RESUMO
The classic model of fever induction is based on the administration of lipopolysaccharide (LPS) from Gram-negative bacteria in experimental animals. LPS-induced fever results in the synthesis/release of many mediators that assemble an LPS-fever cascade. We have previously demonstrated that cytokine-induced neutrophil chemoattractant (CINC)-1, a Glu-Leu-Arg (ELR) + chemokine, centrally administered to rats, induces fever and increases prostaglandin E2 in the cerebrospinal fluid. We now attempt to investigate the involvement of CINC-1 and its functional receptor CXCR2 on the fever induced by exogenous and endogenous pyrogens in rats. We also investigated the effect of reparixin, an allosteric inhibitor of CXCR1/CXCR2 receptors, on fever induced by either systemic administration of LPS or intracerebroventricular injection of CINC-1, as well as TNF-α, IL-1ß, IL-6, or ET-1, known mediators of febrile response. Our results show increased CINC-1 mRNA expression in the liver, hypothalamus, CSF, and plasma following LPS injection. Moreover, reparixin administered right before CINC-1 or LPS abolished the fever induced by CINC-1 and significantly reduced the response induced by LPS. In spite of these results, reparixin does not modify the fever induced by IL-1ß, TNF-α, and IL-6, but significantly reduces ET-1-induced fever. Therefore, it is plausible to suggest that CINC-1 might contribute to LPS-induced fever in rats by activating CXCR2 receptor on the CNS. Moreover, it can be hypothesized that CINC-1 is placed upstream TNF-α, IL-1ß, and IL-6 among the prostaglandin-dependent fever-mediator cascade and amidst the prostaglandin-independent synthesis pathway of fever.
Assuntos
Quimiocina CXCL1/metabolismo , Febre/induzido quimicamente , Febre/metabolismo , Lipopolissacarídeos/farmacologia , Receptores de Interleucina-8B/metabolismo , Animais , Líquido Cefalorraquidiano/efeitos dos fármacos , Líquido Cefalorraquidiano/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Prostaglandinas/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
ETHNOPHARMACOLOGY RELEVANCE: Hydro alcoholic leaves extracts (HALE) of Lychnophora ericoides Mart. ("false arnica" or "arnica-da-serra") had been popularly used against pain and inflammatory process. AIM: The present work aimed to look for possible active volatile compounds that could be found in HALE of Lychnophora ericoides among the non volatile anti-inflammatory and analgesic compounds previously reported. METHODS: Harvests were performed during the end of the wet summer season (April) when scented branches were instantly collected and frozen. HALE's were simulated at the lab by following the procedures lectured by the locals. Mass Spectrometry experiments suggested structural information when using both EI-MS and ESI-MS/MS. After isolation through classical thin layer chromatography (TLC) procedures, the NMR experiments and signals assignments were carried out. The effects on the cytokines or nitric oxide (NO) production were assessed at in vitro assays that had monitored the levels of these substances on the supernatant of LPS-stimulated macrophage primary cell culture. RESULTS: The major metabolite from HALE was isolated from the essential oil and the major compound had its molecular formulae established by Mass Spectrometry (High Resolution) and its structure by NMR. Literature-based investigation enables us to define the structure of the new metabolite as 6-methyl-2-(4-methylcyclohex-4-enyl-2-acetyloxy) hept-5-en-2-ol and its name as orto-acetoxy-bisabolol. In vitro assay of interleukins release inhibition was carried out using rat peritoneal macrophages cultures. IL-1ß and TNF-α levels were significantly reduced when cells were previously treated with low doses of orto-acetoxy-bisabolol, but neither IL-6 nor NO levels have their levels reduced. Results suggest that ethnical knowledge of anti-inflammatory and analgesic effects of the "arnica-da-serra" HALE may be associated to the orto-acetoxy-bisabolol ability on synthesis inhibition of the key inflammatory/hypernociceptive mediators. CONCLUSIONS: Phytochemical investigation of the volatile active compounds in Lychnophora ericoides HALE allows us to isolate a new bisabolane derivative (orto-acetoxy-bisabolol) and to infer that this compound inhibits the synthesis of TNF-α and IL-1ß, two important inflammatory mediators in the hypernociception. Our present data, in addition to literature's data, furnish scientific support to folk's use of Lychnophora ericoides as an endemic wound healer.
Assuntos
Anti-Inflamatórios/farmacologia , Asteraceae , Citocinas/metabolismo , Sesquiterpenos/farmacologia , Animais , Células Cultivadas , Lipopolissacarídeos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Óxido Nítrico/metabolismo , Óleos Voláteis/química , Extratos Vegetais/química , Folhas de Planta , Caules de Planta , Ratos , Ratos Wistar , Sesquiterpenos/isolamento & purificaçãoRESUMO
In this study we aimed at evaluating the effect of the major polar constituents of the medicinal plant Lychnophora ericoides on the production of inflammatory mediators produced by LPS-stimulated U-937 cells. The 6,8-di-C-beta-glucosylapigenin (vicenin-2) presented no effect on tumor necrosis factor (TNF)-alpha production, but inhibited, in a dose-dependent manner, the production of prostaglandin (PG) E2 without altering the expression of cyclooxygenase (COX)-2 protein. 3,5-Dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid, at lower concentrations, had small but significant effects on reducing PGE2 levels; at higher doses these compounds stimulated PGE2 and also TNF-alpha production by the cells. All the caffeoylquinic acid derivatives, in a dose-dependent fashion, were able to inhibit monocyte chemoattractant protein-3 synthesis/release, with 4,5-DCQ being the most potent at the highest tested concentration. These results add important information on the effects of plant natural polyphenols, namely vicenin-2 and caffeoylquinic acid derivatives, on the production of inflammatory mediators by cultured cells.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Asteraceae/química , Dinoprostona/metabolismo , Flavonoides/farmacologia , Mediadores da Inflamação/metabolismo , Extratos Vegetais/farmacologia , Ácido Quínico/análogos & derivados , Fator de Necrose Tumoral alfa/metabolismo , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Western Blotting , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimiocina CCL7/biossíntese , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Flavonoides/química , Flavonoides/isolamento & purificação , Humanos , Imunoensaio , Técnicas In Vitro , Extratos Vegetais/química , Ácido Quínico/química , Ácido Quínico/isolamento & purificação , Ácido Quínico/metabolismoRESUMO
Phenolic compounds are numerous and ubiquitous in the plant kingdom, being particularly present in health-promoting foods. Epidemiological evidences suggest that the consumption of polyphenol-rich foods reduces the incidence of cancer, coronary heart disease and inflammation. Chlorogenic acid (CGA) is one of the most abundant polyphenol compounds in human diet. Data obtained from in vivo and in vitro experiments show that CGA mostly presents antioxidant and anti-carcinogenic activities. However, the effects of CGA on the inflammatory reaction and on the related pain and fever processes have been explored less so far. Therefore, this study was designed to evaluate the anti-inflammatory, antinociceptive and antipyretic activities of CGA in rats. In comparison to control, CGA at doses 50 and 100 mg/kg inhibited carrageenin-induced paw edema beginning at the 2nd hour of the experimental procedure. Furthermore, at doses 50 and 100 mg/kg CGA also inhibited the number of flinches in the late phase of formalin-induced pain test. Such activities may be derived from the inhibitory action of CGA in the peripheral synthesis/release of inflammatory mediators involved in these responses. On the other hand, even at the highest tested dose (200 mg/kg), CGA did not inhibit the febrile response induced by lipopolysaccharide (LPS) in rats. Additional experiments are necessary in order to clarify the true target for the anti-inflammatory and analgesic effects of CGA.
Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Ácido Clorogênico/uso terapêutico , Flavonoides/uso terapêutico , Fenóis/uso terapêutico , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/química , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Carragenina/administração & dosagem , Carragenina/toxicidade , Ácido Clorogênico/administração & dosagem , Ácido Clorogênico/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Edema/induzido quimicamente , Edema/prevenção & controle , Febre/induzido quimicamente , Febre/prevenção & controle , Flavonoides/administração & dosagem , Flavonoides/química , Formaldeído/administração & dosagem , Formaldeído/toxicidade , Membro Posterior/efeitos dos fármacos , Membro Posterior/patologia , Membro Posterior/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/toxicidade , Masculino , Estrutura Molecular , Dor/induzido quimicamente , Dor/prevenção & controle , Fenóis/administração & dosagem , Fenóis/química , Polifenóis , Ratos , Ratos Wistar , Fatores de TempoRESUMO
The Brazilian medicinal plant Lychnophora ericoides Mart. (Asteraceae) has been used in traditional medicine to treat wounds, pain and inflammation. As part of our continuing investigation of this commercial phytomedicine, we focused on the polar fractions of the plant, since it is employed as alcoholic and hydroalcoholic preparations. The analgesic bioguided fractionation of the root polar extract yielded 3,5-di-O-[E]-caffeoylquinic acid, 4,5-di-O-[E]-caffeoylquinic acid and 3,4,5-tri-O-[E]-caffeoylquinic acid. The n-butanol fraction and the di-caffeoylquinic acids showed significant analgesic activity in the acetic acid-induced mouse writhing test at low but not at high doses. These findings support, at least in part, the validity of the use of Lychnophora ericoides roots in traditional medicine.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Arnica , Monossacarídeos/uso terapêutico , Dor/tratamento farmacológico , Ácido Quínico/análogos & derivados , Ácido Quínico/uso terapêutico , Ácido Acético , Animais , Anti-Inflamatórios não Esteroides/isolamento & purificação , Relação Dose-Resposta a Droga , Espectroscopia de Ressonância Magnética , Camundongos , Monossacarídeos/isolamento & purificação , Medição da Dor , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Raízes de Plantas/química , Ácido Quínico/isolamento & purificaçãoRESUMO
The ethyl acetate extract from leaves plus inflorescences of L. salicifolia showed significant trypanocidal activity against trypomastigote forms of T. cruzi, which was due to the flavonoid quercetin-7,3',4'-trimethyl ether and the sesquiterpenoid lychnopholic acid. Despite the use of some species of Lychnophora in folk medicine for pain relief, crude extracts from L. salicifolia Mart. showed no antinociceptive activity in the mouse writhing test.