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 after activation of the
CB2 receptor and
phospholipase A2 by
lenabasum. The pathways then diverge into a
cyclooxygenase 2-mediated and a
lipoxygenase-mediated route. The former leads to increased levels of the
cyclopentenone prostaglandin 15-deoxy-Δ12,14-prostaglandin-J2 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 A4 as well as other signaling molecules called specialized proresolving mediators. These also have
inflammation-resolving actions. It is not well understood under which conditions each of these mechanisms operates and whether there is crosstalk 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 nonpsychoactive
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.