{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T16:28:42Z","timestamp":1786984122887,"version":"build-2736575974"},"posted":{"date-parts":[[2026,6,3]]},"group-title":"In Review","reference-count":0,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,13]]},"abstract":"<title>Abstract<\/title>\n                <p>\n                  Background\n Neuroinflammation and blood\u2013brain barrier (BBB) dysfunction are key contributors to the pathogenesis of many neurological disorders. Cannabinoid receptor 2 (CB\n                  <sub>2<\/sub>\n                  ) agonists possess anti-inflammatory properties and may represent promising therapeutic agents for preserving BBB integrity. This study evaluated the effects of novel orally bioavailable CB\n                  <sub>2<\/sub>\n                  receptor agonists on leukocyte\u2013endothelial interactions and BBB function using\n                  <italic>in vitro<\/italic>\n                  and\n                  <italic>in vivo<\/italic>\n                  models of neuroinflammation.\nMethods\n Novel CB\n                  <sub>2<\/sub>\n                  receptor agonists were tested in an aseptic localized encephalitis mouse model and in a lipopolysaccharide (LPS)-induced systemic inflammatory response model. Leukocyte adhesion and migration within cerebral microvessels were assessed\n                  <italic>in vivo<\/italic>\n                  . BBB permeability was evaluated in LPS-treated mice, while barrier integrity was measured in primary human brain microvascular endothelial cells (BMVECs) using transendothelial electrical resistance (TEER). Cytokine release, adhesion molecule expression (VCAM-1 and ICAM-1), and inflammatory gene expression in isolated cerebral microvessels were also analyzed. Statistical significance was determined using comparative analyses between treatment and control groups.\nResults\n Among the compounds tested, RO6839828 and HU-910 demonstrated the greatest efficacy in reducing leukocyte adhesion to and migration across the BBB. CB\n                  <sub>2<\/sub>\n                  receptor agonists significantly attenuated BBB hyperpermeability in LPS-treated mice and improved endothelial barrier integrity\n                  <italic>in vitro<\/italic>\n                  , as reflected by increased TEER values. Treatment also reduced cytokine release and decreased expression of VCAM-1 and ICAM-1. In addition, CB\n                  <sub>2<\/sub>\n                  agonists attenuated dysregulation of multiple inflammation- and endothelial injury-related genes in cerebral microvessels isolated from LPS-treated mice. Pre-treatment of either BMVECs or primary human monocytes reduced monocyte adhesion to and transmigration across endothelial monolayers\n                  <italic>in vitro<\/italic>\n                  .\nConclusions\n Novel orally bioavailable CB\n                  <sub>2<\/sub>\n                  receptor agonists reduced neuroinflammation-associated BBB dysfunction and leukocyte trafficking in both\n                  <italic>in vitro<\/italic>\n                  and\n                  <italic>in vivo<\/italic>\n                  models. These findings support the therapeutic potential of CB\n                  <sub>2<\/sub>\n                  receptor agonists for the treatment of neurological diseases associated with neuroinflammation and BBB disruption.\n                <\/p>","DOI":"10.21203\/rs.3.rs-9705876\/v1","type":"posted-content","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T10:31:16Z","timestamp":1780482676000},"source":"Crossref","is-referenced-by-count":0,"title":["Orally bioavailable CB2 receptor agonists attenuate neuroinflammation and stabilize the blood\u2013brain barrier"],"prefix":"10.21203","author":[{"given":"Slava","family":"Rom","sequence":"first","affiliation":[{"name":"Temple University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana","family":"Zuluaga-Ramirez","sequence":"additional","affiliation":[{"name":"Temple University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachin","family":"Gaghate","sequence":"additional","affiliation":[{"name":"Temple University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Grether","sequence":"additional","affiliation":[{"name":"Roche (Switzerland)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Guba","sequence":"additional","affiliation":[{"name":"Roche (Switzerland)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy L.","family":"Reichenbach","sequence":"additional","affiliation":[{"name":"Temple University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario Van der","family":"Stelt","sequence":"additional","affiliation":[{"name":"Leiden University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Ullmer","sequence":"additional","affiliation":[{"name":"Roche (Switzerland)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pal","family":"Pacher","sequence":"additional","affiliation":[{"name":"National Institute on Alcohol Abuse and Alcoholism"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri","family":"Persidsky","sequence":"additional","affiliation":[{"name":"Temple University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/www.researchsquare.com\/article\/rs-9705876\/v1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.researchsquare.com\/article\/rs-9705876\/v1.html","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T15:42:54Z","timestamp":1786981374000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.researchsquare.com\/article\/rs-9705876\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,3]]},"references-count":0,"URL":"https:\/\/doi.org\/10.21203\/rs.3.rs-9705876\/v1","relation":{},"subject":[],"published":{"date-parts":[[2026,6,3]]},"subtype":"preprint"}}