Recent progress toward hydrogen medicine: potential of molecular hydrogen for preventive and therapeutic applications

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.

Fig. (1)

Illustration of gaseous diffusion of H₂ in a cell. Most hydrophilic compounds () retain at membranes and cannot reach the cytosole, whereas most hydrophic ones (♦) cannot penetrate biomembranes in the absence of specific carriers. In contrast, H₂ () can rapidly distribute into cytosol and organelles. PC12 cells were placed in culture media containing H2 (0.6 mM) and O₂ (0.24 mM), and then oxidative stress was induced by adding antimycin A (10 µg/mL), an inhibitor of the electron transport chain of mitochondria, and maintained for 1 day. Two markers of oxidative stress were detected by immunostaining with anti-8-hydroxy-Guanine (Nucleus) and anti-4-hydoroxy-2-nonenal (Membrane). Thirty minutes after adding antimycin A with or without H₂, 100 nM tetramethylrhodamine methyl ester (TMRM), a fluorescent detector of the membrane potential of mitochondrion, were added, incubated for 10 min, and cells were imaged with a laser scanning confocal microscope. These results indicate that H₂ reach the nucleus and mitochondria and protects them.

Fig. (2). Measurement of the accumulation of H₂ in rat liver.

The concentration of H₂ in the liver was monitored using a needle-type hydrogen sensor inserted into fed- or overnight fasted-rat liver. Rat received hydrogen water (0.8 mM H₂ in water) orally by stomach gavage at 15 ml/kg. Arrow indicates the time point when rat was administered hydrogen water.