{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T07:54:02Z","timestamp":1777794842154,"version":"3.51.4"},"reference-count":67,"publisher":"SAGE Publications","issue":"11","license":[{"start":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T00:00:00Z","timestamp":1717459200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Cereb Blood Flow Metab"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:p>Endothelial blood-brain barrier (BBB) dysfunction is critical in the pathophysiology of brain injury. Rho-associated protein kinase (ROCK) activation disrupts BBB integrity in the injured brain. We aimed to test the efficacy of a novel ROCK2 inhibitor in preserving the BBB after acute brain injury. We characterized the molecular structure and pharmacodynamic and pharmacokinetic properties of a novel selective ROCK2 inhibitor, NRL-1049, and its first metabolite, 1-hydroxy-NRL-1049 (referred to as NRL-2017 hereon) and tested the efficacy of NRL-1049 on the BBB integrity in rodent models of acute brain injury. Our data show that NRL-1049 and NRL-2017 both inhibit ROCK activity and are 44-fold and 17-fold more selective towards ROCK2 than ROCK1, respectively. When tested in a mouse model of cortical cryoinjury, NRL-1049 significantly attenuated the increase in water content. Interestingly, 60% of the mice in the vehicle arm developed seizures within 2 hours after cryoinjury versus none in the NRL-1049 arm. In spontaneously hypertensive rats, NRL-1049 attenuated the dramatic surge in Evans Blue extravasation compared with the vehicle arm after transient middle cerebral artery occlusion. Hemorrhagic transformation was also reduced. We show that NRL-1049, a selective ROCK2 inhibitor, is a promising drug candidate to preserve the BBB after brain injury.<\/jats:p>","DOI":"10.1177\/0271678x241238845","type":"journal-article","created":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T15:26:58Z","timestamp":1717514818000},"page":"1238-1252","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":8,"title":["The novel ROCK2 selective inhibitor NRL-1049 preserves the blood-brain barrier after acute injury"],"prefix":"10.1177","volume":"44","author":[{"given":"Inge A","family":"Mulder","sequence":"first","affiliation":[{"name":"Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Department of Biomedical Engineering and Physics, Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Microcirculation, Amsterdam, the Netherlands"},{"name":"Amsterdam Neurosciences, Neurovascular Disorders, Amsterdam, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matt","family":"Abbinanti","sequence":"additional","affiliation":[{"name":"BioAxone BioSciences Inc, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah A","family":"Woller","sequence":"additional","affiliation":[{"name":"BioAxone BioSciences Inc, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joerg","family":"Ruschel","sequence":"additional","affiliation":[{"name":"BioAxone BioSciences Inc, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan M","family":"Coutinho","sequence":"additional","affiliation":[{"name":"Amsterdam Neurosciences, Neurovascular Disorders, Amsterdam, the Netherlands"},{"name":"Department of Neurology, Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helga E","family":"de Vries","sequence":"additional","affiliation":[{"name":"Amsterdam Neurosciences, Neurovascular Disorders, Amsterdam, the Netherlands"},{"name":"Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit, Amsterdam, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ed","family":"van Bavel","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering and Physics, Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Microcirculation, Amsterdam, the Netherlands"},{"name":"Amsterdam Neurosciences, Neurovascular Disorders, Amsterdam, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth","family":"Rosen","sequence":"additional","affiliation":[{"name":"BioAxone BioSciences Inc, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"McKerracher","sequence":"additional","affiliation":[{"name":"BioAxone BioSciences Inc, Boston, MA, USA"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cenk","family":"Ayata","sequence":"additional","affiliation":[{"name":"Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Stroke Service, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2024,6,4]]},"reference":[{"key":"bibr1-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1124\/pr.115.010595"},{"key":"bibr2-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-051914-022120"},{"key":"bibr3-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.115.305353"},{"key":"bibr4-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1080\/14737175.2017.1395700"},{"key":"bibr5-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1517\/14728220802539244"},{"key":"bibr6-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1080\/13543776.2017.1272579"},{"key":"bibr7-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1017\/cjn.2015.288"},{"key":"bibr8-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1247\/csf.12018"},{"key":"bibr9-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2015.04.005"},{"key":"bibr10-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2016.03.104"},{"key":"bibr11-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/S0024-3205(01)01229-2"},{"key":"bibr12-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1042\/bj3510095"},{"key":"bibr13-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2003.11.002"},{"key":"bibr14-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.110635"},{"key":"bibr15-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2018.03.008"},{"key":"bibr16-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.116.07430"},{"key":"bibr17-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b00424"},{"key":"bibr18-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1186\/2046-4053-2-33"},{"key":"bibr19-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.2174\/1570161112666140613115813"},{"key":"bibr20-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1177\/11795735221123910"},{"key":"bibr21-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.19"},{"key":"bibr22-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25298"},{"key":"bibr23-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10523"},{"key":"bibr24-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-019-01402-z"},{"key":"bibr25-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00034.2009"},{"key":"bibr26-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.2174\/157015908785777210"},{"key":"bibr27-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/S1537-1891(03)00008-9"},{"key":"bibr28-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2011.12.014"},{"key":"bibr29-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-021-04056-x"},{"key":"bibr30-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2021.06.019"},{"key":"bibr31-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-019-01326-8"},{"key":"bibr32-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0177332"},{"key":"bibr33-0271678X241238845","first-page":"7844","volume":"7","author":"Fu Z","year":"2014","journal-title":"Int J Clin Exp Pathol"},{"key":"bibr34-0271678X241238845","unstructured":"Rosen KM, Am Ruschel J, McKerracher L, et\u00a0al. Rho kinase inhibitor BA-1049 (R) and active metabolites thereof. United States Patent 10,106,525, 23 October 2018 In:\n                      USPTO Patent Full-Text and Image Database\n                      , 2018. DOI: patft.uspto.gov\/netacgi\/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=10106525.PN.&OS=PN\/10106525&RS=PN\/10106525."},{"key":"bibr35-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1007\/s12975-019-00725-8"},{"key":"bibr36-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2018.05.106"},{"key":"bibr37-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhr080"},{"key":"bibr38-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2015.04.018"},{"key":"bibr39-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmpb.2010.01.007"},{"key":"bibr40-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M508847200"},{"key":"bibr41-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2015.03.017"},{"key":"bibr42-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20091258"},{"key":"bibr43-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-0082(98)00047-1"},{"key":"bibr44-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2016.07.006"},{"key":"bibr45-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-017-2994-0"},{"key":"bibr46-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1719"},{"key":"bibr47-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12681"},{"key":"bibr48-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2015.00276"},{"key":"bibr49-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.5772\/47732"},{"key":"bibr50-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.2000.278.1.C57"},{"key":"bibr51-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(99)00144-3"},{"key":"bibr52-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1254\/jjp.80.41"},{"key":"bibr53-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.3171\/jns.1992.76.4.0571"},{"key":"bibr54-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(97)00197-8"},{"key":"bibr55-0271678X241238845","first-page":"601","volume":"15","author":"Sage MR","year":"1994","journal-title":"AJNR Am J Neuroradiol"},{"key":"bibr56-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1007\/BF00571508"},{"key":"bibr57-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2011.08.002"},{"key":"bibr58-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2011.12.045"},{"key":"bibr59-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1021\/cn3000197"},{"key":"bibr60-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1177\/17474930211065917"},{"key":"bibr61-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1186\/s12987-021-00280-1"},{"key":"bibr62-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2005.06.003"},{"key":"bibr63-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1991.tb12355.x"},{"key":"bibr64-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.25.6.1234"},{"key":"bibr65-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1996.tb15579.x"},{"key":"bibr66-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.188524"},{"key":"bibr67-0271678X241238845","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.123.044279"}],"container-title":["Journal of Cerebral Blood Flow &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/0271678X241238845","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/0271678X241238845","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/0271678X241238845","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T20:14:59Z","timestamp":1777493699000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/0271678X241238845"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,4]]},"references-count":67,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2024,11]]}},"alternative-id":["10.1177\/0271678X241238845"],"URL":"https:\/\/doi.org\/10.1177\/0271678x241238845","relation":{},"ISSN":["0271-678X","1559-7016"],"issn-type":[{"value":"0271-678X","type":"print"},{"value":"1559-7016","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,4]]}}}