The evolution of molecular hydrogen - A summary

1. SUMMARY: The evolution of molecular hydrogen: a noteworthy potential therapy with clinical
significance
http://www.medicalgasresearch.com/content/pdf/2045-9912-3-10.pdf
Hydrogen is the most abundant and lightest element on Earth. Most hydrogen exist in compound
form, attached to other metallic and non-metallic elements.
Studies on molecular hydrogen have evolved tremendously from its humble beginnings and have
continued to change throughout the years. Hydrogen is extremely unique since it has the capability to
act at the cellular level.
Hydrogen is qualified to cross the blood brain barrier, to enter the mitochondria, and even has the
ability to translocate to the nucleus under certain conditions. This is extremely favorable since many
known antioxidants lack the ability to target organelles and are not as effective in this manner.
Once in these ideal locations of the cell, previous studies have shown that hydrogen exerts
antioxidant, anti-apoptotic, anti-inflammatory, and cytoprotective properties that are beneficial to the
cell.
As intestinal bacteria constantly produce hydrogen gas during fermentation of unabsorbed
carbohydrates, hydrogen is used as a clinical biomarker to investigate the growth of bacteria in the
intestines.
Antioxidant Mechanism
Hydrogen therapy has been found to be effective as antioxidant, as illustrated in the figure below:
When free radicals or ROS accumulates, usually as a result of cellular processes, it leads to oxidative
stress. Oxidative stress can cause serious damage to tissues and can lead to a variety of deiseases.
Hydrogen is able to combine with the hydroxyl radical to form water and hydrogen. The hydrogen

2. generated from the water forming reaction is then able to combine with the superoxide radical, which
causes another reaction and prevents the formation of more peroxide and hydroxyl radicals.
It has been shown that hydrogen is able to increase antioxidant enzymes to help suppress the
disastrous effects of oxidative stress.
Anti-inflammatory
Hydrogen has been reported to improve liver hemodynamics and reduce hepatic portal hypertension,
as well as reduce liver fibrosis by attenuating inflammatory cytokines.
Cytoprotection
Hydrogen has been postulated to be involved in signal transduction modulator, that resulted in
reduction of inflammation in Type I allergies. Another proposed mechanism for hydrogen is its ability
to provide cytoprotection by increasing other antioxidant enzymes such as superoxide dismutase and
catalase. Hydrogen also has been found to prevent the activation of caspase -3, which through a series
of events can reduce apoptosis cell death.
Signal modulation
A few metabolic pathways such as TNF-α/NFkβ pathway as well as the Ras-ERK1/2-MEK1/2 and Akt
pathways that are involved in immune response and ROS production has been shown to be inhibited
by hydrogen. Since most metabolic syndrome involved the pathways mentioned above, the ability of
hydrogen in suppressing the metabolic pathways is essential in the treatment and prevention of major
metabolic syndrome.
Administration of Hydrogen
Hydrogen is most commonly applied as a gas, water, saline, and can be applied in a variety of other
mediums.
Uses of hydrogen therapy in the USA

3. There are also few side effects involving hydrogen, thus making hydrogen a perfect medical gas
candidate for the convention of novel therapeutic strategies against cardiovascular, cerebrovascular,
cancer, metabolic, and respiratory diseases and disorders.
Hydrogen water was able to improve renal dysfunction caused by neuronephrotoxicity, renal
ischemia and reperfusion injury. It was achieved by reducing oxidative stress as well as loweing
serum creatinine, blood urea nitrogen levels, pro-inflammatory cytokines, MDA levels and more.
A dialysis solution containing a high concentration of dissolved hydrogen gas was created and
administered to 21 hemodialysis patients three times a week for a period of six months. Results
showed that after treatment with hydrogen, high blood pressure generally decreased for the patients
and some instances patients reached normotensive statuses. There were also decreases in MCP and
MPO, which are chemokines and enzymes secreted by monocytes and neutrophils respectively. In
conclusion, hydrogen rich mediums seem to improve the damaging or even reverse in some instances
the damaging effects stemming from renal dysfunction and nephrotoxicity; and may have a potential
in combating nephritis and nephritic syndrome.
Hydrogen was postulated to be able to play a therapeutic role in insulin resistant and diabetes
mellitus. Patients with diabetes mellitus commonly develop skin lesions due to oxidative stress. High
levels of blood glucose causes an overproduction of ROS, that results in oxidative damage that causes
skin lesions. Hydrogen treatment was observed that hydrogen was able to reduce the loss of
membrane potential that is related to skin lesion in diabetes mellitus patients. A study using
streptozotocin-induced diabetic rats was carried out to analyze the effects of hydrogen saline on
erectile dysfunction, a condition commony found in men with diabetes mellitus. Hydrogen might have
restored nitric oxide vasodilation and erectile dysfunction via endothelial nitric oxide synthase and
increased nitric levels in the corpus cavernosum for the treatment group. Treatment with hydrogen
rich saline also revealed that hydrogen restored expression of the anti-apoptotic factor, bcl-2, and
decreased protein expression of bax, a pro-apoptotic factor, in the corpus cavernosum, when
compared to the controls and diabetic groups.
Alzheimer’s disease
Alzheimer's disease (AD) pathogenesis is believed to be driven by the production and deposition of
the amyloid-beta peptide (Abeta). Amyloid-beta peptide induces apoptosis through oxidative stress
that are resulting from several metabolic pathways involving amyloid-beta peptide. Immunotherapy
directed against this peptide has the potential to halt and/or reverse disease progression of this
disease. A reduction amyloid-beta peptide and inflammatory response related to Alzheimer’s disease

4. was reported by Li et al after hydrogen rich saline was administered by rat subjects who has an
intracerebral ventricular injection of amyloid-beta peptide. Major findings concluded that hydrogen
rich salin was able to improve long-tem potentiation, learnin, and memory most likely by reducing
inflammation and oxidative stress.
Cerebrovascular disease
Cerebrovascular disease is the most common life threatening neurological event in the U.S.
Intracranial atherosclerosis is responsible for approximately 40,000 of these attacks per year,
representing 10 percent of all ischemic strokes. The development of such disease involved the
metabolic activity of caspase-2 and caspase-3 molecules in the brain. Cai et al. found that hydrogen
gas was able to reduce neurological cell death by quelling free radicals that trigger pathways that lead
to the activation of caspase-3, a key mediator of neuronal programmed cell death. Researches done on
hypoxic ischemia and other neonatal brain disorders with hydrogen gas administration showed
potential in neurological improvements after brain injury. Sato et al. speculates that administration of
hydrogen rich water may be able to protect neurons against ROS by translocating to the nucleus and
affecting gene transcirption or by acting on inhibiting the production of ROS by mitochondria itself.
For Parkinson disease induced by 6-hydroxydopamine, hydrogen rich water seemed to be effective in
reducing oxidative stress that eventually leads yo neuronal apoptosis. Hydrogen supplemented room
air ventilation has also been found to exhibit the potential of neuro protection. Main mechanism
involved is by reducing the activity cyclooxygenase-2 (COX-2) in the hippocampus after transient
global cerebral ischemia. As a result, ROS production is controlled and neuronal damage is reduced. Hi
et al. demonstrated that hydrogen gas is able to cross over the blood-brain barrier, reducing brain
edema and decrease neurological dysfunction by reducing ROS and oxidative stress in rats after a
traumatic brain injury. More clinical studies however, has to be done in order to further evaluate the
effectiveness of hydrogen in moderate and severe cerebrovascular disease.
Chronic Lower Respiratory issues
A studies on lung injuries induced by intestinal ischemia and reperfusion (occurs when arteries
leading to your intestines become narrowed or blocked, reducing blood flow. The decreased blood
flow can cause pain and can permanently damage your intestine.) revealed that hydrogen saline is
able to reduce edema inflammatory cell infiltration and hemorrhage. Another study on hyperoxia lung
injuries using hydrogen rich saline resulted in pro-inflammatory cytokines and ROS, that lead to
reduces lung injury and lung cell apoptosis.
Inflammation responses involving pro-inflammatory cytokine molecules such as TNF-α and IL-1
during hyperoxia lung injuries have been found reduced upon administration of hydrogen saline too.
Similar to cerebrovascular disease, caspase-3 molecules that were involved in acute pulmonary
ischemia and reperfusion was found to be reduced upon administration of hydrogen rich saline.
Hydrogen saline has been proven to be promising treatments for lower respiratory and lung
associated diseases by preventing the accumulation of ROS and pro-inflammatory cytokines. More
results are required to investigate the mechanism of molecular hydrogen effects on pulmonary
associated diseases.
Malignant neoplasms (Cancer)
Elevated levels of ROS and down regulation of ROS scavengers and antioxidant enzymes are
associated with various human diseases including various cancers. ROS influences central cellular
processes such as proliferation a, apoptosis, senescence which are implicated in the development of
cancer. A few studies involving human tongue carcinoma cells HSC-4 and human fibrosarcoma cells
incubated with hydrogen rich water shows a significant decrease in colonies. Another studies found the
ability of hydrogen rich water in protecting mice from radiation induced thymic lymphomas by
reducing ROS. This is in a controversial situation where ROS has been found to be contributed to the

5. development and killing cancerous cells. More studies are needed to uncover the mechanism of
hydrogen therapy in dealing with cancer.
Cardiovascular
Clinical trials related to cardiovascular disease done on animal models shown various promising
results when hydrogen rich water is administrated.
Chronic cardiac disease is shown to be the results of hydroxyl radical damage on the heart muscles
and related organs. An experiement was done by pre-treating mice with hydrogen rich water prior to
radiation induced heart damage. 80% of the mice with hydrogen treatment lived after 13 days post
radiation. 90% of the mice in control group without hydrogen rich water treatment did not survive on
the radiation. Prominent oxidative stress markers such as melanodialdehyde (MDA0 and eight-
hydroxydeoxyguanosine (8-OHdG) was relatively lower compared to the non-treatment counterparts.
A study by Hayashida et al. shown that hydrogen gas was able to reduce myocardial infarct sizes
resulted from ischemia reperfusion injury. This has been proposed to be achieved by the inhibition of
caspase-3 and apoptosis in cardiomyocytes. Hydrogen rich salin has shown to exhibit ant-
inflammatory and cytoprotective properties by decreasing pro-inflammatory cytokines and
decreasing myocardial cell damage too.
Future aspect of Hydrogen Treatment
Hydrogen has been used to aid decompression sickness in divers for years. No safety issue has arisen
from any of the commercially used hydrogen therapy so far.
Hydrogen therapy has been shown effective in its free radical scavenging ability, especially towards
hydroxyl radicals, OH.
More human clinical trials are expected to cover extensively the efficacy of hydrogen therapy in
various common human chronic diseases. Previous antioxidant clinical trials have failed to achieve
desirable outcome and hence more comphrehensive study of hydrogen as antioxidant has to be done
to investigate the effects of excess accummulation, the reducing potential, dosage, dose duration and
safety of the antioxidant.
Although hydrogen appears to be faultless at times, there still are several deficiencies or snares that
need to be investigated by future studies. Comprehensive research and experiments that alludes to
molecular hydrogen being a novel therapeutic treatment is desperately needed.