Potent Anti‐Inflammatory and Pro‐Resolving Effects of Anabasum in a Human Model of Self‐Resolving Acute Inflammation

Abstract

Anabasum is a synthetic analog of Δ8‐tetrahydrocannabinol (THC)‐11‐oic acid that in preclinical models of experimental inflammation exerts potent anti‐inflammatory actions with minimal central nervous system (CNS) cannabimimetic activity. Here we used a novel model of acute inflammation driven by i.d. UV‐killed E. coli in healthy humans and found that anabasum (5 mg) exerted a potent anti‐inflammatory effect equivalent to that of prednisolone in terms of inhibiting neutrophil infiltration, the hallmark of acute inflammation. These effects arose from the inhibition of the neutrophil chemoattractant LTB4, while the inhibition of antiphagocytic prostanoids (PGE2, TxB2, and PGF2α) resulted in enhanced clearance of inflammatory stimulus from the injected site. Anabasum at the higher dose of 20 mg possessed the additional properties of triggering the biosynthesis of specialized pro‐resolving lipid mediators including LXA4, LXB4, RvD1, and RvD3. Collectively, we demonstrate for the first time a striking anti‐inflammatory and pro‐resolution effects of a synthetic analog of THC in healthy humans.

A Guide to Targeting the Endocannabinoid System in Drug Design

“…Dual CB2/PPARγ agonists, JBT-101 (5 mg/kg), and EHP-101 (a lipidic formulation of VCE-004.8) (20 mg/kg) alleviated skin fibrosis in rodent models of systemic sclerosis (SSc). Moreover, JBT-101 (ajulemic acid, Lenabasum) (5-20 mg) was shown to exert anti-inflammatory action in a human skin inflammation study [209,210]. JBT-101 reached phase III or II clinical trials for several indications (see: Section 11.…”

Endocannabinoid receptor CB2R is significantly expressed in aspirin‐exacerbated respiratory disease: a pilot study

“…Findings included a significant reduction in pulmonary and systemic markers of inflammation after eCA activation in wild-type mice, a response that was not found in either CB1R –/– or CB2R –/– knockouts. Further, Motwani et al 20 examined a selective CB2R agonist in a human model of acute dermal inflammation and identified potent anti-inflammatory activity mediated by inhibition of the leukocyte chemoattractant leukotriene B4, and the antiphagocytic prostanoids PGE2, thromboxane B2, and prostaglandin F2α. The therapeutic potential of CB2R and other eCA modulators for recalcitrant airway inflammation in AERD deserves further study.…”

The Role of Specialized Pro-Resolving Mediators in Cystic Fibrosis Airways Disease

“…SPMs levels are significantly increased in inflammatory exudates in rheumatoid arthritis, skin blisters, bronchoalveolar lavage (BAL) fluids from patients with airway diseases ( Lee et al, 1990 ; Karp et al, 2004 ; Planagumà et al, 2008 ; Morris et al, 2009 ; Ringholz et al, 2014 ; Norling et al, 2016 ; Motwani et al, 2018a ; Motwani et al, 2018b ). However, SPMs levels are shown to be decreased and unbalanced compared to pro-inflammatory eicosanoids in patients with chronic conditions including airway diseases.…”

“…Lenabasum is an endocannabinoid-mimetic that selectively binds to cannabinoid receptor 2 expressed by immune cells, reducing alveolar macrophage secretion of IL-6 and TNFα in preclinical studies ( Ribeiro et al, 2017 ). Those immunomodulatory effects can be explained by lenabasum’s potential to induce SPMs production in animal models ( Zurier et al, 2009 ) and healthy human subjects ( Motwani et al, 2018a ). This last example showcases how treating chronic inflammation by mobilizing the body’s endogenous pro-resolving system rather than trying to stop one of the many triggers of an established and thriving inflammatory process may be the most inclusive and efficient way to treat inflammatory diseases in the future.…”