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

Neuroinflammation and blood-brain barrier (BBB) dysfunction are key contributors to the pathogenesis of many neurological disorders. Cannabinoid receptor 2 (CB₂) agonists possess anti-inflammatory properties and may represent promising therapeutic agents for preserving BBB integrity. This study evaluated the effects of novel orally bioavailable CB₂ receptor agonists on leukocyte-endothelial interactions and BBB function using in vitro and in vivo models of neuroinflammation.

Novel CB₂ 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.

Among the compounds tested, RO6839828 and HU-910 demonstrated the greatest efficacy in reducing leukocyte adhesion to and migration across the BBB. CB₂ 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, CB₂ 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.

Novel orally bioavailable CB₂ 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 CB₂ receptor agonists for the treatment of neurological diseases associated with neuroinflammation and BBB disruption.