Molecular Mechanisms for the Inflammation-Resolving Actions of Lenabasum

Abstract

A first-in-class cannabinoid analog called lenabasum that is a CB2 agonist is being developed as an inflammation-resolving drug candidate. Thus far specific therapeutic targets include scleroderma, cystic fibrosis, dermatomyositis and lupus all of which represent unmet medical needs. Two somewhat independent molecular mechanisms for this type of action are here proposed. Both pathways initially involve the release of free arachidonic acid following activation of the CB2 receptor and PLA 2 by lenabasum. The pathways then diverge into a COX-2 mediated and a lipoxygenase mediated route. The former leads to increased levels of the cyclopentenone prostaglandin 15-deoxy-Δ 12,14-prostaglandin-J 2 that can activate the NLPR3 inflammasome, which, in turn releases caspase-3 leading to apoptosis and the resolution of chronic inflammation. The lipoxygenase mediated pathway stimulates the production of lipoxin A 4 as well as other signaling molecules called specialized pro-resolving mediators (SPMs). These also have inflammation-resolving actions. It is not well understood under which conditions each of these mechanisms operate and if there is cross-talk between them. Thus, much remains to be learned about the mechanisms describing the actions of lenabasum. Significance Statement. The resolution of chronic inflammation is a major unmet medical need. The synthetic non-psychoactive cannabinoid lenabasum could provide a safe and effective drug for this purpose. Two putative molecular mechanisms are suggested to better understand how lenabasum produces this action. In both different metabolites of arachidonic acid act as mediators.

Medicinal cannabis in the treatment of chronic pain

“…13 Notably, a CB2 receptor-preferring agonist, lenabasum, is currently in late-stage clinical trials for the treatment of various inflammatory autoimmune conditions and fibrosis. 19 CBD, in contrast to THC, does not directly activate CB1 receptors, and this explains its absence of intoxicating effects. 20 CBD interacts, however, with a range of ECS-related receptors, and enzymes, to produce an array of anticonvulsant, anxiolytic, antipsychotic, anti-inflammatory and possible analgesic effects.…”

Cannabinoids for the Treatment of Dermatologic Conditions

“…Lenabasum is a non-psychoactive synthetic cannabinoid that is a CB2 receptor agonist. Its therapeutic effects occur through modulation of the immune system and resolution of fibrosis, via two putative molecular mechanisms (Burstein, 2021). After CB2 receptor-and phospholipase A2 activation, free arachidonic acid enters one of two pathways: the cyclooxygenase-2 (COX-2)-or lipoxygenase-mediated pathway (Burstein, 2021).…”

“…Its therapeutic effects occur through the modulation of the immune system and resolution of fibrosis, through two putative molecular mechanisms ( Burstein, 2021 ). After CB2R and phospholipase A2 activation, free arachidonic acid enters one of two pathways: the cyclooxygenase-2– or lipoxygenase-mediated pathway ( Burstein, 2021 ). The cyclooxygenase-2 pathway facilitates caspase production and ultimately apoptosis and resolution of chronic inflammation, whereas the lipoxygenase pathway produces lipoxin A 4 and other proresolving mediators ( Burstein, 2021 ).…”

“…After CB2R and phospholipase A2 activation, free arachidonic acid enters one of two pathways: the cyclooxygenase-2– or lipoxygenase-mediated pathway ( Burstein, 2021 ). The cyclooxygenase-2 pathway facilitates caspase production and ultimately apoptosis and resolution of chronic inflammation, whereas the lipoxygenase pathway produces lipoxin A 4 and other proresolving mediators ( Burstein, 2021 ).…”

The Potential Use of Cannabis in Tissue Fibrosis

“…These effects were achieved by stimulating PPAR-γ signaling ( Gonzalez et al, 2012 ). Lenabasum has been shown to have an anti-inflammatory capacity by directly affecting both arachidonic acid pathways ( Burstein, 2021 ). Lenabasum was the only synthetic cannabinoid studied in human fibrotic diseases.…”