Orally bioavailable CB2 receptor agonists attenuate neuroinflammation and stabilize the blood–brain barrier

Background Neuroinflammation and blood–brain barrier (BBB) dysfunction are key contributors to the pathogenesis of many neurological disorders. Cannabinoid receptor 2 (CB ₂ ) 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 ₂ receptor agonists on leukocyte–endothelial interactions and BBB function using in vitro and in vivo models of neuroinflammation. Methods Novel CB ₂ 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 in vivo . 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. Results Among the compounds tested, RO6839828 and HU-910 demonstrated the greatest efficacy in reducing leukocyte adhesion to and migration across the BBB. CB ₂ receptor agonists significantly attenuated BBB hyperpermeability in LPS-treated mice and improved endothelial barrier integrity in vitro , as reflected by increased TEER values. Treatment also reduced cytokine release and decreased expression of VCAM-1 and ICAM-1. In addition, CB ₂ 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 in vitro . Conclusions Novel orally bioavailable CB ₂ receptor agonists reduced neuroinflammation-associated BBB dysfunction and leukocyte trafficking in both in vitro and in vivo models. These findings support the therapeutic potential of CB ₂ receptor agonists for the treatment of neurological diseases associated with neuroinflammation and BBB disruption.