Cannabinoid derivatives acting as dual PPARγ/CB2 agonists as therapeutic agents for systemic sclerosis

Biochem Pharmacol. 2019 May;163:321-334. doi: 10.1016/j.bcp.2019.02.029. Epub 2019 Feb 27.


The endocannabinoid system (ECS) may play a role in the pathophysiology of systemic sclerosis (SSc). Cannabinoids acting as dual PPARγ/CB2 agonists, such as VCE-004.8 and Ajulemic acid (AjA), have been shown to alleviate skin fibrosis and inflammation in SSc models. Since both compounds are being tested in humans, we compared their activities in the bleomycin (BLM) SSc model. Specifically, the pharmacotranscriptomic signature of the compounds was determined by RNA-Seq changes in the skin of BLM mice treated orally with AjA or EHP-101, a lipidic formulation of VCE-004.8. While both compounds down-regulated the expression of genes involved in the inflammatory and fibrotic components of the disease and the pharmacotranscriptomic signatures were similar for both compounds in some pathways, we found key differences between the compounds in vasculogenesis. Additionally, we found 28 specific genes with translation potential by comparing with a list of human scleroderma genes. Immunohistochemical analysis revealed that both compounds prevented fibrosis, collagen accumulation and Tenascin C (TNC) expression. The endothelial CD31+/CD34+ cells and telocytes were reduced in BLM mice and restored only by EHP-101 treatment. Finally, differences were found in plasmatic biomarker analysis; EHP-101, but not AjA, enhanced the expression of some factors related to angiogenesis and vasculogenesis. Altogether the results indicate that dual PPARγ/CB2 agonists qualify as a novel therapeutic approach for the treatment of SSc and other fibrotic diseases. EHP-101 demonstrated unique mechanisms of action related to the pathophysiology of SSc that could be beneficial in the treatment of this complex disease without current therapeutic options.

Keywords: Bleomycin; Cannabinoids; Inflammation; Systemic fibrosis; Transcriptomic signature; Vasculopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Bleomycin / toxicity
  • Cannabinoids / pharmacology*
  • Dronabinol / administration & dosage
  • Dronabinol / analogs & derivatives*
  • Dronabinol / pharmacology
  • Female
  • Fibrosis / chemically induced
  • Gene Expression Regulation / drug effects*
  • Hydroquinones / administration & dosage
  • Hydroquinones / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • PPAR gamma / agonists*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Pulmonary Fibrosis
  • Receptor, Cannabinoid, CB2 / agonists*
  • Receptor, Cannabinoid, CB2 / genetics
  • Receptor, Cannabinoid, CB2 / metabolism
  • Scleroderma, Systemic / drug therapy*
  • Skin / drug effects
  • Skin / pathology


  • Biomarkers
  • Cannabinoids
  • Hydroquinones
  • PPAR gamma
  • Receptor, Cannabinoid, CB2
  • Bleomycin
  • Dronabinol
  • ajulemic acid