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Oral hydrogen water induces neuroprotective ghrelin secretion in mice

The therapeutic potential of molecular hydrogen (H2) is emerging in a number of human diseases and in their animal models, including in particular Parkinson’s disease (PD). H2 supplementation of drinking water has been shown to exert disease-modifying effects in PD patients and neuroprotective effects in experimental PD model mice. However, H2 supplementation does not result in detectable changes in striatal H2 levels, indicating an indirect effect. Here we show that H2 supplementation increases gastric expression of mRNA encoding ghrelin, a growth hormone secretagogue, and ghrelin secretion, which are antagonized by the b1-adrenoceptor blocker, atenolol. Strikingly, the neuroprotective effect of H2 water was abolished by either administration of the ghrelin receptor-antagonist, D-Lys3 GHRP-6, or atenolol. Thus, the neuroprotective effect of H2 in PD is mediated by enhanced production of ghrelin. Our findings point to potential, novel strategies for ameliorating pathophysiology in which a protective effect of H2 supplementation has been demonstrated. Therapeutic applications of molecular hydrogen (H2) have been reported in a variety of human diseases and their animal models1, including ischemia-reperfusion injury2–4, metabolic syndrome5, diabetes mellitus type 6 7–9 10,11 2 , organ transplantation, reduction of adverse effects of anti-tumor drug therapy and radiation therapy12,13.

Although the mechanism of action of H2 has not been clearly demonstrated, it is assumed that its anti-oxidative properties, particularly against hydroxyl radical (?OH) and peroxinitrite (ONOO2), are likely to underlie therapeutic efficacy2. Unlike other medical-gas therapy, H2 can be applied in air for inhalation or in solution for drinking, intravenous injection or dialysis. Whereas intravenous injection or dialysis delivers H2 directly into the blood stream, oral hydrogen-supplemented water (hydrogen water, H2-water) must be absorbed into the circulation resulting in limited H2 concentrations in the blood and in target organs7,14.

Parkinson’s disease (PD) has been a major focus in the field of oxidative stress and disease, because it is thought that degeneration of dopaminergic neurons can be triggered and aggravated by the accumulation of oxidative damage. However, although antioxidant therapies have been assessed in PD patients, clinical efficacy has not been established15,16. In contrast, a pilot study of hydrogen water therapy in PD patients has shown promising results17, and it has been reported that hydrogen water exhibits neuroprotective effects14 in the murine MPTP (1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine)-induced PD model18. H2 levels were below measurable thresholds in the substantia nigra in PD model mice14, and hydrogen water, but not continuous inhalation of 2% H2, prevented the development of PD in a rat model19. These findings suggest that the therapeutic effects of hydrogen water may not require its anti-oxidant activity in the brain, and further that its efficacy requires processing that is consequent upon oral administration.

The purpose of the present study was to employ PD model mice to elucidate the underlying mechanism of the neuroprotective effects of oral H2-water. In particular, we hypothesized that oral H2 induces a messenger molecule, which travels to the brain and exerts neuroprotective activity.

Results

Oral hydrogen water induces ghrelin gene expression in the stomach. The stomach functions as an endocrine organ that secretes various peptide hormones with a broad range of physiological effects. We first focused on the stomach to investigate possible effects of oral H2-water at the level of gene induction. In a previous study14, it was reported that drinking H2-water for a period of 7 days prior to MPTP injection protected against MPTP toxicity. We administered oral H2-water for 4 consecutive days and analyzed expression in stomach tissue of gastrin,

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