{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T16:37:12Z","timestamp":1788280632700,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:00:00Z","timestamp":1750636800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science","award":["Nos. 23790750 and 22K05545"],"award-info":[{"award-number":["Nos. 23790750 and 22K05545"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Reactive oxygen species (ROS) contribute to cerebral damage in transient cerebral ischemia, making their elimination a key therapeutic target. Osteogenic disorder Shionogi (ODS) rats, which lack endogenous L-ascorbic acid (AA) synthesis, serve as a useful model for investigating AA\u2019s protective effects against ischemic brain injury. ODS rats were given an AA-free diet (0% AA), 0.1% AA, or 1% AA in drinking water for two weeks before undergoing middle cerebral artery occlusion and reperfusion (MCAO\/Re). The 0% AA group exhibited pronounced damage following MCAO\/Re, characterized by the induction of lipid peroxidation, O2\u2212 production, inflammation-related gene expression, and extensive infarct formation. In contrast, the 1% AA group showed reductions in these markers, along with fewer TUNEL-positive cells and a smaller infarct volume. Notably, sodium-dependent vitamin C transporter 2 (SVCT2) expression increased in both two AA-supplemented groups, although the 0.1% AA group did not exhibit sufficient improvement in post-ischemic damage. A two-week intake of AA significantly alleviated MCAO\/Re-mediated injuries associated with oxidative stress and inflammation in ODS rats. Sufficient AA intake is thus supposed to mitigate ischemic damage, possibly through SVCT2 upregulation and enhanced AA availability, leading to the suppression of oxidative stress and inflammation.<\/jats:p>","DOI":"10.3390\/antiox14070773","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T09:24:18Z","timestamp":1750757058000},"page":"773","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Administration of Ascorbic Acid Alleviates Neuronal Damage After Cerebral Ischemia in ODS Rats"],"prefix":"10.3390","volume":"14","author":[{"given":"Naohiro","family":"Iwata","sequence":"first","affiliation":[{"name":"Laboratory of Immunobiochemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiochemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Imai","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiochemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siti Sabirah Binti","family":"Ridzuan","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiochemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinya","family":"Kamiuchi","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiochemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0592-5160","authenticated-orcid":false,"given":"Hirokazu","family":"Matsuzaki","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiyan","family":"Xuan","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiochemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"},{"name":"Laboratory of Organic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3406-258X","authenticated-orcid":false,"given":"Bo","family":"Yuan","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari","family":"Okazaki","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiochemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"},{"name":"Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhide","family":"Hibino","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiochemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/bs.vh.2022.10.008","article-title":"Ascorbic acid as antioxidant","volume":"Volume 121","author":"Skrzydlewska","year":"2023","journal-title":"Vitamins and Hormones"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1111\/j.1432-1033.1987.tb11155.x","article-title":"Iron transport and storage","volume":"164","author":"Crichton","year":"1987","journal-title":"Eur. J. Biochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1203s","DOI":"10.1093\/ajcn\/54.6.1203s","article-title":"Molecular basis for the deficiency in humans of gulonolactone oxidase, a key enzyme for ascorbic acid biosynthesis","volume":"54","author":"Nishikimi","year":"1991","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1080\/07315724.2001.10719040","article-title":"Relation of serum ascorbic acid to mortality among US adults","volume":"20","author":"Simon","year":"2001","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"870","DOI":"10.2105\/AJPH.94.5.870","article-title":"Vitamin C deficiency and depletion in the United States: The Third National Health and Nutrition Examination Survey, 1988 to 1994","volume":"94","author":"Hampl","year":"2004","journal-title":"Am. J. Public. Health"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1080\/10408398.2011.649149","article-title":"Authors\u2019 perspective: What is the optimum intake of vitamin C in humans?","volume":"52","author":"Frei","year":"2012","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.brainres.2010.05.090","article-title":"Vitamin C distribution and retention in the mouse brain","volume":"1348","author":"Harrison","year":"2010","journal-title":"Brain Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.freeradbiomed.2008.12.018","article-title":"Vitamin C function in the brain: Vital role of the ascorbate transporter SVCT2","volume":"46","author":"Harrison","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1385\/MN:31:1-3:105","article-title":"Oxidative stress and neuronal death\/survival signaling in cerebral ischemia","volume":"31","author":"Saito","year":"2005","journal-title":"Mol. Neurobiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0022-510X(00)00386-5","article-title":"Brain ischemia and reperfusion: Molecular mechanisms of neuronal injury","volume":"179","author":"White","year":"2000","journal-title":"J. Neurol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1016\/0003-4975(95)00077-X","article-title":"Glutamate, calcium, and free radicals as mediators of ischemic brain damage","volume":"59","author":"Zhao","year":"1995","journal-title":"Ann. Thorac. Surg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1248\/jhs.56.20","article-title":"Protective effects of oral administrated ascorbic acid against oxidative stress and neuronal damage after cerebral ischemia\/reperfusion in diabetic rats","volume":"56","author":"Iwata","year":"2010","journal-title":"J. Health Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.3390\/nu6041554","article-title":"Orally administrated ascorbic acid suppresses neuronal damage and modifies expression of SVCT2 and GLUT1 in the brain of diabetic rats with cerebral ischemia-reperfusion","volume":"6","author":"Iwata","year":"2014","journal-title":"Nutrients"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.freeradbiomed.2020.05.015","article-title":"Therapeutic treatment with vitamin C reduces focal cerebral ischemia-induced brain infarction in rats by attenuating disruptions of blood brain barrier and cerebral neuronal apoptosis","volume":"155","author":"Chang","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1046\/j.1471-4159.2003.01891.x","article-title":"Effect of middle cerebral artery occlusion on mRNA expression for the sodium-coupled vitamin C transporter SVCT2 in rat brain","volume":"86","author":"Berger","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"21973","DOI":"10.1016\/S0021-9258(19)36708-0","article-title":"A missense mutation of L-gulono-gamma-lactone oxidase causes the inability of scurvy-prone osteogenic disorder rats to synthesize L-ascorbic acid","volume":"267","author":"Kawai","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1007\/BF01952551","article-title":"A rat mutant unable to synthesize vitamin C","volume":"40","author":"Mizushima","year":"1984","journal-title":"Experientia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1093\/jn\/115.12.1630","article-title":"Requirement for ascorbic acid in a rat mutant unable to synthesize ascorbic acid","volume":"115","author":"Horio","year":"1985","journal-title":"J. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1742-4658.2006.05607.x","article-title":"Vitamin C: Biosynthesis, recycling and degradation in mammals","volume":"274","author":"Linster","year":"2007","journal-title":"FEBS J."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Gess, B., Sevimli, S., Strecker, J.K., Young, P., and Sch\u00e4bitz, W.R. (2011). Sodium-dependent vitamin C transporter 2 (SVCT2) expression and activity in brain capillary endothelial cells after transient ischemia in mice. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017139"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/978-94-007-2199-9_6","article-title":"Vitamin C transport and its role in the central nervous system","volume":"56","author":"May","year":"2012","journal-title":"Sub-Cell. Biochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/0009-8981(73)90158-7","article-title":"Vitamin C in plasma: A comparative study of the vitamin stabilized with trichloroacetic acid or metaphosphoric acid and the effects of storage at \u221270 degrees, \u221220 degrees, 4 degrees, and 25 degrees on the stabilized vitamin","volume":"44","author":"Bradley","year":"1973","journal-title":"Clin. Chim. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"119","DOI":"10.4327\/jsnfs.61.119","article-title":"Protective effects of a water-soluble extract from culture medium of Ganoderma lucidum mycelia against neuronal damage after cerebral ischemia\/reperfusion in diabetic rats","volume":"61","author":"Iwata","year":"2008","journal-title":"J. Jpn. Soc. Nutr. Food Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.brainresbull.2015.11.019","article-title":"Curcumin pretreatment attenuates inflammation and mitochondrial dysfunction in experimental stroke: The possible role of Sirt1 signaling","volume":"121","author":"Miao","year":"2016","journal-title":"Brain Res. Bull."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Martinovich, G.G., Golubeva, E.N., Martinovich, I.V., and Cherenkevich, S.N. (2012). Redox regulation of calcium signaling in cancer cells by ascorbic acid involving the mitochondrial electron transport chain. J. Biophys., 2012.","DOI":"10.1155\/2012\/921653"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S1567-7249(01)00016-2","article-title":"Ascorbate reduces superoxide production and improves mitochondrial respiratory chain function in human fibroblasts with electron transport chain deficiencies","volume":"1","author":"Sharma","year":"2001","journal-title":"Mitochondrion"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1089\/152308601317203594","article-title":"GSH is required to recycle ascorbic acid in cultured liver cell Lines","volume":"3","author":"Li","year":"2001","journal-title":"Antioxid. Redox Signal."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1007\/BF00762775","article-title":"The role of ascorbate in antioxidant protection of biomembranes: Interaction with vitamin E and coenzyme Q","volume":"26","author":"Beyer","year":"1994","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/j.1749-6632.1975.tb29271.x","article-title":"Distribution of ascorbic acid, metabolites and analogues in man and animals","volume":"258","author":"Hornig","year":"1975","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1079\/BJN19710048","article-title":"The retention of ascorbic acid by guinea-pig tissues","volume":"26","author":"Hughes","year":"1971","journal-title":"Br. J. Nutr."},{"key":"ref_31","first-page":"565","article-title":"Ascorbic acid inhibits chemically induced uroporphyria in ascorbate-requiring rats","volume":"22","author":"Sinclair","year":"1995","journal-title":"Hepatology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"C135","DOI":"10.1152\/ajpcell.00136.2018","article-title":"Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke","volume":"316","author":"Yang","year":"2019","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kawade, N., Murai, A., Suzuki, W., Takeuchi, K., Kondo, M., Kobayashi, M., and Horio, F. (2020). Ascorbic acid deficiency induces hepatic and intestinal expression of inflammation-related genes irrespective of the presence or absence of gut microbiota in ODS rats. J. Nutr. Biochem., 86.","DOI":"10.1016\/j.jnutbio.2020.108485"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"481","DOI":"10.3177\/jnsv.68.481","article-title":"Low Ascorbic Acid Intake Induces Inflammatory Changes in Intestine and Liver of ODS Rats","volume":"68","author":"Kawade","year":"2022","journal-title":"J. Nutr. Sci. Vitaminol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1124\/jpet.107.127035","article-title":"Cyclooxygenase inhibition limits blood-brain barrier disruption following intracerebral injection of tumor necrosis factor-alpha in the rat","volume":"323","author":"Taheri","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1750-1326-7-21","article-title":"Inhibition of MMP-9 by a selective gelatinase inhibitor protects neurovasculature from embolic focal cerebral ischemia","volume":"7","author":"Cui","year":"2012","journal-title":"Mol. Neurodegener."},{"key":"ref_37","unstructured":"Balestrino, M. (2012). Diabetes-Mediated Exacerbation of Neuronal Damage and Inflammation After Cerebral Ischemia in Rat: Protective Effects of Water-Soluble Extract from Culture Medium of Ganoderma lucidum Mycelia. Advances in the Preclinical Study of Ischemic Stroke, IntechOpen."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Choi, Y.K., and Kim, Y.M. (2022). Beneficial and Detrimental Roles of Heme Oxygenase-1 in the Neurovascular System. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23137041"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1089\/ars.2006.1519","article-title":"Hypoxia-mediated induction of heme oxygenase type I and carbon monoxide release from astrocytes protects nearby cerebral neurons from hypoxia-mediated apoptosis","volume":"9","author":"Imuta","year":"2007","journal-title":"Antioxid. Redox Signal."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Nitti, M., Piras, S., Brondolo, L., Marinari, U.M., Pronzato, M.A., and Furfaro, A.L. (2018). Heme oxygenase 1 in the nervous system: Does it favor neuronal cell survival or induce neurodegeneration?. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082260"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1161\/01.STR.0000221708.17159.64","article-title":"Potential contribution of NF-kappaB in neuronal cell death in the glutathione peroxidase-1 knockout mouse in response to ischemia-reperfusion injury","volume":"37","author":"Crack","year":"2006","journal-title":"Stroke"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1046\/j.1471-4159.2001.00535.x","article-title":"Increased infarct size and exacerbated apoptosis in the glutathione peroxidase-1 (Gpx-1) knockout mouse brain in response to ischemia\/reperfusion injury","volume":"78","author":"Crack","year":"2001","journal-title":"J. Neurochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1038\/s41390-021-01515-5","article-title":"Ascorbate deficiency confers resistance to hippocampal neurodegeneration after asphyxial cardiac arrest in juvenile rats","volume":"91","author":"Wolf","year":"2022","journal-title":"Pediatr. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1159\/000080525","article-title":"Functional expression of sodium-dependent vitamin C transporter 2 in human endothelial cells","volume":"41","author":"Seno","year":"2004","journal-title":"J. Vasc. Res."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Salazar, K., Espinoza, F., Cerda-Gallardo, G., Ferrada, L., Magdalena, R., Ram\u00edrez, E., Ulloa, V., Saldivia, N., Troncoso, N., and Oviedo, M.J. (2021). Svct2 overexpression and ascorbic acid uptake increase cortical neuron differentiation, which is dependent on vitamin c recycling between neurons and astrocytes. Antioxidants, 10.","DOI":"10.3390\/antiox10091413"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Burgess, E.R., Praditi, C., Phillips, E., Vissers, M.C.M., Robinson, B.A., Dachs, G.U., and Wiggins, G.A.R. (2025). Role of Sodium-Dependent Vitamin C Transporter-2 and Ascorbate in Regulating the Hypoxic Pathway in Cultured Glioblastoma Cells. J. Cell. Biochem., 126.","DOI":"10.1002\/jcb.30658"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.bbrc.2015.01.096","article-title":"Ascorbic acid transport in brain microvascular pericytes","volume":"458","author":"Parker","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"104316","DOI":"10.1016\/j.neuint.2018.10.013","article-title":"Inflammation and neural repair after ischemic brain injury","volume":"130","author":"Sakai","year":"2019","journal-title":"Neurochem. Int."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/14\/7\/773\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:57:19Z","timestamp":1760032639000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/14\/7\/773"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,23]]},"references-count":48,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["antiox14070773"],"URL":"https:\/\/doi.org\/10.3390\/antiox14070773","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,23]]}}}