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3.
Br J Pharmacol ; 172(1): 142-58, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25205418

RESUMO

BACKGROUND AND PURPOSE: Palmitoylethanolamide (PEA) acts via several targets, including cannabinoid CB1 and CB2 receptors, transient receptor potential vanilloid type-1 (TRPV1) ion channels, peroxisome proliferator-activated receptor alpha (PPAR α) and orphan G protein-coupled receptor 55 (GRR55), all involved in the control of intestinal inflammation. Here, we investigated the effect of PEA in a murine model of colitis. EXPERIMENTAL APPROACH: Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS). Inflammation was assessed by evaluating inflammatory markers/parameters and by histology; intestinal permeability by a fluorescent method; colonic cell proliferation by immunohistochemistry; PEA and endocannabinoid levels by liquid chromatography mass spectrometry; receptor and enzyme mRNA expression by quantitative RT-PCR. KEY RESULTS: DNBS administration caused inflammatory damage, increased colonic levels of PEA and endocannabinoids, down-regulation of mRNA for TRPV1 and GPR55 but no changes in mRNA for CB1 , CB2 and PPARα. Exogenous PEA (i.p. and/or p.o., 1 mg·kg(-1) ) attenuated inflammation and intestinal permeability, stimulated colonic cell proliferation, and increased colonic TRPV1 and CB1 receptor expression. The anti-inflammatory effect of PEA was attenuated or abolished by CB2 receptor, GPR55 or PPARα antagonists and further increased by the TRPV1 antagonist capsazepine. CONCLUSIONS AND IMPLICATIONS: PEA improves murine experimental colitis, the effect being mediated by CB2 receptors, GPR55 and PPARα, and modulated by TRPV1 channels.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/tratamento farmacológico , Etanolaminas/uso terapêutico , Ácidos Palmíticos/uso terapêutico , Administração Oral , Amidas , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Benzenossulfonatos , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Modelos Animais de Doenças , Endocanabinoides/metabolismo , Etanolaminas/administração & dosagem , Etanolaminas/farmacocinética , Etanolaminas/farmacologia , Absorção Intestinal/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Ácidos Oleicos/metabolismo , PPAR alfa/genética , Ácidos Palmíticos/administração & dosagem , Ácidos Palmíticos/farmacocinética , Ácidos Palmíticos/farmacologia , Peroxidase/metabolismo , RNA Mensageiro/metabolismo , Receptor CB1 de Canabinoide/genética , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/genética , Receptores de Canabinoides/genética , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/genética
4.
Biochem Pharmacol ; 85(9): 1306-16, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23415610

RESUMO

Inflammatory bowel disease (IBD) is an incurable disease which affects millions of people in industrialized countries. Anecdotal and scientific evidence suggests that Cannabis use may have a positive impact in IBD patients. Here, we investigated the effect of cannabigerol (CBG), a non-psychotropic Cannabis-derived cannabinoid, in a murine model of colitis. Colitis was induced in mice by intracolonic administration of dinitrobenzene sulphonic acid (DNBS). Inflammation was assessed by evaluating inflammatory markers/parameters (colon weight/colon length ratio and myeloperoxidase activity), by histological analysis and immunohistochemistry; interleukin-1ß, interleukin-10 and interferon-γ levels by ELISA, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) by western blot and RT-PCR; CuZn-superoxide dismutase (SOD) activity by a colorimetric assay. Murine macrophages and intestinal epithelial cells were used to evaluate the effect of CBG on nitric oxide production and oxidative stress, respectively. CBG reduced colon weight/colon length ratio, myeloperoxidase activity, and iNOS expression, increased SOD activity and normalized interleukin-1ß, interleukin-10 and interferon-γ changes associated to DNBS administration. In macrophages, CBG reduced nitric oxide production and iNOS protein (but not mRNA) expression. Rimonabant (a CB1 receptor antagonist) did not change the effect of CBG on nitric oxide production, while SR144528 (a CB2 receptor antagonist) further increased the inhibitory effect of CBG on nitric oxide production. In conclusion, CBG attenuated murine colitis, reduced nitric oxide production in macrophages (effect being modulated by the CB2 receptor) and reduced ROS formation in intestinal epithelial cells. CBG could be considered for clinical experimentation in IBD patients.


Assuntos
Anti-Inflamatórios/farmacologia , Canabinoides/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Canabinoides/uso terapêutico , Linhagem Celular , Colite/tratamento farmacológico , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Ciclo-Oxigenase 2/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Doenças Inflamatórias Intestinais/patologia , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Antígeno Ki-67/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico Sintase Tipo II/metabolismo , Permeabilidade , Peroxidase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Superóxido Dismutase/metabolismo
5.
Rare Tumors ; 1(2): e41, 2009 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-21139920

RESUMO

We describe the clinicopathological and morphological features of an unusual breast carcinoma classifiable as a lipid-rich variant of ductal invasive carcinoma, with a basal-type immunohistochemical profile. Basal-type breast cancers show no hormonal receptor expression, rarely over-express HER-2 but exhibit molecular high weight cytokeratins, EGFR and c-kit positivity. Special stains and histochemistry tests were used to elucidate the nature of vescicles in the neoplastic cells. Sudan IV was performed on formalin-fixed tissue. Commercially available antibodies tested were: ER, PgR, EGFR, HER2, c-kit, high molecular weight cytokeratins. Cytoplasmic lipids were highlighted as red-orange droplets on Sudan IV staining. As for immunohistochemistry, the tumor showed no reactivity to ER, PgR and HER2 (triple negative), and diffuse and strong positivity to high weight cytokeratins, EGFR and c-kit, such as a basal-type breast carcinoma. A basaloid phenotype in a lipid-rich carcinoma has not been previously reported.

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