hydroxyl radicals, although it was effective in protecting the cells. Therefore, they suggested that an additional mechanism must be at play to protect the cells.
Because of these amazing effects of hydrogen, it is being used as a novel therapeutic agent in cardiovascular, metabolic, respiratory, neurological and cancer treatment. In the future, not only oxygen but also hydrogen (Brown's gas) would be administered simultaneously in emergency medicine.
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. (Engl.), 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.