Molecular hydrogen (H2) showed protection against various kinds of oxidative-stress-related diseases. First, it was reported that the mechanism of therapeutic effects of H2 was antioxidative effect due to inhibition of the most cytotoxic reactive oxygen species, hydroxy radical (• OH). However, after chronic administration of H2 in drinking water, oxidative-stress-induced nerve injury is significantly attenuated even in the absence of H2. It suggests indirect signaling of H2 and gastrointestinal tract is involved. Indirect effects of H2 could be tested by giving H2 water only before nerve injury, as preconditioning. For example, preconditioning of H2 for certain a period (∼7 days) in Parkinson’s disease model mice shows significant neuroprotection. As the mechanism of indirect effect, H2 in drinking water induces ghrelin production and release from the stomach via β1-adrenergic receptor stimulation. Released ghrelin circulates in the body, being transported across the blood–brain barrier, activates its receptor, growth-hormone secretagogue receptor. H2-induced upregulation of ghrelin mRNA is also shown in ghrelin-producing cell line, SG-1. These observations help with understanding the chronic effects of H2 and raise intriguing preventive and therapeutic options using H2.
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