“The endocannabinoid system(ECS) may play a role in the pathophysiology of systemic sclerosis (SSc). Cannabinoids actingas dual PPARγ/CB2agonists, such as VCE-004.8 and Ajulemic acid (AjA), havebeen shown to alleviate skin fibrosis and inflammation in SSc models. Since bothcompounds are being tested in humans, we compared their activities in the bleomycin(BLM) SSc model.Specifically, the pharmacotranscriptomicsignature of the compounds was determined by RNA-Seq changes in the skin of BLM mice treated orallywith AjA or EHP-101, a lipidicformulation of VCE-004.8. While both compounds down-regulatedthe expression of genes involved in the inflammatoryand fibrotic components of the disease and the pharmacotranscriptomicsignatures were similar for both compounds in some pathways, we found keydifferences between the compounds in vasculogenesis. Additionally, we found 28 specific genes withtranslation potential by comparing with a list of humanscleroderma genes. Immunohistochemical analysis revealed that both compounds prevented fibrosis, collagen accumulation andTenascin C (TNC) expression. Theendothelial CD31+/CD34+ cells and telocyteswere reduced in BLM mice and restored only byEHP-101 treatment. Finally, differences were found inplasmatic biomarker analysis; EHP-101, but not AjA, enhanced the expressionof some factors related to angiogenesisand vasculogenesis. Altogether the results indicate that dual PPARγ/CB2agonists qualify as a novel therapeutic approach for the treatment of SSc and other fibrotic diseases. EHP-101 demonstratedunique mechanisms of action related to the pathophysiology of SSc that could be beneficial in the treatment of this complex disease without current therapeutic options.”
https://www.ncbi.nlm.nih.gov/pubmed/30825431
https://www.sciencedirect.com/science/article/abs/pii/S0006295219300772?via%3Dihub