Contrasting Cannabinoid Receptor 2 (CB2R)-Associated Responses in Two Different Cerebrovascular Endothelial Cell Lines in a Blood Brain Barrier Model in the Context of HIV.

Delorme-Walker V.; Au K.; Lim W.; Sasaki T.; Furihata T.; Lima D.; Grubbs N.; Castaneda J.; Kufareva I.; Iudicello J. et al. · Cells · 2026

**Background & Methods** This in vitro study employed a polycellular blood-brain barrier (BBB) model using two distinct human cerebrovascular endothelial cell lines (hCMEC/D3 and HBMEC/ci18) to evaluate cannabinoid receptor 2 (CB2R)-mediated effects on BBB integrity in the context of latent HIV infection, simulated by adding conditioned media from HIV-infected promonocytes. **Key Findings** - Both endothelial cell lines responded similarly to HIV-conditioned media by exhibiting increased dextran permeability and decreased tight junction protein expression; however, their responses to cannabinoids via CB2R were markedly divergent, with hCMEC/D3 cells demonstrating improved BBB integrity across all measures while HBMEC/ci18 cells showed no benefit or worsening of damage. - CB2R-elicited baseline G protein-coupled receptor (GPCR) response thresholds differed significantly between cell lines, with forskolin-induced cAMP levels 50-200-fold higher in hCMEC/D3 compared to HBMEC/ci18, correlating with higher baseline CB2R expression in hCMEC/D3 cells and independent of HIV-induced signaling defects. - CBD/THC-induced phosphorylation of p38 MAPK was substantially stronger in hCMEC/D3 cells and was blocked by a CB2R inverse agonist/antagonist, suggesting CB2R mechanistic involvement in differential cannabinoid responses between cell lines. **Dosage & Administration** Not reported. Study used cannabinoid compounds (CBD/THC) in an in vitro system without specified concentrations or exposure parameters provided in the abstract. **Safety & Adverse Effects** Not reported. The study did not identify safety concerns in either cell line; however, HBMEC/ci18 cells showed aggravation of BBB damage with cannabinoid exposure in the HIV context, indicating potential cell type-dependent adverse effects requiring further investigation. **Evidence Quality** This is an in vitro mechanistic study with significant limitations regarding clinical applicability. Findings are restricted to two specific endothelial cell lines and do not reflect the complexity of the intact BBB or systemic cannabinoid pharmacokinetics. The authors acknowledge the need for validation in primary cells, animal models, and clinical cohorts. The identified biomarkers (CB2R expression and GPCR activation thresholds) are proposed as candidates but remain unvalidated predictors of clinical response.

More recent cannabis research