Circulating messenger for neuroprotection induced by molecular hydrogen.

Molecular hydrogen (H) showed protection against various kinds of oxidative-stress-related diseases. First, it was reported that the mechanism of therapeutic effects of H was antioxidative effect due to inhibition of the most cytotoxic reactive oxygen species, hydroxy radical (•OH). However, after chronic administration of H in drinking water, oxidative-stress-induced nerve injury is significantly attenuated even in the absence of H. It suggests indirect signaling of H and gastrointestinal tract is involved. Indirect effects of H could be tested by giving H water only before nerve injury, as preconditioning. For example, preconditioning of H for certain a period (∼7 days) in Parkinson's disease model mice shows significant neuroprotection. As the mechanism of indirect effect, H 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. H-induced upregulation of ghrelin mRNA is also shown in ghrelin-producing cell line, SG-1. These observations help with understanding the chronic effects of H and raise intriguing preventive and therapeutic options using H.