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Hydrogen acts as a therapeutic antioxidant

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Hydrogen acts as a therapeutic antioxidant ( hydrogen-acts-as-therapeutic-antioxidant )

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ARTICLES Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals Ikuroh Ohsawa1, Masahiro Ishikawa1, Kumiko Takahashi1, Megumi Watanabe1,2, Kiyomi Nishimaki1, Kumi Yamagata1, Ken-ichiro Katsura2, Yasuo Katayama2, Sadamitsu Asoh1 & Shigeo Ohta1 Acute oxidative stress induced by ischemia-reperfusion or inflammation causes serious damage to tissues, and persistent oxidative stress is accepted as one of the causes of many common diseases including cancer. We show here that hydrogen (H2) has potential as an antioxidant in preventive and therapeutic applications. We induced acute oxidative stress in cultured cells by three independent methods. H2 selectively reduced the hydroxyl radical, the most cytotoxic of reactive oxygen species (ROS), and effectively protected cells; however, H2 did not react with other ROS, which possess physiological roles. We used an acute rat model in which oxidative stress damage was induced in the brain by focal ischemia and reperfusion. The inhalation of H2 gas markedly suppressed brain injury by buffering the effects of oxidative stress. Thus H2 can be used as an effective antioxidant therapy; owing to its ability to rapidly diffuse across membranes, it can reach and react with cytotoxic ROS and thus protect against oxidative damage. Oxidative stress arises from the strong cellular oxidizing potential of excess reactive oxygen species (ROS), or free radicals1–5. Most of the superoxide anion radical (O–2􏰣) produced is generated in mitochondria by electron leakage from the electron transport chain and the Krebs cycle6. O–2􏰣 is also produced by metabolic oxidases, including NADPH oxidase and xanthine oxidase7. Superoxide dismutase converts O–2􏰣 into hydrogen peroxide (H2O2)8, which is detoxified into H2O by either glutathione peroxidase or catalase. Excess O–2􏰣 reduces transition metal ions such as Fe3+ and Cu2+ (ref. 2), the reduced forms of which in turn can react with H2O2 to produce hydroxyl radicals (􏰣OH) by the Fenton reaction. 􏰣OH is the strongest of the oxidant species and reacts indiscriminately with nucleic acids, lipids and proteins. There is no known detoxification system for 􏰣OH; therefore, scavenging 􏰣OH is a critical antioxidant process9. Despite their cytotoxic effects, O–2􏰣 and H2O2 play important physiological roles at low concentrations: they function as regulatory signaling molecules that are involved in numerous signal transduction cascades and also regulate biological processes such as apoptosis, cell proliferation and differentiation7,10. At higher concentrations, H2O2 is converted into hypochlorous acid by myeloperoxidase; hypochlorous acid defends against bacterial invasion5. Nitric oxide (NO􏰣), another ROS, functions as a neurotransmitter and is essential for the dilation of blood vessels11. Thus, cytotoxic radicals such as 􏰣OH must be neu- tralized without compromising the essential biological activities of other, physiologically beneficial, ROS. Here we demonstrate that mole- cular hydrogen (dihydrogen, H2) can alleviate 􏰣OH-induced cytotoxi- city without affecting the other ROS, and propose that H2 has potential as an antioxidant for preventive and therapeutic applications. RESULTS H2 selectively reduces 􏰣OH in cultured cells H2 reduces the 􏰣OH that is produced by radiolysis or photolysis of water12; however, whether H2 can effectively neutralize 􏰣OH in living cells has not been directly investigated. As the cellular damage produced by spontaneous generation of 􏰣OH is not sufficient to be detectable, we induced O–2􏰣 production in PC12 cultured cells. To do this, we treated the cells with a mitochondrial respiratory complex III inhibitor, antimycin A (ref. 13); following such treatment, O–2􏰣 in these cells is rapidly converted into H2O2. The addition of antimycin A increased levels of O–2􏰣 and H2O2, as judged by the fluore- scence signals emitted by the oxidized forms of MitoSOX (Fig. 1a) and 2¢,7¢-dichlorodihydrofluorescein (H2DCF) (Supplementary Fig. 1 online), respectively. We dissolved H2 and O2 into medium as described in the Methods, and confirmed the prolonged (24 h long) maintenance of H2 levels (Supplementary Fig. 2 online). H2 dissolved in culture medium did not decrease MitoSOX and DCF signals in the cells (Fig. 1a,b and Supplementary Fig. 1). Additionally, H2 did not decrease the steady-state level of NO􏰣 (Supplementary Fig. 1). In contrast, H2 treatment significantly decreased levels of 􏰣OH, as assessed by the fluorescence signal emitted by the oxi- dized form of 2-[6-(4¢-hydroxy)phenoxy-3H-xanthen-3-on-9-yl] benzoate (HPF) (refs. 14,15 and Fig. 1c,d). When we exposed the cells to antimycin A (30 mg/ml) in the absence of H2, the HPF signals increased in both the nuclear region and the cytoplasm, probably because H2O2 diffused from the mitochondria to produce 􏰣OH. Notably, H2 decreased 􏰣OH levels even in the nuclear region (Fig. 1c). 1Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki City 211-8533, Japan. 2Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan. Correspondence should be addressed to S.O. (ohta@nms.ac.jp). Received 25 September 2006; accepted 15 March 2007; published online 7 May 2007; doi:10.1038/nm1577 6 8 8 VOLUME 13 [ NUMBER 6 [ JUNE 2007 NATURE MEDICINE © 2007 Nature Publishing Group http://www.nature.com/naturemedicine

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