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 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 (vascular cell adhesion molecule-1 [VCAM-1] and intercellular adhesion molecule-1 [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 appeared most effective in reducing leukocyte adhesion to and migration across the BBB, although direct statistical comparisons between compounds were not performed.

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 mRNA 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. When administered before the inflammatory challenge, orally bioavailable CB2 receptor agonists prevented neuroinflammation-associated BBB dysfunction and leukocyte trafficking in both in vitro and in vivo models. Because all models were prevention paradigms, these data establish prophylactic rather than therapeutic efficacy.

They support further investigation of CB2 receptor agonists for the treatment of neurological diseases associated with neuroinflammation and BBB disruption. This work was supported in part by NIH research grants AA015913 (YP), MH1106967 (YP), MH65151 (YP), U01AA023552 (YP, PP) and NS101135 (SR), and the Intramural Research Program of NIH/NIAAA (to PP). The contributions of the NIH author(s) are considered Works of the United States Government.