Complexity of Stomach-Brain Interaction Induced by Molecular Hydrogen in Parkinson's Disease Model Mice

Molecular hydrogen (H₂), as a new medical gas, has protective effects in neurological disorders including Parkinson's disease (PD). In our previous report, the neuroprotective effect of drinking water with saturated H₂ (H₂ water) in PD mice might be due to stomach-brain interaction via release of gastric hormone, ghrelin. In the present study, we assessed the effect of H₂-induced ghrelin more precisely. To confirm the contribution of ghrelin in H₂ water-drinking PD model mice, ghrelin-knock out (KO) mice were used. Despite the speculation, the effect of H₂ water was still observed in ghrelin-KO PD model mice. To further check the involvement of ghrelin, possible contribution of ghrelin-induced vagal afferent effect was tested by performing subdiaphragmatic vagotomy before treating with H₂ water and administration of MPTP (1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine). The protective effect of H₂ water was still observed in the vagotomized mice in substantia nigra, suggesting that stimulation of vagal afferent nerves is not involved in H₂-induced neuroprotection. Other neuroprotective substitutes in ghrelin-KO mice were speculated because H₂-induced neuroprotection was not cancelled by ghrelin receptor antagonist, D-Lys³ GHRP-6, in ghrelin-KO PD model mice, unlike in wild-type PD model mice. Our results indicate that ghrelin may not be the only factor for H₂-induced neuroprotection and other factors can substitute the role of ghrelin when ghrelin is absent, raising intriguing options of research for H₂-responsive factors.