{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T06:13:38Z","timestamp":1780640018536,"version":"3.54.1"},"reference-count":30,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T00:00:00Z","timestamp":1672099200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sou Hashimoto"},{"name":"Doctors Man Co., Ltd."}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Intraperitoneal administration of hydrogen (H<jats:sub>2<\/jats:sub>)-containing saline inhibited neuronal cell death in ischemic stroke in a number of animal models, but it is unknown whether H<jats:sub>2<\/jats:sub> is absorbed from the abdominal cavity into the blood and reaches the brain. In this study, we investigated whether intraperitoneal administration of saline containing H<jats:sub>2<\/jats:sub> inhibits neuronal cell death caused by cerebral ischemia and measured the concentration of H<jats:sub>2<\/jats:sub> in the carotid artery and inferior vena cava (IVC). Gerbils were subjected to transient unilateral cerebral ischemia twice, and saline or H<jats:sub>2<\/jats:sub>-rich saline was administered intraperitoneally three or seven times every 12 hours. We evaluated the number of apoptotic cells in the hippocampus and cerebral cortex on day 3 and the number of viable neurons in the hippocampus and cerebral cortex on day 7. In addition, a single dose of saline or H<jats:sub>2<\/jats:sub>-rich saline was administered intraperitoneally, and blood H<jats:sub>2<\/jats:sub> levels in the carotid artery and IVC were measured. On day 3 of ischemia\/reperfusion, the number of neurons undergoing apoptosis in the cortex was significantly lower in the H<jats:sub>2<\/jats:sub>-rich saline group than in the saline group, and on day 7, the number of viable neurons in the hippocampus and cerebral cortex was significantly higher in the H<jats:sub>2<\/jats:sub>-rich saline group. Intraperitoneal administration of H<jats:sub>2<\/jats:sub>-rich saline resulted in large increases in H<jats:sub>2<\/jats:sub> concentration in the IVC ranging from 0.00183 mg\/L (0.114%) to 0.00725 mg\/L (0.453%). In contrast, carotid H<jats:sub>2<\/jats:sub> concentrations remained in the range of 0.00008 mg\/L (0.0049%) to 0.00023 (0.0146%). On average, H<jats:sub>2<\/jats:sub> concentrations in carotid artery were 0.04 times lower than in IVC. These results indicate that intraperitoneal administration of H<jats:sub>2<\/jats:sub>-rich saline significantly suppresses neuronal cell death after cerebral ischemia, even though H<jats:sub>2<\/jats:sub> hardly reaches the brain.<\/jats:p>","DOI":"10.1371\/journal.pone.0279410","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T18:35:20Z","timestamp":1672166120000},"page":"e0279410","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Pharmacokinetics of hydrogen administered intraperitoneally as hydrogen-rich saline and its effect on ischemic neuronal cell death in the brain in gerbils"],"prefix":"10.1371","volume":"17","author":[{"given":"Momoko","family":"Hirano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhisa","family":"Sugai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2343-0324","authenticated-orcid":true,"given":"Masahiko","family":"Fujisawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiji","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinori","family":"Katsumata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoji","family":"Hakamata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1771-8310","authenticated-orcid":true,"given":"Motoaki","family":"Sano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,12,27]]},"reference":[{"issue":"6","key":"pone.0279410.ref001","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/nm1577","article-title":"Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals","volume":"13","author":"I Ohsawa","year":"2007","journal-title":"Nat Med"},{"issue":"24","key":"pone.0279410.ref002","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.1161\/CIRCULATIONAHA.114.011848","article-title":"Hydrogen inhalation during normoxic resuscitation improves neurological outcome in a rat model of cardiac arrest independently of targeted temperature management","volume":"130","author":"K Hayashida","year":"2014","journal-title":"Circulation"},{"issue":"1","key":"pone.0279410.ref003","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.bbrc.2008.05.165","article-title":"Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury","volume":"373","author":"K Hayashida","year":"2008","journal-title":"Biochem Biophys Res Commun"},{"issue":"11","key":"pone.0279410.ref004","doi-asserted-by":"crossref","first-page":"e08359","DOI":"10.1016\/j.heliyon.2021.e08359","article-title":"Pharmacokinetics of hydrogen after ingesting a hydrogen-rich solution: A study in pigs.","volume":"7","author":"G Ichihara","year":"2021","journal-title":"Heliyon."},{"issue":"10","key":"pone.0279410.ref005","doi-asserted-by":"crossref","first-page":"e0222863","DOI":"10.1371\/journal.pone.0222863","article-title":"Organ preservation solution containing dissolved hydrogen gas from a hydrogen-absorbing alloy canister improves function of transplanted ischemic kidneys in miniature pigs.","volume":"14","author":"E Kobayashi","year":"2019","journal-title":"PLoS One"},{"issue":"3","key":"pone.0279410.ref006","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1097\/TA.0000000000001620","article-title":"Hydrogen gas inhalation inhibits progression to the \"irreversible\" stage of shock after severe hemorrhage in rats.","volume":"83","author":"T Matsuoka","year":"2017","journal-title":"J Trauma Acute Care Surg"},{"issue":"1","key":"pone.0279410.ref007","doi-asserted-by":"crossref","first-page":"20173","DOI":"10.1038\/s41598-020-77349-8","article-title":"Daily inhalation of hydrogen gas has a blood pressure-lowering effect in a rat model of hypertension","volume":"10","author":"K Sugai","year":"2020","journal-title":"Sci Rep"},{"issue":"3","key":"pone.0279410.ref008","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1097\/SHK.0000000000001459","article-title":"Hydrogen Gas Inhalation Attenuates Endothelial Glycocalyx Damage and Stabilizes Hemodynamics in a Rat Hemorrhagic Shock Model","volume":"54","author":"T Tamura","year":"2020","journal-title":"Shock"},{"issue":"2","key":"pone.0279410.ref009","doi-asserted-by":"crossref","first-page":"214","DOI":"10.3164\/jcbn.19-101","article-title":"Hydrogen gas inhalation alleviates oxidative stress in patients with post-cardiac arrest syndrome","volume":"67","author":"T Tamura","year":"2020","journal-title":"J Clin Biochem Nutr"},{"issue":"2","key":"pone.0279410.ref010","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.jacbts.2021.11.005","article-title":"H2 Inhibits the Formation of Neutrophil Extracellular Traps","volume":"7","author":"K Shirakawa","year":"2022","journal-title":"JACC Basic Transl Sci"},{"issue":"10","key":"pone.0279410.ref011","doi-asserted-by":"crossref","first-page":"674","DOI":"10.14740\/jocmr4323","article-title":"Low-Flow Nasal Cannula Hydrogen Therapy.","volume":"12","author":"M Sano","year":"2020","journal-title":"J Clin Med Res."},{"issue":"6","key":"pone.0279410.ref012","doi-asserted-by":"crossref","first-page":"e0234626","DOI":"10.1371\/journal.pone.0234626","article-title":"Pharmacokinetics of a single inhalation of hydrogen gas in pigs.","volume":"15","author":"M Sano","year":"2020","journal-title":"PLoS One."},{"issue":"3","key":"pone.0279410.ref013","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/0014-4886(66)90062-8","article-title":"Effects of ischemia and other procedures on the brain and retina of the gerbil (Meriones unguiculatus).","volume":"16","author":"S Levine","year":"1966","journal-title":"Exp Neurol"},{"issue":"1","key":"pone.0279410.ref014","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/BF00454893","article-title":"Repeated unilateral carotid occlusion in Mongolian gerbils: quantitative analysis of cortical neuronal loss","volume":"86","author":"S Hanyu","year":"1993","journal-title":"Acta Neuropathol"},{"issue":"6","key":"pone.0279410.ref015","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.1161\/STROKEAHA.108.534990","article-title":"Degeneration of astrocytic processes and their mitochondria in cerebral cortical regions peripheral to the cortical infarction: heterogeneity of their disintegration is closely associated with disseminated selective neuronal necrosis and maturation of injury","volume":"40","author":"U Ito","year":"2009","journal-title":"Stroke"},{"issue":"4","key":"pone.0279410.ref016","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1111\/neup.12113","article-title":"Mannitol infusion immediately after reperfusion suppresses the development of focal cortical infarction after temporary cerebral ischemia in gerbils","volume":"34","author":"U Ito","year":"2014","journal-title":"Neuropathology"},{"issue":"1","key":"pone.0279410.ref017","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/0006-8993(84)90552-3","article-title":"Regional cerebral blood flow and stroke index after left carotid artery ligation in the conscious gerbil","volume":"297","author":"K Ohno","year":"1984","journal-title":"Brain Res"},{"issue":"4","key":"pone.0279410.ref018","first-page":"494","article-title":"Hydrogen-rich saline ameliorates hippocampal neuron apoptosis through up-regulating the expression of cystathionine beta-synthase (CBS) after cerebral ischemia- reperfusion in rats.","volume":"23","author":"HM Cong","year":"2020","journal-title":"Iran J Basic Med Sci."},{"key":"pone.0279410.ref019","doi-asserted-by":"crossref","first-page":"113359","DOI":"10.1016\/j.expneurol.2020.113359","article-title":"Delayed recanalization after MCAO ameliorates ischemic stroke by inhibiting apoptosis via HGF\/c-Met\/STAT3\/Bcl-2 pathway in rats","volume":"330","author":"H Tang","year":"2020","journal-title":"Exp Neurol"},{"issue":"2","key":"pone.0279410.ref020","doi-asserted-by":"crossref","first-page":"126","DOI":"10.3892\/etm.2021.11049","article-title":"Hydrogen-rich saline alleviates early brain injury through inhibition of necroptosis and neuroinflammation via the ROS\/HO-1 signaling pathway after traumatic brain injury.","volume":"23","author":"Y Hu","year":"2022","journal-title":"Exp Ther Med."},{"issue":"8","key":"pone.0279410.ref021","doi-asserted-by":"crossref","first-page":"e360804","DOI":"10.1590\/acb360804","article-title":"Hydrogen-rich saline alleviates early brain injury through regulating of ER stress and autophagy after experimental subarachnoid hemorrhage","volume":"36","author":"B Jiang","year":"2021","journal-title":"Acta Cir Bras"},{"issue":"5","key":"pone.0279410.ref022","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s11095-021-03046-4","article-title":"The Mitochondrial mitoNEET Ligand NL-1 Is Protective in a Murine Model of Transient Cerebral Ischemic Stroke","volume":"38","author":"P Saralkar","year":"2021","journal-title":"Pharm Res"},{"key":"pone.0279410.ref023","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainresbull.2021.04.003","article-title":"Hydrogen-saturated saline mediated neuroprotection through autophagy via PI3K\/AKT\/mTOR pathway in early and medium stages of rotenone-induced Parkinson\u2019s disease rats","volume":"172","author":"Z Zhang","year":"2021","journal-title":"Brain Res Bull"},{"issue":"4 Pt 1","key":"pone.0279410.ref024","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1016\/0016-5085(92)90765-Q","article-title":"Production, metabolism, and excretion of hydrogen in the large intestine.","volume":"102","author":"SU Christl","year":"1992","journal-title":"Gastroenterology."},{"issue":"12","key":"pone.0279410.ref025","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1002\/1873-3468.13064","article-title":"Metabolism of hydrogen gases and bile acids in the gut microbiome","volume":"592","author":"PB Hylemon","year":"2018","journal-title":"FEBS Lett"},{"issue":"1","key":"pone.0279410.ref026","first-page":"20","article-title":"Gaseous exchange between the blood and the lumen of the stomach and intestines","volume":"76","author":"MA McIver","year":"1926","journal-title":"American Physiological Society"},{"issue":"4 Pt 1","key":"pone.0279410.ref027","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1016\/0016-5085(92)90790-6","article-title":"Maintaining intestinal H2 balance: credit the colonic bacteria","volume":"102","author":"A Strocchi","year":"1992","journal-title":"Gastroenterology"},{"issue":"12","key":"pone.0279410.ref028","doi-asserted-by":"crossref","first-page":"e0208313","DOI":"10.1371\/journal.pone.0208313","article-title":"Quantification of hydrogen production by intestinal bacteria that are specifically dysregulated in Parkinson\u2019s disease.","volume":"13","author":"A Suzuki","year":"2018","journal-title":"PLoS One."},{"issue":"2","key":"pone.0279410.ref029","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/ams2.320","article-title":"Promising novel therapy with hydrogen gas for emergency and critical care medicine.","volume":"5","author":"M Sano","year":"2018","journal-title":"Acute Med Surg"},{"key":"pone.0279410.ref030","doi-asserted-by":"crossref","first-page":"3273","DOI":"10.1038\/srep03273","article-title":"Oral \u2019hydrogen water\u2019 induces neuroprotective ghrelin secretion in mice.","volume":"3","author":"A Matsumoto","year":"2013","journal-title":"Sci Rep"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0279410","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T18:35:47Z","timestamp":1672166147000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0279410"}},"subtitle":[],"editor":[{"given":"Alexander A.","family":"Mongin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,12,27]]},"references-count":30,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12,27]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0279410","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,27]]}}}