Background
Diatomic hydrogen (H2) is the smallest molecule known to mankind, with a bond length of 0.74 Å. One of the common use of H2 is in welding, where the blue flame results from the combustion of H2:O2 gas mixture. Similarly, the combustion of H2 with O2 provides the main propulsion force for rockets. That said, H2 is not combustible with O2 at less than 4% (vol/vol) concentration. Recent research developments suggest that H2 has massive potential to be used as an antioxidant for treatment against many disease models, owing to gaseous diffusion across the blood-brain barrier and cell membrane.
Suggestion of the antioxidant properties of molecular hydrogen (H2) against alkyl radical and hydroxyl radical was first proposed in 1975 by Dole and colleagues. However, the research that really drew attention to the potential of H2 as an antioxidant in therapeutic use is published by Profesor Shigeo Ohta's group in 2007. In that study, they showed that cells cultured in H2-enriched media has a significant decrease in hydroxyl radical (•OH) level when treated with a mitochondrial electron transport chain inhibitor, antimycin A, as judged by the fluorescent signal emitted by the oxidised form of HPF (Ohsawa et al., 2007). In contrast, H2 treatment did not significantly reduce the fluorescent signals from the oxidized form of MitoSox and DCF, which corresponds to the level of •O2- and H2O2, respectively. This result was reciprocated in a cell free system, in which well established antioxidant, ascorbate (vitamin C) was also used as a positive control that reduce the amount of •O2-, H2O2, and •OH indiscriminately (Ohsawa et al., 2007). Further study using mouse models also showed that inhalation of H2 gas significantly reduced the size of brain infarction and suppressed the damage progression, following deliberate ischemic/ reperfusion injury (Ohsawa et al., 2007).
Following the landmark study in 2007, many other physiology studies regarding the potential application of hydrogen therapy on various conditions were subsequently published, surpassing 300 publications in 2013. The list is extensive, and there are some well written reviews on the prospect of hydrogen-based treatment for various medical conditions (Ohta, 2014, Dixon et al., 2013, Ohno et al., 2012, Ishibashi, 2013). Nonetheless, several medical conditions will be further elaborated.
Most cellular damage to the organs following cardiac arrest is due to excessive ROS generation during the reperfusion process. Treatment with H2 gas or H2-enriched saline reduced ischemia/ reperfusion injury in brain, heart and kidney (Ohsawa et al., 2007, Yoshida et al., 2012, Wang et al., 2011). Indeed, H2-rich cold water bath was used to preserve cardiac grafts during heart transplantation procedure by Noda and colleagues (2013), and was reported to reduce tissue injury to the grafts.
Both Parkinson's disease and Alzheimer's disease rat models showed improvements after H2-based interventions using saline or water (Fu et al., 2009, Fujita et al., 2009, Li et al., 2010, Wang et al., 2011). A rat model of hemi-Parkinson's disease was made by injection of neurotoxin to only the right striatum, while the left striatum was used as control. Administration of H2-enriched water in ad libitum manner for a week prior to toxin injection abolishes the development of hemi-Parkinson's symptoms. The number of dopaminergic cells in the right striatum remains at 83.0% of the control left striatum in rats fed with H2-enriched water, compared to 40.2% for rats fed with normal water (Fu et al., 2009).
Rheumatoid arthritis is essentially the chronic inflammation of joints characterized by irreversible destruction of bone and cartilage. Reactive oxygen species (ROS) was implicated in directly and indirectly causing damage to the bone and cartilage. ROS directly oxidize and degrade collagen and hyaluronic acid, and the oxidized products can be detected in joint fluids (Winyard et al., 2011). In addition, ROS is also responsible for the activation of pro-inflammatory events, in a positive feedback loop manner that often exacerbates the condition. A prospective study using hydrogen treatment (drinking 500 mL H2-enriched water for 4 weeks) was shown to effectively reduce oxidative stress and the disease activity of rheumatoid athritis by complementing conventional therapy (Ishibashi et al., 2012).
Increasing obese and diabetic population put major strain on the healthcare system. Using db/db obesity model mice, Kamimura and colleagues (2011) showed that H2-rich water consumption has significant reductive effect on the body weight and body fat after 18-weeks. Biochemical analysis of the blood samples further revealed that plasma glucose, insulin, and triglyceride levels were reduced in mice given H2-rich water ad libitum. These observations are in line with an earlier report where patients with type 2 diabetes or impaired glucose tolerance showed improved lipid and glucose metabolism following H2-rich water intake (900 mL/day) for 8 weeks (Kajiyama et al., 2008).
Cancer patients often suffer from side effects and compromised quality of life when undergoing radiotherapy or chemotherapy treatments. Many of the side effects can be associated with increased oxidative stress generated as a result of treatment. Administration of H2 by either H2 gas (1% vol/vol) or H2-rich water (0.8 mM) was shown to reduce mortality and body-weight loss caused by cisplatin, without affecting the anti-tumor activity in mice (Nakashima-Kamimura et al., 2009). Cancer patients provided with H2-rich water (1.5-2 L/day, 0.55-0.65 mM H2) during radiotherapy (6 weeks) showed significant improvement in their quality of life score and reduced oxidative stress markers, without affecting the treatment efficacy (Kang et al., 2011). Similarly, reduced oxidative stress markers and tissue scarring were observed in the lung of mice fed with H2-rich water after radiation treatment (Terasaki et al., 2011).
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