Elsevier

Medical Hypotheses

Volume 84, Issue 4, April 2015, Pages 350-355
Medical Hypotheses

Potential ghrelin-mediated benefits and risks of hydrogen water

https://doi.org/10.1016/j.mehy.2015.01.018Get rights and content

Abstract

Molecular hydrogen (H2) can scavenge hydroxyl radical and diminish the toxicity of peroxynitrite; hence, it has interesting potential for antioxidant protection. Recently, a number of studies have explored the utility of inhaled hydrogen gas, or of hydrogen-saturated water, administered parenterally or orally, in rodent models of pathology and in clinical trials, oftentimes with very positive outcomes. The efficacy of orally ingested hydrogen-rich water (HW) has been particularly surprising, given that only transient and rather small increments in plasma hydrogen can be achieved by this method. A recent study in mice has discovered that orally administered HW provokes increased gastric production of the orexic hormone ghrelin, and that this ghrelin mediates the favorable impact of HW on a mouse model of Parkinson’s disease. The possibility that most of the benefits observed with HW in experimental studies are mediated by ghrelin merits consideration. Ghrelin is well known to function as an appetite stimulant and secretagogue for growth hormone, but it influences physiological function throughout the body via interaction with the widely express GHS-R1a receptor. Rodent and, to a more limited extent, clinical studies establish that ghrelin has versatile neuroprotective and cognitive enhancing activity, favorably impacts vascular health, exerts anti-inflammatory activity useful in autoimmune disorders, and is markedly hepatoprotective. The stimulatory impact of ghrelin on GH-IGF-I activity, while potentially beneficial in sarcopenia or cachectic disorders, does raise concerns regarding the long-term impact of ghrelin up-regulation on cancer risk. The impact of ingesting HW water on ghrelin production in humans needs to be evaluated; if HW does up-regulate ghrelin in humans, it may have versatile potential for prevention and control of a number of health disorders.

Section snippets

Antioxidant and clinical potential of molecular hydrogen

A great deal of research has been conducted in the last few years, primarily in Japan, to evaluate the presumed antioxidant benefits of inhaled hydrogen gas and of water near-saturated with molecular hydrogen (up to 0.8 mM, or 1.6 ppm), administered parenterally or orally. This research is rooted in the discovery that H2 can act as an efficient scavenger of hydroxyl radicals and oppose the oxidizing activity of peroxynitrite [1], [2]. A great many intriguing findings in a wide range of

Physiological role of ghrelin

Ghrelin is a 28-amino acid peptide produced by proteolytic cleavage of its precursors pre-pro-ghrelin and pro-ghrelin; this occurs primarily in specialized cells within the gastric mucosa [13]. For ghrelin to express its characteristic hormonal activity, a post-translational modification involving conjugation of octanoic acid to Ser-3 of pro-ghrelin is required, mediated by the hormone ghrelin-O-acyltransferase (GOAT), which is coexpressed in ghrelin-producing cells. Ghrelin’s physiological

Ghrelin’s role in cognition and neuroprotection

Ghrelin plays a physiological role in promoting efficient cognition in the hippocampus and has a broad range of neuroprotective activities. Indeed, ghrelin may prove to be a key mediator of the neuroprotection associated with alternate-day fasting or daily calorie restriction. Within the hippocampus, ghrelin and ghrelin receptor agonists have been shown to bind to neurons and promote dendritic spine formation, enhancing long-term potentiation, spatial learning and memory [22], [38], [39], [40],

Ghrelin promotes vascular health

Ghrelin is also of notable interest for its vascular-protective effects [68], [69], [70], [71]. These appear to stem largely from the fact that ghrelin stimulates increased expression and increased activation of the nitric oxide synthase in endothelial cells and endothelial progenitor cells, an effect which may in part be attributable to activation of PI3K and AMPK in these cells [72], [73], [74], [75], [76]. Antioxidant and anti-inflammatory effects of ghrelin on vascular endothelium are

Ghrelin suppresses inflammation and autoimmunity

Ghrelin exerts certain anti-inflammatory effects, and may have potential for control of autoimmunity. Notably, ghrelin acts on monocytes and T lymphocytes to suppress their production of IL-1b, IL-6, INF-alpha – pro-inflammatory cytokines which can induce anorexia during infection and also often during cancer progression [100]. This effect evidently aids ghrelin fundamental “mission” of promoting eating – but it also helps to quell inflammation. Ghrelin also modifies the number and activities

Overview

This brief review suggests that a chronic up-regulation of ghrelin levels or activity has potential for preventing and controlling neurodegenerative disorders, promoting vascular health, ameliorating autoimmunity, and protecting the liver. Hence, ghrelin secretagogues or mimics may have a bright furture in preventive and therapeutic medicine. The ability of ghrelin activity to restore youthful patterns of GH secretion in older people may prove useful in the management of sarcopenia and in

Conflict of interest statement

The author has no conflicts of interest.

References (122)

  • V.P. Carlini et al.

    Ghrelin and memory: differential effects on acquisition and retrieval

    Peptides

    (2010)
  • Z. Zhao et al.

    Ghrelin administration enhances neurogenesis but impairs spatial learning and memory in adult mice

    Neuroscience

    (2014)
  • S.J. Spencer et al.

    Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress

    Biol Psychiatry

    (2012)
  • P.J. Currie et al.

    Ghrelin is an orexigenic peptide and elicits anxiety-like behaviors following administration into discrete regions of the hypothalamus

    Behav Brain Res

    (2012)
  • M. Kanehisa et al.

    Administration of antisense DNA for ghrelin causes an antidepressant and anxiolytic response in rats

    Prog Neuropsychopharmacol Biol Psychiatry

    (2006)
  • V.P. Carlini et al.

    Ghrelin increases anxiety-like behavior and memory retention in rats

    Biochem Biophys Res Commun

    (2002)
  • I. Kyoraku et al.

    Ghrelin reverses experimental diabetic neuropathy in mice

    Biochem Biophys Res Commun

    (2009)
  • W. Tsuchimochi et al.

    Ghrelin prevents the development of experimental diabetic neuropathy in rodents

    Eur J Pharmacol

    (2013)
  • L. Liu et al.

    Ghrelin prevents 1-methyl-4-phenylpyridinium ion-induced cytotoxicity through antioxidation and NF-kappaB modulation in MES23.5 cells

    Exp Neurol

    (2010)
  • A. Theodoropoulou et al.

    Ghrelin and leptin secretion in patients with moderate Alzheimer’s disease

    J Nutr Health Aging

    (2012)
  • J. Li et al.

    Hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer’s disease by reduction of oxidative stress

    Brain Res

    (2010)
  • J. Isgaard et al.

    Ghrelin in cardiovascular disease and atherogenesis

    Mol Cell Endocrinol

    (2011)
  • X. Chen et al.

    Ghrelin induces cell migration through GHSR1a-mediated PI3K/Akt/eNOS/NO signaling pathway in endothelial progenitor cells

    Metabolism

    (2013)
  • Y. Shimizu et al.

    Ghrelin improves endothelial dysfunction through growth hormone-independent mechanisms in rats

    Biochem Biophys Res Commun

    (2003)
  • A. Kawczynska-Drozdz et al.

    Ghrelin inhibits vascular superoxide production in spontaneously hypertensive rats

    Am J Hypertens

    (2006)
  • F. Rossi et al.

    Ghrelin inhibits contraction and proliferation of human aortic smooth muscle cells by cAMP/PKA pathway activation

    Atherosclerosis

    (2009)
  • Q. Zhang et al.

    Ghrelin protects H9c2 cells from hydrogen peroxide-induced apoptosis through NF-kappaB and mitochondria-mediated signaling

    Eur J Pharmacol

    (2011)
  • L. Kui et al.

    Ghrelin inhibits apoptosis induced by high glucose and sodium palmitate in adult rat cardiomyocytes through the PI3K-Akt signaling pathway

    Regul Pept

    (2009)
  • N. Nagaya et al.

    Ghrelin, a novel growth hormone-releasing peptide, in the treatment of chronic heart failure

    Regul Pept

    (2003)
  • K. Kotani et al.

    Serum ghrelin and carotid atherosclerosis in older Japanese people with metabolic syndrome

    Arch Med Res

    (2006)
  • M. Zhang et al.

    Plasma ghrelin levels are closely associated with stenosis severity and morphology of angiographically-detected coronary atherosclerosis in patients with coronary artery disease

    Int J Cardiol

    (2011)
  • I. Ohsawa et al.

    Consumption of hydrogen water prevents atherosclerosis in apolipoprotein E knockout mice

    Biochem Biophys Res Commun

    (2008)
  • G. Song et al.

    Hydrogen-rich water decreases serum LDL-cholesterol levels and improves HDL function in patients with potential metabolic syndrome

    J Lipid Res

    (2013)
  • S. Kajiyama et al.

    Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance

    Nutr Res

    (2008)
  • I. Ohsawa et al.

    Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals

    Nat Med

    (2007)
  • T. Hanaoka et al.

    Molecular hydrogen protects chondrocytes from oxidative stress and indirectly alters gene expressions through reducing peroxynitrite derived from nitric oxide

    Med Gas Res

    (2011)
  • K. Ohno et al.

    Molecular hydrogen as an emerging therapeutic medical gas for neurodegenerative and other diseases

    Oxid Med Cell Longev

    (2012)
  • B.J. Dixon et al.

    The evolution of molecular hydrogen: a noteworthy potential therapy with clinical significance

    Med Gas Res

    (2013)
  • M. Ito et al.

    Drinking hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamine-induced Parkinson’s disease in rats

    Med Gas Res

    (2012)
  • A. Matsumoto et al.

    Oral ‘hydrogen water’ induces neuroprotective ghrelin secretion in mice

    Sci Rep

    (2013)
  • K. Fujita et al.

    Hydrogen in drinking water reduces dopaminergic neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease

    PLoS One

    (2009)
  • V.V. Dos Santos et al.

    Ghrelin as a neuroprotective and palliative agent in Alzheimer’s and Parkinson’s disease

    Curr Pharm Des

    (2013)
  • A. Yoritaka et al.

    Pilot study of H(2) therapy in Parkinson’s disease: a randomized double-blind placebo-controlled trial

    Mov Disord

    (2013)
  • M. Kojima et al.

    Ghrelin: from gene to physiological function

    Results Probl Cell Differ

    (2010)
  • R.G. Albarran-Zeckler et al.

    The ghrelin receptors (GHS-R1a and GHS-R1b)

    Endocr Dev

    (2013)
  • L.M. Frago et al.

    Neuroprotective actions of ghrelin and growth hormone secretagogues

    Front Mol Neurosci

    (2011)
  • W. Zhang et al.

    Effect of des-acyl ghrelin on adiposity and glucose metabolism

    Endocrinology

    (2008)
  • T.J. Zhao et al.

    Ghrelin secretion stimulated by {beta}1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice

    Proc Natl Acad Sci USA

    (2010)
  • W.A. Banks et al.

    Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure

    J Pharmacol Exp Ther

    (2002)
  • M. Schaeffer et al.

    Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons

    Proc Natl Acad Sci USA

    (2013)
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    Financial support provided by Catalytic Longevity, a non-profit organization.

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