Local administration of WIN 55,212-2 reduces chronic granuloma-associated angiogenesis in rat by inhibiting NF-kappaB activation.
Chronic inflammation is often associated with granuloma formation that is a hallmark of many human diseases. The transcription factor nuclear factor-kappa B (NF-kappaB) plays a central role in this process by regulating the expression of several pro-inflammatory genes. Cannabinoids (CBs) from Cannabis sativa L. exert a large number of biological effects including anti-inflammatory and anti-angiogenic effects. In this study, we investigated the role of CBs on granuloma formation induced by lambda-carrageenin-soaked sponge implant in rat. Our results show that local administration of WIN 55,212-2, a CB(1)/CB(2) agonist, given daily or at time of implantation significantly decreased weight and neo-angiogenesis in granuloma tissue and inhibited nuclear factor-kappa B (NF-kappaB)/DNA binding that was associated with a reduced inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), tumor necrosis factor alpha (TNF-alpha), and vascular endothelial growth factor (VEGF) messenger RNA (mRNA) and protein expression. Also, arachidonyl-2-chloroethylamide (ACEA), a CB(1) selective agonist, and JWH-015, a CB(2) selective agonist, exhibited the same effects that were reversed by SR141716-A and SR144528, respectively, CB(1) and CB(2) selective antagonists. These results indicate that CBs given locally may represent a potential therapeutic tool in controlling chronic inflammation avoiding psychotropic effects.
De Filippis
Daniele
D
Dipartimento di Farmacologia Sperimentale, Università degli Studi di Napoli Federico II, Via D. Montesano 49, Napoli, 80131, Italy.
Russo
Annapina
A
De Stefano
Daniela
D
Maiuri
Maria Chiara
MC
Esposito
Giuseppe
G
Cinelli
Maria Pia
MP
Pietropaolo
Concetta
C
Carnuccio
Rosa
R
Russo
Giulia
G
Iuvone
Teresa
T
D000700:Analgesics / Q000008:administration & dosage* / Q000494:pharmacology*; D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage* / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D002351:Carrageenan / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006099:Granuloma / Q000473:pathology*; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D008297:Male; D009025:Morpholines / Q000008:administration & dosage* / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism*; D009281:Naphthalenes / Q000008:administration & dosage* / Q000494:pharmacology*; D009389:Neovascularization, Pathologic; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000700:Analgesics; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D009025:Morpholines; D016328:NF-kappa B; D009281:Naphthalenes; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D002351:Carrageenan