メディカルガスによる酸化ストレス耐性シグナリングと神経系保護および老化遅延
Neuroprotection and slow aging induced by oxidative stress-resistant signaling driven by medical gas
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新規メディカルガス概論・分子状水素による神経疾患の予防と健康長寿の実現
Overview on new medical gases: molecular hydrogen medicine for neuroprotection and slow aging

○大澤郁朗1
○Ikuroh Ohsawa1
東京都健康長寿医療センター研究所 環境老化研究1
Tokyo Metropolitan Genriatric Hospital and Institute of Gerontology1

In the past two decades, much attention has been focused on the use of several pharmaceutical gaseous molecules to attenuate oxidative stress. We have previously reported that the smallest molecule, molecular hydrogen (H2), selectively reduces hydroxyl radical and ameliorates oxidative stress-induced injuries in vivo (Ohsawa et al., Nat Med, 2007). Reactive oxygen species (ROS) have been proposed to be responsible for aging and several neurodegenerative diseases. They are produced during normal metabolism mainly in mitochondria, sometimes accidentally and sometimes for useful purposes. For example, nitric oxide and superoxide controls vascular physiology. Thus, excess elimination of ROS interferes their physiological functions. H2 is a weak reductant and reduces only highly toxic ROS including hydroxyl radical. Recently, it has been shown that inhalation of H2 gas limits the infarct volume of the brain, heart and liver by reducing ischemia/reperfusion (I/R) injury and ameliorates transplant injuries in animal studies. H2-loaded eye drops also protected retinal I/R injury. One clinical trial demonstrated an improvement of acute brain stem infarction after the combined infusion of Edaravone and H2. Moreover, consumption of the water nearly saturated with H2 (hydrogen water) prevents stress-induced cognitive decline, degeneration of dopaminergic neurons, allergic reaction and lifestyle diseases in animal and clinical studies. Since H2 has the potential to easily diffuse into organs and no known toxic effects on the human body, treatment with H2 has several potential advantages over current therapies used for oxidative stress- and inflammation-related diseases. However, when hydrogen water is orally administrated, the amount of H2 is too small to detoxify a huge amount of hydroxyl radical at diseased tissue. Therefore, molecular mechanisms underlying the remarkable effect with a small amount of H2 remain to be elucidated.
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神経系の酸化ストレス病態に対する分子状水素の作用基盤
Molecular hydrogen on oxidative stress diseases in nervous system

○大野欽司1
○Kinji Ohno1
名古屋大学大学院医学系研究科 神経遺伝情報学1
Neurogenetics, Nagoya University Graduate School of Medicine1

Effects of molecular hydrogen on neurodegenerative and other diseases have been documented for more than 60 disease models and human diseases in the past five years. We examined the effects of molecular hydrogen on animal models of Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS).We made a rat model of hemi-PD by stereotactically injecting catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) in the right striatum. Ad libitum administration of hydrogen-rich water starting one week before surgery completely abolished the development of hemi-Parkinson's symptoms. The number of dopaminergic neurons on the toxin-injected side was reduced to 40.2% of that on the control side, whereas hydrogen treatment improved the reduction to 83.0%.We also examined the effects of hydrogen gas and lactulose on the rat PD model. Lactulose is exclusively catalyzed by intestinal bacteria and produces a large amount of hydrogen gas. To our surprise, continuous exposure of the PD rat to 2% hydrogen gas and per os administration of lactulose had no effect. On the other hand, intermittent administration of 2% hydrogen gas prevented PD in 4 of 6 rats.We also analyzed the effects of ad libitum administration of hydrogen-rich water on a mouse model of ALS that carried G93A mutation in SOD1. The transgenic (Tg) mouse develops muscle weakness in 3 to 4 months after birth. We started giving hydrogen-rich water from age 9 weeks. Both a running wheel test and a rotarod test showed that hydrogen water successfully retarded development of ALS symptoms, although both mice died at age 21 to 23 weeks.The lack of dose responses of hydrogen and the presence of favorable effects with hydrogen water as well as with intermittent hydrogen gas suggest that signal-modulating activities of hydrogen are likely to be essential for exerting protective effects against neurodegenerative disorders.
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Hydrogen is neuroprotective and preserves cerebrovascular reactivity
○Ferenc Domoki1, Valeria Toth-Szuki1, Peter Temesvari2, Ferenc Bari3, Orsolya Olah1
Department of Physiology, University of Szeged School of Medicine, Hungary1, University Teaching Hospital Oroshaza, Oroshaza, Hungary2, Dept Medical Informatics, University of Szeged School of Medicine, Hungary3

The neurovascular unit encompasses the functional interactions of cerebrovascular and brain parenchymal cells necessary for the metabolic homeostasis of neurons. Previous studies indicated severe, reactive oxygen species (ROS)-dependent neurovascular dysfunction in newborn pigs after hypoxic/ischemic (H/I) stress. Hydrogen gas has been reported to neutralize toxic reactive oxygen species (ROS).
We examined if 2.1% H2 supplemented room air ventilation would preserve cerebrovascular reactivity (CR) and brain morphology after asphyxia/reventilation (A/R) in newborn pigs. Asphyxia was induced by suspending ventilation (8-10 min) in anesthetized, ventilated piglets that were reventilated with air, or air+2.1% H2 for 4h. CR of pial arterioles was determined using closed cranial window/intravital microscopy 4h or 24h after asphyxia to the endothelium dependent cerebrovascular stimulus hypercapnia, the neuronal function dependent stimulus NMDA, norepinephrine, and sodium nitroprusside. The brains were subjected to histopathology.
Hemodynamic parameters, blood gases, and core temperature did not differ significantly among the experimental groups. In the early reventilation period, the recovery of EEG activity was significantly better in H2 treated animals. Asphyxia/reventilation severely attenuated cerebrovascular reactivity to hypercapnia and NMDA, however, reactivity to norepinephrine and sodium nitroprusside were unaltered. H2 fully or partially preserved cerebrovascular reactivity to hypercapnia or NMDA, respectively. Histopathology revealed modest neuroprotection afforded by H2.
Severe stimulus selective neurovascular dysfunction develops and persists even after mild H/I stress. H2 alleviates this delayed neurovascular dysfunction that can contribute to its neuroprotective effect.
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水素による炎症抑制のメカニズム
Molecular mechanism of the inhibitory effect of hydrogen on inflammation

○伊藤雅史1
○Masafumi Ito1
東京都健康長寿医療センター研究所 老化機構研究チーム1
Tokyo Metropolitan Genriatric Hospital and Institute of Gerontology1

Molecular hydrogen has been shown to exhibit beneficial effects in a number of diseases. Although the mechanism of hydrogen effects has been ascribed to the reduction of oxidative stress, we previously reported that oral intake of hydrogen-rich water abolishes passive cutaneous anaphylaxis reaction in mice and that hydrogen attenuates phosphorylation of the FcεRI-associated Lyn and its downstream signal transduction in RBL-2H3 mast cells. Based on these in vivo and in vitro effects of hydrogen on type I allergy, we proposed modulation of signal transduction as another mechanism for the hydrogen effect. We then examined the hydrogen effect on inflammation. Nitric oxide (NO) is involved in a variety of important physiological processes, but an excessive amount of NO is detrimental, resulting in inflammatory diseases such as rheumatoid arthritis. We studied if hydrogen could affect lipopolysaccharide/interferon-γ(LPS/IFN-γ)-stimulated NO production in RAW264.7 macrophage cells. Hydrogen reduced LPS/IFN-γ-stimulated induction of inducible isoform of nitric oxide synthase (iNOS) and production of NO. Hydrogen also inhibited LPS/IFN-γ-stimulated phosphorylation of ASK1 and its downstream signaling molecules including p38, JNK and IκBα. Furthermore, oral intake of hydrogen-rich water ameliorated anti-type II collagen antibody-induced arthritis in mice, a model for rheumatoid arthritis. These results suggested that hydrogen inhibits inflammation in part through modulation of signal transduction. Since hydrogen has been shown to be effective in animal models of Alzheimer's disease and Parkinson's disease, we examined the effect of hydrogen on neuroinflammation which is involved in the pathogenesis of various neurodegenerative diseases. We found that hydrogen inhibits LPS-stimulated NO production in primary microglial cells and BV2 microglial cells, suggesting the involvement of inflammation control in the hydrogen effect on neurodegenerative diseases.
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水素ガスによる神経系の酸化ストレス耐性獲得メカニズム
Mechanism of oxidative stress-resistance in nervous system induced by hydrogen

○野田百美1, 藤田慶大1東智恵里1, 山藤芽実1, 秋元望1, 城戸瑞穂3, 田中喜典4, 中別府雄作5
○Mami Noda1, Kyota Fujita1, Margaret Hamner2, Chieri Higashi1, Megumi Yamafuji1, Nozomi Akimoto1, Mizuho Kido3, Yoshinori Tanaka4, Yusaku Nakabeppu5, Bruce Ransom2
九州大学大学院・薬学研究院・病態生理学分野1, ワシントン大学医学部神経科2, 九州大学歯学研究院分子口腔解剖学分野3, パナソニック株式会社アプライアンス社技術本部4, 九州大学生体防御医学研究所脳機能制御学分野5
Lab Pathophysiol, Grad Sch of Pharm Sci, Kyushu Univ1, Dept Neurol, Univ of Washington Sch of Med, Seattle, Washington, USA2, Dept Oral Anatomy and Cell Biology, Grad Sch of Dental Sci, Kyushu University, Fukuoka, Japan3, Corp Engineering Div, Appliances Company, Panasonic Corporation, Japan4, Div Neurofunctional Genomics, Med Inst of Bioregulation, Kyushu University, Fukuoka, Japan5

Molecular hydrogen selectively reduces hydroxyl radicals, the most cytotoxic of reactive oxygen species (ROS). Hydrogen (H2) in drinking water reduced dopaminergic neuronal loss in substantia nigra by buffering ROS in Parkinson's Disease model animals. In the brain, oxidative damage in not only gray matter but also white matter (WM) is important clinical problem. Among them, WM ischemia may produce injury, in part, by ROS-induced mitochondrial dysfunction. Using the mouse optic nerve (MON) WM model, H2 in drinking water (H2 water) reduced functional WM ischemic injury, even though the intake of H2 was before starting in vitro experiments. Oxygen and glucose deprivation (OGD) in the perfusing solution as an ischemic condition caused prompt loss of the compound action potential (CAP). After 60 min, MON was reperfused with oxygen and glucose for 3 hours, which produced CAP area recovery only 20% in average. After mice received H2 water for 7-10 days, the CAP area did not disappear during OGD and recovered to a significantly great extent during reperfusion with oxygen and glucose. Immunostaining of axonal neurofilaments also showed significant protection by previous drinking of H2 water. These results show that several days of H2 intake reduced the extent of irreversible injury in MON neurofilaments associated with oxidative stress. The importance of these observations is that neuroprotection against oxidative stress by H2 took several days to develop, lasted several days and provided partial protection in a novel manner from what has been previously described. These observations raise intriguing therapeutic options.


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