CB2 receptor‐selective agonists as candidates for targeting infection, inflammation, and immunity in SARS‐CoV‐2 infections

Abstract

The COVID‐19 pandemic caused by SARS‐CoV‐2 is a deadly disease afflicting millions. The pandemic continues affecting population due to nonavailability of drugs and vaccines. The pathogenesis and complications of infection mainly involve hyperimmune‐inflammatory responses. Thus, therapeutic strategies rely on repurposing of drugs aimed at reducing infectivity and inflammation and modulate immunity favourably. Among, numerous therapeutic targets, the endocannabinoid system, particularly activation of cannabinoid type‐2 receptors (CB2R) emerged as an important one to suppress the hyperimmune‐inflammatory responses. Recently, potent antiinflammatory, antiviral and immunomodulatory properties of CB2R selective ligands of endogenous, plant, and synthetic origin were showed mediating CB2R selective functional agonism. CB2R activation appears to regulate numerous signaling pathways to control immune‐inflammatory mediators including cytokines, chemokines, adhesion molecules, prostanoids, and eicosanoids. Many CB2R ligands also exhibit off‐target effects mediating activation of PPARs, opioids, and TRPV, suggestive of adjuvant use with existing drugs that may maximize efficacy synergistically and minimize therapeutic doses to limit adverse/ side effects. We hypothesize that CB2R agonists, due to immunomodulatory, antiinflammatory, and antiviral properties may show activity against COVID‐19. Based on the organoprotective potential, relative safety, lack of psychotropic effects, and druggable properties, CB2R selective ligands might make available promising candidates for further investigation.

Use of Antioxidants for the Neuro-Therapeutic Management of COVID-19

“…Other proposed candidates as neuroprotectors in patients with COVID-19 for their antioxidant capacity are: salicyl-carnosine [ 288 ], molecular hydrogen [ 224 ], cannabinoid type-2 receptor-selective agonists [ 289 ], propolis [ 290 ], thymoquinone, nigellidine, and α-hederin [ 291 ], agomelatine [ 292 ], and ozone [ 293 ].…”

Cannabinoid Type-2 Receptor Agonist, JWH133 May Be a Possible Candidate for Targeting Infection, Inflammation, and Immunity in COVID-19

“…In present manuscript, the possible therapeutic role of JWH133 in COVID-19 has been proposed based on the previously reported potent pharmacological activity of JWH133 against infection, inflammation, and immunity in experimental models of human diseases involving dysregulated immune-inflammatory and redox homeostasis. Many authors proposed the hypotheses that CB2R, an important constituent in endocannabinoid system may play role in maintaining immune system and targeting inflammation and infection [18,21,140]. A recent report suggests that CB2R may play role in targeting the trinity of infection, inflammation and immune dysregulation [18,21].…”

“…Many authors proposed the hypotheses that CB2R, an important constituent in endocannabinoid system may play role in maintaining immune system and targeting inflammation and infection [18,21,140]. A recent report suggests that CB2R may play role in targeting the trinity of infection, inflammation and immune dysregulation [18,21]. Given the possible role of CB2R activation in attenuating inflammation, viral replication and favorably modulating immune systems, it has been speculated that JWH133 endowed with CB2 selective agonist property and showing affinity to M pro may be a candidate for further investigation for its possible use in management of COVID-19.…”

“…The roles of cannabinoids are well explored for their antiviral, anti-inflammatory, and immunomodulatory properties [8,19,20] and gaining attention for their candidature for potential in COVID-19 [21]. It has become apparent that agents that have antiviral, anti-inflammatory and immunomodulatory properties altogether could be important in context of COVID-19 to target the trinity of infection, inflammation and immunity.…”

The Endocannabinoid System as Prognostic Biomarker of the Obstructive Sleep Apnea Morbidity in COVID-19-Recovered Individuals

“…Although the role of the endocannabinoid system in the sleep control has been studied in recent years, there are several gaps that will require further focus, including the characterization of the molecular mechanisms of action by which the endocannabinoids regulate the neurobiological networks linked to the sleep disturbances. Moreover, the lack of evidence suggesting the disruption of the functioning of the endocannabinoid system either during the SARS-CoV-2 infection or after recovery of COVID-19 is limited; however, recent evidence has suggested a likely involvement of the CB 2 cannabinoid receptor and COVID-19 [ 63 – 66 ]. Whether additional members of the endocannabinoid system, such as AEA, 2-AG, or FAAH, FAAH, DAGL, MAGL and, AMT, might be affected in post-COVID-19 disease, remains to be determined.…”