{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T02:36:25Z","timestamp":1792895785708,"version":"4.5.0"},"reference-count":52,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,2,5]],"date-time":"2021-02-05T00:00:00Z","timestamp":1612483200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2019A1515010279"],"award-info":[{"award-number":["2019A1515010279"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81771957"],"award-info":[{"award-number":["81771957"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Thrombolytic stroke therapy with tissue plasminogen activator (tPA) is limited by risks of hemorrhagic transformation (HT). We have reported that a new 12\/15\u2010lipoxygenase (12\/15\u2010LOX) inhibitor ML351 reduced tPA related HT in mice subjected to experimental stroke under anticoagulation. In this study, we asked whether ML351 can ameliorate tPA induced HT in an embolic stroke model. Rats were subjected to embolic middle cerebral artery occlusion with 2 or 3\u00a0hr ischemia and tPA infusion, with or without ML351. Regional cerebral blood flow was monitored 2\u00a0hr after ischemia and continuously monitored for 1\u00a0hr after treatment for determining reperfusion. Hemoglobin was determined in brain homogenates and infarct volume was quantified at 24\u00a0hr after stroke.12\/15\u2010LOX, cluster of differentiation 68(CD68), immunoglobulin G (IgG), and tight junction proteins expression was detected by immunohistochemistry. ML351 significantly reduced tPA related hemorrhage after stroke without affecting its thrombolytic efficacy. ML351 also reduced blood\u2013brain barrier disruption and improved preservation of junction proteins. ML351 and tPA combination improved neurological deficit of rats even though ML351 did not further reduce the infarct volume compared to tPA alone treated animals. Pro\u2010inflammatory cytokines were suppressed by ML351 both in vivo and in vitro experiments. We further showed that ML351 suppressed the expression of c\u2010Jun\u2010N\u2010terminal kinase (JNK) in brains and microglia cultures, whereas exogenous 12\u2010HETE attenuated this effect in vitro. In conclusion, ML351 and tPA combination therapy is beneficial in ameliorating HT after ischemic stroke. This protective effect is probably because of 12\/15\u2010LOX inhibition and suppression of JNK\u2010mediated microglia\/macrophage activation.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15308-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15308","type":"journal-article","created":{"date-parts":[[2021,1,23]],"date-time":"2021-01-23T02:08:13Z","timestamp":1611367693000},"page":"586-598","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Effects of ML351 and tissue plasminogen activator combination therapy in a rat model of focal embolic stroke"],"prefix":"10.1111","volume":"157","author":[{"given":"Guangsen","family":"Cheng","sequence":"first","affiliation":[{"name":"Zhuhai Interventional Medical Center Zhuhai Precision Medical Center Zhuhai People\u2019s Hospital Zhuhai People\u2019s Hospital of Jinan University Zhuhai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Zhuhai Interventional Medical Center Zhuhai Precision Medical Center Zhuhai People\u2019s Hospital Zhuhai People\u2019s Hospital of Jinan University Zhuhai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjie","family":"Xin","sequence":"additional","affiliation":[{"name":"Zhuhai Interventional Medical Center Zhuhai Precision Medical Center Zhuhai People\u2019s Hospital Zhuhai People\u2019s Hospital of Jinan University Zhuhai 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