title: Evaluation of selective cannabinoid CB(1) and CB(2) receptor agonists in a mouse model of lipopolysaccharide-induced interstitial cystitis.
abstract: Interstitial cystitis is a debilitating bladder inflammation disorder. To date, the understanding of the causes of interstitial cystitis remains largely fragmentary and there is no effective treatment available. Recent experimental results have shown a functional role of the endocannabinoid system in urinary bladder. In this study, we evaluated the anti-inflammatory effect of selective cannabinoid CB1 and CB2 receptor agonists in a mouse model of interstitial cystitis. Bladder inflammation was induced in mice by lipopolysaccharide (LPS) and whole bladders were removed 24h later. LPS induced a significant increase of the contractile amplitude in spontaneous activity and a hypersensitivity to exogenous acetylcholine-induced contraction of whole-isolated bladder. Next, we evaluated the anti-inflammatory activity of cannabinoidergic compounds by pretreating mice with CB1 or CB2 selective agonist compounds, respectively ACEA and JWH015. Interestingly, JWH015, but not ACEA, antagonized LPS-induced bladder inflammation. Additionally, anti-inflammatory activity was studied by evaluation, leukocytes mucosa infiltration, myeloperoxidase activity, and mRNA expression of pro-inflammatory interleukin (IL-1α and IL-1β), tumor necrosis factor-alpha (TNF-α) and cannabinoid CB1 and CB2 receptors. JWH015 significantly decreased leukocytes infiltration in both submucosa and mucosa, as well as the myeloperoxydase activity, in LPS treated mice. JWH015 reduced mRNA expression of IL-1α, IL-1β, and TNF-α. LPS treatment increased expression of bladder CB2 but not CB1 mRNA. Taken together, these findings strongly suggest that modulation of the cannabinoid CB2 receptors might be a promising therapeutic strategy for the treatment of bladder diseases and conditions characterized by inflammation, such as interstitial cystitis.
authors.affiliation: Neuroscienze PharmaNess S.c.a r.l., Edificio 5, Loc. Piscinamanna, 09010 Pula, CA, Italy; Department of Pharmacology & Toxicology, School of Pharmacy, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS, USA. Electronic address: simone.tambaro@pharmaness.com.
authors.forename: Simone
authors.initials: S
authors.lastname: Tambaro
authors.affiliation: CNR, Istituto di Farmacologia Traslazionale, UOS Cagliari, Edificio 5, Loc. Piscinamanna, 09010 Pula, CA, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Casu
authors.affiliation: CNR, Istituto di Farmacologia Traslazionale, UOS Cagliari, Edificio 5, Loc. Piscinamanna, 09010 Pula, CA, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mastinu
authors.affiliation: Neuroscienze PharmaNess S.c.a r.l., Edificio 5, Loc. Piscinamanna, 09010 Pula, CA, Italy; Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via F.Muroni 23/A, 07100 Sassari, SS, Italy; KemoTech Srl, Edificio 3, Loc. Piscinamanna, 09010 Pula, CA, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Lazzari
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D002186:Cannabinoids / Q000494:pharmacology / Q000627:therapeutic use; D018856:Cystitis, Interstitial / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D009924:Organ Culture Techniques; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000502:physiology; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000502:physiology
chemical_list: D001095:Arachidonic Acids; D002186:Cannabinoids; D007211:Indoles; D008070:Lipopolysaccharides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C119325:arachidonyl-2-chloroethylamide; C402944:JHW 015
keywords: ACEA (PubChem CID: 4273744); AM630 (PubChem CID: 4302963); Acetylcholine (PubChem CID: 6060); Intestitial cystitis; Isolated bladder assay; JWH015; JWH015 (PubChem CID: 5311066); Leukocytes infiltration; Mast cells; Myeloperoxidase activity