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Methods Enzymol. 2015;555:289-317. doi: 10.1016/bs.mie.2014.11.038. Epub 2015 Jan 21.

Molecular hydrogen as a novel antioxidant: overview of the advantages of

hydrogen for medical applications.
Ohta S1.
Author information
Abstract
Molecular hydrogen (H2) was believed to be inert and nonfunctional in mammalian cells. We
overturned this concept by demonstrating that H2 reacts with highly reactive oxidants such as
hydroxyl radical ((•)OH) and peroxynitrite (ONOO(-)) inside cells. H2 has several advantages
exhibiting marked effects for medical applications: it is mild enough neither to disturb metabolic
redox reactions nor to affect signaling by reactive oxygen species. Therefore, it should have no or
little adverse effects. H2 can be monitored with an H2-specific electrode or by gas chromatography.
H2 rapidly diffuses into tissues and cells to exhibit efficient effects. Thus, we proposed the potential
of H2 for preventive and therapeutic applications. There are several methods to ingest or consume
H2: inhaling H2 gas, drinking H2-dissolved water (H2-water), injecting H2-dissolved saline (H2-
saline), taking an H2 bath, or dropping H2-saline onto the eyes. Recent publications revealed that, in
addition to the direct neutralization of highly reactive oxidants, H2 indirectly reduces oxidative stress
by regulating the expression of various genes. Moreover, by regulating gene expression, H2
functions as an anti-inflammatory, antiallergic, and antiapoptotic molecule, and stimulates energy
metabolism. In addition to growing evidence obtained by model animal experiments, extensive
clinical examinations were performed or are under way. Since most drugs specifically act on their
specific targets, H2 seems to differ from conventional pharmaceutical drugs. Owing to its great
efficacy and lack of adverse effects, H2 has potential for clinical applications for many diseases.

© 2015 Elsevier Inc. All rights reserved.

KEYWORDS:
Clinical examination; Hydroxyl radical; Inert gas; No adverse effect; Peroxynitrite; Rapid diffusion; Selective reduction

PMID:

25747486

DOI:

10.1016/bs.mie.2014.11.038
 [PubMed - indexed for MEDLINE]

Pharmacol Ther. 2014 Oct;144(1):1-11. doi: 10.1016/j.pharmthera.2014.04.006. Epub 2014 Apr 24.

Molecular hydrogen as a preventive and therapeutic medical

gas: initiation, development and potential of hydrogen
medicine.
Ohta S1.
Author information
Abstract
Molecular hydrogen (H2) has been accepted to be an inert and nonfunctional molecule in our body.
We have turned this concept by demonstrating that H2 reacts with strong oxidants such as hydroxyl
radical in cells, and proposed its potential for preventive and therapeutic applications. H2 has a
number of advantages exhibiting extensive effects: H2 rapidly diffuses into tissues and cells, and it is
mild enough neither to disturb metabolic redox reactions nor to affect signaling reactive oxygen
species; therefore, there should be no or little adverse effects of H2. There are several methods to
ingest or consume H2; inhaling H2 gas, drinking H2-dissolved water (H2-water), injecting H2-
dissolved saline (H2-saline), taking an H2 bath, or dropping H2-saline into the eyes. The numerous
publications on its biological and medical benefits revealed that H2 reduces oxidative stress not only
by direct reactions with strong oxidants, but also indirectly by regulating various gene expressions.
Moreover, by regulating the gene expressions, H2 functions as an anti-inflammatory and anti-
apoptotic, and stimulates energy metabolism. In addition to growing evidence obtained by model
animal experiments, extensive clinical examinations were performed or are under investigation.
Since most drugs specifically act to their targets, H2 seems to differ from conventional
pharmaceutical drugs. Owing to its great efficacy and lack of adverse effects, H2 has promising
potential for clinical use against many diseases.

Copyright © 2014 Elsevier Inc. All rights reserved.

KEYWORDS:
Anti-inflammation; Antioxidant; Clinical examination; No adverse effect; Oxidative stress;
Reactive oxygen species

PMID:

24769081

DOI:

10.1016/j.pharmthera.2014.04.006
 [PubMed - indexed for MEDLINE]
Free full text

Curr Pharm Des. 2011;17(22):2241-52.

Recent progress toward hydrogen medicine: potential of

molecular hydrogen for preventive and therapeutic
applications.
Ohta S1.
Author information
Abstract
Persistent oxidative stress is one of the major causes of most lifestyle-related diseases, cancer and
the aging process. Acute oxidative stress directly causes serious damage to tissues. Despite the
clinical importance of oxidative damage, antioxidants have been of limited therapeutic success. We
have proposed that molecular hydrogen (H(2)) has potential as a "novel" antioxidant in preventive
and therapeutic applications [Ohsawa et al., Nat Med. 2007: 13; 688-94]. H(2) has a number of
advantages as a potential antioxidant: H(2) rapidly diffuses into tissues and cells, and it is mild
enough neither to disturb metabolic redox reactions nor to affect reactive oxygen species (ROS) that
function in cell signaling, thereby, there should be little adverse effects of consuming H(2). There are
several methods to ingest or consume H(2), including inhaling hydrogen gas, drinking H(2)-dissolved
water (hydrogen water), taking a hydrogen bath, injecting H(2)- dissolved saline (hydrogen saline),
dropping hydrogen saline onto the eye, and increasing the production of intestinal H(2) by bacteria.
Since the publication of the first H(2) paper in Nature Medicine in 2007, the biological effects of H(2)
have been confirmed by the publication of more than 38 diseases, physiological states and clinical
tests in leading biological/medical journals, and several groups have started clinical examinations.
Moreover, H(2) shows not only effects against oxidative stress, but also various anti-inflammatory
and antiallergic effects. H(2) regulates various gene expressions and protein-phosphorylations,
though the molecular mechanisms underlying the marked effects of very small amounts of H(2)
remain elusive.

PMID:

21736547

PMCID:

PMC3257754
[PubMed - indexed for MEDLINE]
Free PMC Article
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Curr Pharm Des. 2011;17(22):2253-63.

The principle and the potential approach to ROS-dependent cytotoxicity by

non-pharmaceutical therapies: optimal use of medical gases with
antioxidant properties.
Noda M1, Fujita K, Lee CH, Yoshioka T.
Author information
Abstract
Regulation of cellular redox balances is important for the homeostasis of human health. Thus, many
important human diseases, such as inflammation, diabetes, glaucoma, cancers, ischemia and
neurodegenerative diseases, have been investigated in the field of reactive oxygen species (ROS)
and oxidative stress. To overcome the harmful effect of oxidative stress and ROS, one can directly
eliminate them by medical gases such as carbon monoxide (CO), hydrogen sulphide (H(2)S), and
molecular hydrogen (H(2)), or one can induce ROS-resistant proteins and antioxidant enzymes to
antagonize oxidative stresses. This article reviews the molecular mechanisms how these medical
gasses work as antioxidants, and how ROS resistant proteins are produced in the physiological
context. Targeted therapeutic modalities to scavenge or prevent ROS might be applied in the
prevention and treatment of ROS-related diseases in the near future.

PMID:

21736540
[PubMed - indexed for MEDLINE]

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Nat Med. 2007 Jun;13(6):688-94. Epub 2007 May 7.

 Hydrogen acts as a therapeutic antioxidant by selectively reducing
cytotoxic oxygen radicals.
Ohsawa I1, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, Katayama
Y, Asoh S, Ohta S.
Author information
Abstract
Acute oxidative stress induced by ischemia-reperfusion or inflammation causes serious
damage to tissues, and persistent oxidative stress is accepted as one of the causes of many
common diseases including cancer. We show here that hydrogen (H(2)) has potential as an
antioxidant in preventive and therapeutic applications. We induced acute oxidative stress in
cultured cells by three independent methods. H(2) selectively reduced the hydroxyl radical,
the most cytotoxic of reactive oxygen species (ROS), and effectively protected cells;
however, H(2) did not react with other ROS, which possess physiological roles. We used an
acute rat model in which oxidative stress damage was induced in the brain by focal ischemia
and reperfusion. The inhalation of H(2) gas markedly suppressed brain injury by buffering
the effects of oxidative stress. Thus H(2) can be used as an effective antioxidant therapy;
owing to its ability to rapidly diffuse across membranes, it can reach and react with cytotoxic
ROS and thus protect against oxidative damage.

Comment in

 The hydrogen highway to reperfusion therapy. [Nat Med. 2007]

PMID:

17486089

DOI:

10.1038/nm1577
[PubMed - indexed for MEDLINE]