{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T22:59:55Z","timestamp":1778799595107,"version":"3.51.4"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,8,8]],"date-time":"2019-08-08T00:00:00Z","timestamp":1565222400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,8,8]],"date-time":"2019-08-08T00:00:00Z","timestamp":1565222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Reduced adenosine triphosphate (ATP) levels in ischemic stroke constitute an upstream contributor to neuronal cell death. We have recently created a small chemical, named Kyoto University Substance 121 (KUS121), which can reduce cellular ATP consumption. In this study, we examined whether KUS121 has neuroprotective effects in rodent cerebral ischemia models. We evaluated cell viability and ATP levels <jats:italic>in vitro<\/jats:italic> after oxygen glucose deprivation (OGD) in rat cortical primary neuronal cultures incubated with or without KUS121. We found that KUS121 protected neurons from cell death under OGD by preventing ATP depletion. We also used <jats:italic>in vivo<\/jats:italic> ischemic stroke models of transient distal middle cerebral artery occlusion in C57BL\/6 and B-17 mice. Administration of KUS121 in these models improved functional deficits and reduced brain infarction volume after transient focal cerebral ischemia in both C57BL\/6 and B-17 mice. These results indicate that KUS121 could be a novel type of neuroprotective drug for ischemic stroke.<\/jats:p>","DOI":"10.1038\/s41598-019-47993-w","type":"journal-article","created":{"date-parts":[[2019,8,8]],"date-time":"2019-08-08T10:20:54Z","timestamp":1565259654000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["KUS121, a valosin-containing protein modulator, attenuates ischemic stroke via preventing ATP depletion"],"prefix":"10.1038","volume":"9","author":[{"given":"Hisanori","family":"Kinoshita","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takakuni","family":"Maki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken","family":"Yasuda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natsue","family":"Kishida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norio","family":"Sasaoka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasushi","family":"Takagi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Kakizuka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryosuke","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,8,8]]},"reference":[{"key":"47993_CR1","doi-asserted-by":"publisher","first-page":"2095","DOI":"10.1016\/S0140-6736(12)61728-0","volume":"380","author":"R Lozano","year":"2012","unstructured":"Lozano, R. et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2095\u20132128 (2012).","journal-title":"Lancet"},{"key":"47993_CR2","doi-asserted-by":"crossref","unstructured":"The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet 349, 1569\u20131581 (1997).","DOI":"10.1016\/S0140-6736(97)04011-7"},{"key":"47993_CR3","doi-asserted-by":"publisher","first-page":"1581","DOI":"10.1056\/NEJM199512143332401","volume":"333","author":"National Institute of Neurological, D. & Stroke rt, P.A.S.S.G.","year":"1995","unstructured":"National Institute of Neurological, D. & Stroke rt, P.A.S.S.G. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333, 1581\u20131587 (1995).","journal-title":"N Engl J Med"},{"key":"47993_CR4","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1056\/NEJMoa1411587","volume":"372","author":"OA Berkhemer","year":"2015","unstructured":"Berkhemer, O. A. et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 372, 11\u201320 (2015).","journal-title":"N Engl J Med"},{"key":"47993_CR5","doi-asserted-by":"publisher","first-page":"e46","DOI":"10.1161\/STR.0000000000000158","volume":"49","author":"WJ Powers","year":"2018","unstructured":"Powers, W. J. et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association\/American Stroke Association. Stroke 49, e46\u2013e110 (2018).","journal-title":"Stroke"},{"key":"47993_CR6","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1016\/S1474-4422(16)00114-9","volume":"15","author":"A Chamorro","year":"2016","unstructured":"Chamorro, A., Dirnagl, U., Urra, X. & Planas, A. M. Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol 15, 869\u2013881 (2016).","journal-title":"Lancet Neurol"},{"key":"47993_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/srep05970","volume":"4","author":"HO Ikeda","year":"2014","unstructured":"Ikeda, H. O. et al. Novel VCP modulators mitigate major pathologies of rd10, a mouse model of retinitis pigmentosa. Sci Rep 4, 5970 (2014).","journal-title":"Sci Rep"},{"key":"47993_CR8","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/ncb2407","volume":"14","author":"H Meyer","year":"2012","unstructured":"Meyer, H., Bug, M. & Bremer, S. Emerging functions of the VCP\/p97 AAA-ATPase in the ubiquitin system. Nat Cell Biol 14, 117\u2013123 (2012).","journal-title":"Nat Cell Biol"},{"key":"47993_CR9","doi-asserted-by":"publisher","first-page":"e00096","DOI":"10.1016\/j.heliyon.2016.e00096","volume":"2","author":"N Nakano","year":"2016","unstructured":"Nakano, N. et al. Neuroprotective effects of VCP modulators in mouse models of glaucoma. Heliyon 2, e00096 (2016).","journal-title":"Heliyon"},{"key":"47993_CR10","doi-asserted-by":"publisher","DOI":"10.1038\/srep31184","volume":"6","author":"T Hasegawa","year":"2016","unstructured":"Hasegawa, T. et al. Neuoroprotective efficacies by KUS121, a VCP modulator, on animal models of retinal degeneration. Sci Rep 6, 31184 (2016).","journal-title":"Sci Rep"},{"key":"47993_CR11","doi-asserted-by":"publisher","DOI":"10.1038\/srep44873","volume":"7","author":"M Hata","year":"2017","unstructured":"Hata, M. et al. KUS121, a VCP modulator, attenuates ischemic retinal cell death via suppressing endoplasmic reticulum stress. Sci Rep 7, 44873 (2017).","journal-title":"Sci Rep"},{"key":"47993_CR12","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/j.ebiom.2017.07.024","volume":"22","author":"M Nakano","year":"2017","unstructured":"Nakano, M. et al. ATP Maintenance via Two Types of ATP Regulators Mitigates Pathological Phenotypes in Mouse Models of Parkinson\u2019s Disease. EBioMedicine 22, 225\u2013241 (2017).","journal-title":"EBioMedicine"},{"key":"47993_CR13","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1007\/978-1-4939-2152-2_15","volume":"1254","author":"CI Tasca","year":"2015","unstructured":"Tasca, C. I., Dal-Cim, T. & Cimarosti, H. In vitro oxygen-glucose deprivation to study ischemic cell death. Methods Mol Biol 1254, 197\u2013210 (2015).","journal-title":"Methods Mol Biol"},{"key":"47993_CR14","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.neures.2013.04.001","volume":"76","author":"Y Kasahara","year":"2013","unstructured":"Kasahara, Y. et al. A highly reproducible model of cerebral ischemia\/reperfusion with extended survival in CB-17 mice. Neurosci Res 76, 163\u2013168 (2013).","journal-title":"Neurosci Res"},{"key":"47993_CR15","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.jneumeth.2012.03.003","volume":"207","author":"KP Doyle","year":"2012","unstructured":"Doyle, K. P., Fathali, N., Siddiqui, M. R. & Buckwalter, M. S. Distal hypoxic stroke: a new mouse model of stroke with high throughput, low variability and a quantifiable functional deficit. J Neurosci Methods 207, 31\u201340 (2012).","journal-title":"J Neurosci Methods"},{"key":"47993_CR16","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1038\/sj.cdd.4401365","volume":"11","author":"S Tajiri","year":"2004","unstructured":"Tajiri, S. et al. Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP. Cell Death Differ 11, 403\u2013415 (2004).","journal-title":"Cell Death Differ"},{"key":"47993_CR17","doi-asserted-by":"publisher","first-page":"4702","DOI":"10.1074\/jbc.M609267200","volume":"282","author":"WX Ding","year":"2007","unstructured":"Ding, W. X. et al. Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. J Biol Chem 282, 4702\u20134710 (2007).","journal-title":"J Biol Chem"},{"key":"47993_CR18","doi-asserted-by":"publisher","first-page":"3066","DOI":"10.1101\/gad.1250704","volume":"18","author":"SJ Marciniak","year":"2004","unstructured":"Marciniak, S. J. et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 18, 3066\u20133077 (2004).","journal-title":"Genes Dev"},{"key":"47993_CR19","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/sj.cdd.4401373","volume":"11","author":"S Oyadomari","year":"2004","unstructured":"Oyadomari, S. & Mori, M. Roles of CHOP\/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11, 381\u2013389 (2004).","journal-title":"Cell Death Differ"},{"key":"47993_CR20","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1111\/j.1747-4949.2012.00839.x","volume":"7","author":"C Xing","year":"2012","unstructured":"Xing, C., Arai, K., Lo, E. H. & Hommel, M. Pathophysiologic cascades in ischemic stroke. Int J Stroke 7, 378\u2013385 (2012).","journal-title":"Int J Stroke"},{"key":"47993_CR21","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.neuron.2010.07.002","volume":"67","author":"MA Moskowitz","year":"2010","unstructured":"Moskowitz, M. A., Lo, E. H. & Iadecola, C. The science of stroke: mechanisms in search of treatments. Neuron 67, 181\u2013198 (2010).","journal-title":"Neuron"},{"key":"47993_CR22","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/B978-0-12-394309-5.00006-7","volume":"298","author":"T Kalogeris","year":"2012","unstructured":"Kalogeris, T., Baines, C. P., Krenz, M. & Korthuis, R. J. Cell biology of ischemia\/reperfusion injury. Int Rev Cell Mol Biol 298, 229\u2013317 (2012).","journal-title":"Int Rev Cell Mol Biol"},{"key":"47993_CR23","doi-asserted-by":"publisher","first-page":"2085","DOI":"10.1523\/JNEUROSCI.13-05-02085.1993","volume":"13","author":"M Tymianski","year":"1993","unstructured":"Tymianski, M., Charlton, M. P., Carlen, P. L. & Tator, C. H. Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J Neurosci 13, 2085\u20132104 (1993).","journal-title":"J Neurosci"},{"key":"47993_CR24","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1385\/MN:24:1-3:107","volume":"24","author":"R Sattler","year":"2001","unstructured":"Sattler, R. & Tymianski, M. Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death. Mol Neurobiol 24, 107\u2013129 (2001).","journal-title":"Mol Neurobiol"},{"key":"47993_CR25","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.ejmech.2018.11.014","volume":"162","author":"Y Luo","year":"2019","unstructured":"Luo, Y. et al. Recent advances in the development of neuroprotective agents and therapeutic targets in the treatment of cerebral ischemia. Eur J Med Chem 162, 132\u2013146 (2019).","journal-title":"Eur J Med Chem"},{"key":"47993_CR26","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1038\/321519a0","volume":"321","author":"AB MacDermott","year":"1986","unstructured":"MacDermott, A. B., Mayer, M. L., Westbrook, G. L., Smith, S. J. & Barker, J. L. NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. Nature 321, 519\u2013522 (1986).","journal-title":"Nature"},{"key":"47993_CR27","first-page":"1213","volume":"8","author":"G Yu","year":"2015","unstructured":"Yu, G., Wu, F. & Wang, E. S. BQ-869, a novel NMDA receptor antagonist, protects against excitotoxicity and attenuates cerebral ischemic injury in stroke. Int J Clin Exp Pathol 8, 1213\u20131225 (2015).","journal-title":"Int J Clin Exp Pathol"},{"key":"47993_CR28","doi-asserted-by":"publisher","first-page":"3221","DOI":"10.1242\/jeb.01022","volume":"207","author":"DS Warner","year":"2004","unstructured":"Warner, D. S., Sheng, H. & Batinic-Haberle, I. Oxidants, antioxidants and the ischemic brain. J Exp Biol 207, 3221\u20133231 (2004).","journal-title":"J Exp Biol"},{"key":"47993_CR29","doi-asserted-by":"publisher","first-page":"467","DOI":"10.3389\/fneur.2017.00467","volume":"8","author":"A Mizuma","year":"2017","unstructured":"Mizuma, A. & Yenari, M. A. Anti-Inflammatory Targets for the Treatment of Reperfusion Injury in Stroke. Front Neurol 8, 467 (2017).","journal-title":"Front Neurol"},{"key":"47993_CR30","doi-asserted-by":"publisher","first-page":"e374","DOI":"10.1371\/journal.pbio.0040374","volume":"4","author":"DT Rutkowski","year":"2006","unstructured":"Rutkowski, D. T. et al. Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol 4, e374 (2006).","journal-title":"PLoS Biol"},{"key":"47993_CR31","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.neuroscience.2004.07.051","volume":"129","author":"AT Nies","year":"2004","unstructured":"Nies, A. T. et al. Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain. Neuroscience 129, 349\u2013360 (2004).","journal-title":"Neuroscience"},{"key":"47993_CR32","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1177\/39.8.1649855","volume":"39","author":"W Cammer","year":"1991","unstructured":"Cammer, W., Downing, M., Clarke, W. & Schenkman, J. B. Immunocytochemical staining of the RLM6 form of cytochrome P-450 in oligodendrocytes and myelin of rat brain. J Histochem Cytochem 39, 1089\u20131094 (1991).","journal-title":"J Histochem Cytochem"},{"key":"47993_CR33","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/0378-4274(95)03508-7","volume":"82\u201383","author":"V Ravindranath","year":"1995","unstructured":"Ravindranath, V. et al. Xenobiotic metabolism in brain. Toxicol Lett 82\u201383, 633\u2013638 (1995).","journal-title":"Toxicol Lett"},{"key":"47993_CR34","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1016\/j.neuint.2005.05.014","volume":"47","author":"A Melani","year":"2005","unstructured":"Melani, A. et al. ATP extracellular concentrations are increased in the rat striatum during in vivo ischemia. Neurochem Int 47, 442\u2013448 (2005).","journal-title":"Neurochem Int"},{"key":"47993_CR35","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/S0197-0186(00)00088-7","volume":"38","author":"F Cavaliere","year":"2001","unstructured":"Cavaliere, F. et al. Glucose deprivation and chemical hypoxia: neuroprotection by P2 receptor antagonists. Neurochem Int 38, 189\u2013197 (2001).","journal-title":"Neurochem Int"},{"key":"47993_CR36","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/S0028-3908(01)00197-6","volume":"42","author":"S Amadio","year":"2002","unstructured":"Amadio, S. et al. P2 receptor modulation and cytotoxic function in cultured CNS neurons. Neuropharmacology 42, 489\u2013501 (2002).","journal-title":"Neuropharmacology"},{"key":"47993_CR37","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.scr.2015.05.001","volume":"15","author":"T Maki","year":"2015","unstructured":"Maki, T. et al. Adrenomedullin promotes differentiation of oligodendrocyte precursor cells into myelin-basic-protein expressing oligodendrocytes under pathological conditions in vitro. Stem Cell Res 15, 68\u201374 (2015).","journal-title":"Stem Cell Res"},{"key":"47993_CR38","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1002\/acn3.79","volume":"1","author":"T Maki","year":"2014","unstructured":"Maki, T. et al. Phosphodiesterase III inhibitor promotes drainage of cerebrovascular beta-amyloid. Ann Clin Transl Neurol 1, 519\u2013533 (2014).","journal-title":"Ann Clin Transl Neurol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47993-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47993-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47993-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T12:19:53Z","timestamp":1671279593000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47993-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,8]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["47993"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-47993-w","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,8]]},"assertion":[{"value":"23 January 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 July 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 August 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"In relation to this manuscript, Kyoto University applied for patents; T.M., H.K., A.K. and R.T. were the inventors of the patents. A.K. is a stock ownership for Kyoto Drug Discovery & Development Co., Ltd., a start-up company for the development of VCP modulators. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"11519"}}