{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T21:57:08Z","timestamp":1781042228430,"version":"3.54.1"},"reference-count":47,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2021R1A2C1005520"],"award-info":[{"award-number":["NRF-2021R1A2C1005520"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2025-16066207"],"award-info":[{"award-number":["RS-2025-16066207"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2020-NR049589"],"award-info":[{"award-number":["RS-2020-NR049589"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Stroke is the leading cause of death and long-term disability worldwide, with ischemic stroke accounting for nearly 87% of all cases. Vascular occlusion, a key pathological event in ischemic stroke, has been reliably reproduced in preclinical studies using permanent ischemic stroke models. This study demonstrated the neuroprotective effect of NXC736, a functional antagonist of sphingosine-1-phosphate receptor 4 (S1P4, currently in phase II clinical trials for alopecia areata), against acute injury in mice with permanent middle cerebral artery occlusion (pMCAO). pMCAO-challenged mice received oral NXC736 1 h after occlusion. NXC736 demonstrated substantial therapeutic activity against permanent ischemic stroke by attenuating pMCAO-induced acute brain infarction, neurological deficits, and apoptosis. Additionally, NXC736 reduced blood\u2013brain barrier disruption and edema in the injured brain. Moreover, NXC736 reduced microglial activation and proliferation, oxidative stress, and suppressed pro-inflammatory cytokine expression, suggesting that the efficacy of NXC736 in permanent ischemic stroke is associated with the suppression of neuroinflammatory responses. Mechanistically, we found that NXC736-mediated neuroprotective effects were dependent on the inactivation of NF-\u03baB and MAPKs, including ERK1\/2, JNK, and p38. Collectively, our findings indicate that NXC736 is an effective neuroprotective drug for permanent ischemic brain stroke, highlighting S1P4 as a promising therapeutic target for ischemic stroke.<\/jats:p>","DOI":"10.3390\/molecules30234504","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T17:28:07Z","timestamp":1763746087000},"page":"4504","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["NXC736, a Functional Antagonist of S1P4, Attenuates Brain Injury in Mice with Permanent Ischemic Stroke"],"prefix":"10.3390","volume":"30","author":[{"given":"Nikita","family":"Basnet","sequence":"first","affiliation":[{"name":"College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon 21936, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Supriya","family":"Tiwari","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon 21936, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9532-1581","authenticated-orcid":false,"given":"Kyung Hee","family":"Choi","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon 21936, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8773-6528","authenticated-orcid":false,"given":"Donghee","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon 21936, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Woong","family":"Choi","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon 21936, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.bbalip.2012.07.015","article-title":"Lysophospholipids and their receptors in the central nervous system","volume":"1831","author":"Choi","year":"2013","journal-title":"Biochim. 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