{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T14:31:55Z","timestamp":1792506715118,"version":"4.5.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T00:00:00Z","timestamp":1648080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81730095 81961128024 31900686 81903583"],"award-info":[{"award-number":["81730095 81961128024 31900686 81903583"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS102452 NS114716"],"award-info":[{"award-number":["NS102452 NS114716"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Acidosis is a hallmark of ischemic stroke and a promising neuroprotective target for preventing neuronal injury. Previously, genetic manipulations showed that blockade of acid-sensing ion channel 1a (ASIC1a)-mediated acidotoxicity could dramatically alleviate the volume of brain infarct and restore neurological function after cerebral ischemia. However, few pharmacological candidates have been identified to exhibit efficacy on ischemic stroke through inhibition of ASIC1a. In this work, we examined the ability of a toxin-inspired compound 5b (C5b), previously found to effectively inhibit ASIC1a <jats:italic>in vitro<\/jats:italic>, to exert protective effects in animal models of ischemic stroke <jats:italic>in vivo<\/jats:italic>. We found that C5b exerts significant neuroprotective effects not only in acid-induced neuronal death <jats:italic>in vitro<\/jats:italic> but also ischemic brain injury <jats:italic>in vivo<\/jats:italic>, suggesting that ASIC1a is a druggable target for therapeutic development. More importantly, C5b is able to cross the blood brain barrier and significantly reduce brain infarct volume when administered intravenously in the ischemic animal model, highlighting its systemic availability for therapies against neurodegeneration due to acidotoxicity. Together, our data demonstrate that C5b is a promising lead compound for neuroprotection through inhibiting ASIC1a, which warrants further translational studies.<\/jats:p>","DOI":"10.3389\/fphar.2022.849498","type":"journal-article","created":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T06:16:28Z","timestamp":1648534588000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Pharmacological Validation of ASIC1a as a Druggable Target for Neuroprotection in Cerebral Ischemia Using an Intravenously Available Small Molecule Inhibitor"],"prefix":"10.3389","volume":"13","author":[{"given":"Xin","family":"Qi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Fei","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Yue","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Jun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu-Bing","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Lan","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing-Lei","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Yi","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Ting","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleg","family":"Krishtal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leng-Chen","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael X.","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-Le","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1016\/j.cell.2014.01.011","article-title":"X-ray Structure of Acid-Sensing Ion Channel 1-snake Toxin Complex Reveals Open State of a Na(+)-Selective Channel","volume":"156","author":"Baconguis","year":"2014","journal-title":"Cell"},{"key":"B2","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1038\/nature11375","article-title":"Structural Plasticity and Dynamic Selectivity of Acid-Sensing Ion Channel-Spider Toxin Complexes","volume":"489","author":"Baconguis","year":"2012","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.neuropharm.2015.01.005","article-title":"Pharmacology of Acid-Sensing Ion Channels - Physiological and Therapeutical Perspectives","volume":"94","author":"Baron","year":"2015","journal-title":"Neuropharmacology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1113\/jphysiol.2001.014837","article-title":"ASIC-like, Proton-Activated Currents in Rat Hippocampal Neurons","volume":"539","author":"Baron","year":"2002","journal-title":"J. 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