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1.
Inflammopharmacology ; 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32141011

RESUMO

Evidence demonstrates the pronounced anti-inflammatory activity of a beetroot (Beta vulgaris) dye enriched in betalains obtained using precipitation with ethanol. Herein, we expand upon our previous observations and demonstrate the analgesic and antioxidant effect of betalains. Betalains [10-1000 mg/kg; intraperitoneal route (i.p.)] diminished acetic acid- and PBQ-induced abdominal contortions, and the overt pain-like behaviour induced by complete Freund`s adjuvant (CFA) and formalin (intraplantar; i.pl.) injection. Moreover, betalains (100 mg/kg) administered by various routes [i.p. or subcutaneous (s.c.)] or as a post-treatment reduced carrageenin- or CFA-induced hyperalgesia. Mechanistically, betalains mitigated carrageenin-induced tumour necrosis factor-alpha (TNF-α), interleukin (IL)-1ß, superoxide anion levels, and lipid peroxidation. Betalains also stopped the depletion of reduced glutathione (GSH) levels and ferric reducing ability produced by carrageenin, as well as upregulated Nrf2 and Ho1 transcript expression in the plantar tissue of mice. Furthermore, betalains showed hydroxyl radical, 2,2'-azino-di-(3-ethylbenzthiazoline-6-sulphonic acid) radical (ABTS+), and 2,2-diphenyl-1-picryl-hydrazyl radical (DPPH•) scavenging ability and iron-chelating activity (bathophenantroline assay), and inhibited iron-independent and iron-dependent lipid peroxidation (LPO) in vitro. Finally, betalains-treated bone marrow-derived macrophages exhibited lower levels of cytokines (TNF-α and IL-1ß), and superoxide anion levels and nuclear factor kappa B (NF-κB) activation following lipopolysaccharide (LPS) stimulation. Therefore, this betalain-rich dye extracted using a novel precipitation approach presents prominent analgesic effect in varied models of pain by mechanisms targeting cytokines and oxidative stress.

2.
Front Pharmacol ; 9: 1076, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319413

RESUMO

Background: Gout is the most common inflammatory arthritis worldwide. It is a painful inflammatory disease induced by the deposition of monosodium urate (MSU) crystals in the joints and peri-articular tissues. Sesquiterpene lactones (SLs) are secondary metabolite biosynthesized mainly by species from the family Asteraceae. It has been demonstrated that SLs present anti-inflammatory, analgesic, antitumoral, antiparasitic, and antimicrobial activities. In this study, we aimed at evaluating the efficacy of the SL budlein A in a model of acute gout arthritis in mice. Methods: Experiments were conducted in male Swiss or male LysM-eGFP mice. Animals were treated with budlein A (1 or 10 mg/kg) or vehicle 30 min before stimulus with MSU (100 µg/10 µL, intra-articular). Knee joint withdrawal threshold and edema were evaluated using electronic von Frey and caliper, respectively, 1-15 h after MSU injection. Leukocyte recruitment was determined by counting cells (Neubauer chamber), H&E staining, and using LysM-eGFP mice by confocal microscopy. Inflammasome components, Il-1ß, and Tnf-α mRNA expression were determined by RT-qPCR. IL-1ß and TNF-α production (in vitro) and NF-κB activation (in vitro and in vivo) were evaluated by ELISA. In vitro analysis using LPS-primed bone marrow-derived macrophages (BMDMs) was performed 5 h after stimulation with MSU crystals. For these experiments, BMDMs were either treated or pre-treated with budlein A at concentrations of 1, 3, or 10 µg/mL. Results: We demonstrated that budlein A reduced mechanical hypersensitivity and knee joint edema. Moreover, it reduced neutrophil recruitment, phagocytosis of MSU crystals by neutrophils, and Il-1ß and Tnf-α mRNA expression in the knee joint. In vitro, budlein A decreased TNF-α production, which might be related to the inhibition of NF-κB activation. Furthermore, budlein A also reduced the IL-1ß maturation, possibly by targeting inflammasome assembly in macrophages. Conclusion: Budlein A reduced pain and inflammation in a model of acute gout arthritis in mice. Therefore, it is likely that molecules with the ability of targeting NF-κB activation and inflammasome assembly, such as budlein A, are interesting approaches to treat gout flares.

3.
Biomed Pharmacother ; 102: 175-184, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29554596

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by articular lesions, recruitment of inflammatory cells and increased levels of pro-inflammatory cytokine. The intra-articular administration of zymosan is an experimental model that promotes inflammatory parameters resembling RA. Therefore, this model was used to investigate the efficacy of quercetin as a treatment of articular inflammation. Treatment with quercetin dose-dependently reduced zymosan-induced hyperalgesia, articular edema and the recruitment of neutrophils to the knee joint cavity. Histological analysis confirmed that quercetin inhibited zymosan-induced arthritis. The treatment with quercetin also inhibited zymosan-induced depletion of reduced glutathione (GSH) levels, TNFα and IL-1ß production, and gp91phox, prepro-endothelin-1 (preproET-1), and cyclooxygenase-2 mRNA expression. These molecular effects of quercetin were related to the inhibition of the nuclear factor kappa-B and induction of Nuclear factor erythroid 2- related factor (Nrf2)/home oxygenase (HO-1) pathway. Thus, quercetin exerted anti-inflammatory, analgesic and antioxidant effects in experimental arthritis, suggesting quercetin is a possible candidate for arthritis treatment.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Artrite Experimental/prevenção & controle , Artrite Reumatoide/prevenção & controle , Quercetina/uso terapêutico , Animais , Antioxidantes/administração & dosagem , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Relação Dose-Resposta a Droga , Heme Oxigenase-1/biossíntese , Masculino , Proteínas de Membrana/biossíntese , Camundongos , Fator 2 Relacionado a NF-E2/biossíntese , Quercetina/administração & dosagem , Transdução de Sinais , Zimosan
5.
Inflammation ; 40(6): 2020-2032, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28780730

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by debilitating pain, cartilage destruction, and loss of joint function. Management of RA includes drugs that target NF-κB and downstream cytokine production. Therefore, molecules that act by inhibiting this signaling pathway without the severe side effects of, for instance, corticoids would be suitable therapeutic strategies. Budlein A is a sesquiterpene lactone with antinociceptive and anti-inflammatory properties related to the inhibition of pro-inflammatory cytokines and neutrophil recruitment. In this study, the effect of budlein A was evaluated in antigen-induced arthritis (AIA) in mice. At the 26th day, leukocyte recruitment to the knee joint, knee contents of proteoglycans, blood levels of ALT and AST, stomach tissue myeloperoxidase activity, and RT-qPCR for pro-inflammatory gene mRNA expression in knee joint samples was performed. NF-κB luciferase activity was evaluated in RAW 264.7 macrophages. Budlein A treatment dose-dependently inhibited AIA-induced mechanical hyperalgesia, edema, total leukocytes and neutrophil recruitment, and proteoglycan degradation. Budlein A did not induce gastric or liver damage. Budlein also inhibited AIA-induced Il-33, Tnf, Il-1ß, preproET-1, and Cox-2 mRNA expression. In vitro, budlein reduced TNF- and IL-1ß-induced NF-κB activity in RAW 264.7 macrophages. Altogether, we demonstrate that budlein A ameliorates AIA-induced inflammation and pain by targeting NF-κB. Importantly, budlein A does not induce in vivo side effects, suggesting that it possesses a favorable pre-clinical profile as analgesic and it is a prosperous molecule to be further investigated for the treatment of RA.


Assuntos
Artrite Experimental/tratamento farmacológico , Lactonas/farmacologia , Sesquiterpenos/farmacologia , Animais , Antígenos/efeitos adversos , Artrite Experimental/induzido quimicamente , Citocinas/efeitos dos fármacos , Inflamação/prevenção & controle , Camundongos , NF-kappa B/antagonistas & inibidores , Dor/prevenção & controle , Células RAW 264.7
6.
Biomed Res Int ; 2017: 9584819, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28589150

RESUMO

The present study evaluated the anti-inflammatory and analgesic effects of the superoxide dismutase mimetic agent tempol in superoxide anion-induced pain and inflammation. Mice were treated intraperitoneally with tempol (10-100 mg/kg) 40 min before the intraplantar injection of a superoxide anion donor, potassium superoxide (KO2, 30 µg). Mechanical hyperalgesia and thermal hyperalgesia, paw edema, and mRNA expression of peripheral and spinal cord mediators involved in inflammatory pain, TNFα, IL-1ß, IL-10, COX-2, preproET-1, gp91phox, Nrf2, GFAP, and Iba-1, were evaluated. Peripheral and spinal cord reductions of antioxidant defenses and superoxide anion were also assessed. Tempol reduced KO2-induced mechanical hyperalgesia and thermal hyperalgesia and paw edema. The increased mRNA expression of the evaluated mediators and oxidative stress in the paw skin and spinal cord and increased mRNA expression of glial markers in the spinal cord induced by KO2 were successfully inhibited by tempol. KO2-induced reduction in Nrf2 mRNA expression in paw skin and spinal cord was also reverted by tempol. Corroborating the effect of tempol in the KO2 model, tempol also inhibited carrageenan and CFA inflammatory hyperalgesia. The present study demonstrates that tempol inhibits superoxide anion-induced molecular and behavioral alterations, indicating that tempol deserves further preclinical studies as a promising analgesic and anti-inflammatory molecule for the treatment of inflammatory pain.


Assuntos
Materiais Biomiméticos/farmacologia , Óxidos N-Cíclicos/farmacologia , Dor , Superóxido Dismutase , Superóxidos/metabolismo , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas dos Microfilamentos/metabolismo , NADPH Oxidase 2/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Dor/tratamento farmacológico , Dor/metabolismo , Dor/patologia , Marcadores de Spin
7.
Eur J Pharmacol ; 809: 52-63, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28501577

RESUMO

Probucol 4,4'- (Isopropylidenedithio)bis(2,6-di-tert-butylphenol) is a synthetic molecule clinically used for prevention and treatment of hypercholesterolemia and atherosclerosis. Recent studies have shown that the beneficial effects of probucol mainly derive from its anti-inflammatory and antioxidant properties. Gram-negative bacteria are common infectious agents and their wall components, e.g. lipopolysaccharide (LPS), are important elicitors of inflammation. LPS is sensed by tissue resident cells and it triggers a Toll-like receptor 4/MyD88-dependent signaling cascade resulting in endothelial activation, leukocyte recruitment and nociception. Therefore the present study aimed to investigate the anti-inflammatory and analgesic effects of probucol in models of LPS-induced acute inflammation. Probucol at 0.3-30mg/kg was administrated to male Swiss mice per oral 1h before intraplantar or intraperitoneal lipopolysaccharide stimulus. Probucol at 3mg/kg reduced lipopolysaccharide-induced mechanical and thermal hyperalgesia. These effects were accompanied by reduced leukocyte influx and cytokine production in both paw skin and peritoneum exudate. Unexpectedly, probucol did not alter lipopolysaccharide-induced tissue oxidative stress at anti-inflammatory /analgesic dose. On the other hand, probucol inhibited lipopolysaccharide-induced nuclear factor kappa B (NF-кB) activation in paw tissue as well as NF-кB activity in cultured macrophages in vitro, reinforcing the inhibitory effect of probucol over the NF-кB signaling pathway. In this sense, we propose that probucol acts on resident immune cells, such as macrophages, targeting the NF-кB pathway. As a result, it prevents the amplification and persistence of the inflammatory response by attenuating NF-кB-dependent cytokine production and leukocyte recruitment explaining its analgesic effects as well.


Assuntos
Citocinas/biossíntese , Hiperalgesia/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , Probucol/farmacologia , Animais , Hiperalgesia/complicações , Hiperalgesia/imunologia , Hiperalgesia/metabolismo , Inflamação/complicações , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Cavidade Peritoneal , Probucol/uso terapêutico , Células RAW 264.7
8.
J Drug Target ; 25(3): 264-274, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27701898

RESUMO

The present study investigated whether endothelin-1 acts via ETA or ETB receptors to mediate superoxide anion-induced pain and inflammation. Mice were treated with clazosentan (ETA receptor antagonist) or BQ-788 (ETB receptor antagonist) prior to stimulation with the superoxide anion donor, KO2. Intraplantar treatment with 30 nmol of clazosentan or BQ-788 reduced mechanical hyperalgesia (47% and 42%), thermal hyperalgesia (68% and 76%), oedema (50% and 30%); myeloperoxidase activity (64% and 32%), and overt-pain like behaviours, such as paw flinching (42% and 42%) and paw licking (38% and 62%), respectively. Similarly, intraperitoneal treatment with 30 nmol of clazosentan or BQ-788 reduced leukocyte recruitment to the peritoneal cavity (58% and 32%) and abdominal writhing (81% and 77%), respectively. Additionally, intraplantar treatment with clazosentan or BQ-788 decreased spinal (45% and 41%) and peripheral (47% and 47%) superoxide anion production as well as spinal (47% and 47%) and peripheral (33% and 54%) lipid peroxidation, respectively. Intraplantar treatment with clazosentan, but not BQ-788, reduced spinal (71%) and peripheral (51%) interleukin-1 beta as well as spinal (59%) and peripheral (50%) tumor necrosis factor-alpha production. Therefore, the present study unveils the differential mechanisms by which ET-1, acting on ETA or ETB receptors, regulates superoxide anion-induced inflammation and pain.


Assuntos
Citocinas/biossíntese , Inflamação/metabolismo , Estresse Oxidativo , Dor/metabolismo , Receptor de Endotelina A/fisiologia , Receptor de Endotelina B/fisiologia , Superóxidos/metabolismo , Animais , Antagonistas do Receptor de Endotelina A/farmacologia , Masculino , Camundongos
9.
J Nutr Biochem ; 33: 8-14, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27260463

RESUMO

Lipopolysaccharide (LPS) is the major structural component of Gram-negative bacteria cell wall and a highly pro-inflammatory toxin. Naringenin is found in Citrus fruits and exhibits antioxidant and anti-inflammatory properties through inhibition of NF-κB activation but its effects in LPS-induced inflammatory pain and leukocyte recruitment were not investigated yet. We investigated the effects of naringenin in mechanical hyperalgesia, thermal hyperalgesia and leukocyte recruitment induced by intraplantar injection of LPS in mice. We found that naringenin reduced hyperalgesia to mechanical and thermal stimuli, myeloperoxidase (MPO, a neutrophil and macrophage marker) and N-acetyl-ß-D-glucosaminidase (NAG, a macrophage marker) activities, oxidative stress and cytokine (TNF-α, IL-1ß, IL-6, and IL-12) production in the paw skin. In the peritoneal cavity, naringenin reduced neutrophil and mononuclear cell recruitment, and abrogated MPO and NAG activity, cytokine and superoxide anion production, and lipid peroxidation. In vitro, pre-treatment with naringenin inhibited superoxide anion and cytokine (TNF-α, IL-1ß, IL-6, and IL-12) production by LPS-stimulated RAW 264.7 macrophages. Finally, we demonstrated that naringenin inhibited NF-κB activation in vitro and in vivo. Therefore, naringenin is a promising compound to treat LPS-induced inflammatory pain and leukocyte recruitment.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Suplementos Nutricionais , Flavanonas/uso terapêutico , Hiperalgesia/prevenção & controle , Leucócitos Mononucleares/imunologia , Neutrófilos/imunologia , Fator de Transcrição RelA/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/metabolismo , Antioxidantes/uso terapêutico , Comportamento Animal , Biomarcadores/metabolismo , Flavanonas/metabolismo , Temperatura Alta/efeitos adversos , Hiperalgesia/imunologia , Hiperalgesia/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/toxicidade , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células RAW 264.7 , Pele/efeitos dos fármacos , Pele/imunologia , Pele/metabolismo , Estresse Mecânico , Fator de Transcrição RelA/metabolismo
10.
Scientifica (Cairo) ; 2016: 8656397, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27293981

RESUMO

Tephrosia toxicaria, which is currently known as Tephrosia sinapou (Buc'hoz) A. Chev. (Fabaceae), is a source of compounds such as flavonoids. T. sinapou has been used in Amazonian countries traditional medicine to alleviate pain and inflammation. The purpose of this study was to evaluate the analgesic effects of T. sinapou ethyl acetate extract in overt pain-like behavior models in mice by using writhing response and flinching/licking tests. We demonstrated in this study that T. sinapou extract inhibited, in a dose (1-100 mg/kg) dependent manner, acetic acid- and phenyl-p-benzoquinone- (PBQ-) induced writhing response. Furthermore, it was active via intraperitoneal, subcutaneous, and peroral routes of administration. T. sinapou extract also inhibited formalin- and complete Freund's adjuvant- (CFA-) induced flinching/licking at 100 mg/kg dose. In conclusion, these findings demonstrate that T. sinapou ethyl acetate extract reduces inflammatory pain in the acetic acid, PBQ, formalin, and CFA models of overt pain-like behavior. Therefore, the potential of analgesic activity of T. sinapou indicates that it deserves further investigation.

11.
Inflammopharmacology ; 24(2-3): 97-107, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27160222

RESUMO

We evaluated the effect of pyrrolidine dithiocarbamate (PDTC) in superoxide anion-induced inflammatory pain. Male Swiss mice were treated with PDTC and stimulated with an intraplantar or intraperitoneal injection of potassium superoxide, a superoxide anion donor. Subcutaneous PDTC treatment attenuated mechanical hyperalgesia, thermal hyperalgesia, paw oedema and leukocyte recruitment (neutrophils and macrophages). Intraplantar injection of superoxide anion activated NF-κB and increased cytokine production (IL-1ß, TNF-α and IL-10) and oxidative stress (nitrite and lipid peroxidation levels) at the primary inflammatory foci and in the spinal cord (L4-L6). PDTC treatment inhibited superoxide anion-induced NF-κB activation, cytokine production and oxidative stress in the paw and spinal cord. Furthermore, intrathecal administration of PDTC successfully inhibited superoxide anion-induced mechanical hyperalgesia, thermal hyperalgesia and inflammatory response in peripheral foci (paw). These results suggest that peripheral stimulus with superoxide anion activates the local and spinal cord oxidative- and NF-κB-dependent inflammatory nociceptive mechanisms. PDTC targets these events, therefore, inhibiting superoxide anion-induced inflammatory pain in mice.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Dor/metabolismo , Pirrolidinas/administração & dosagem , Medula Espinal/metabolismo , Tiocarbamatos/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/metabolismo , Edema/prevenção & controle , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/prevenção & controle , Masculino , Camundongos , NF-kappa B/antagonistas & inibidores , Estresse Oxidativo/fisiologia , Dor/induzido quimicamente , Dor/prevenção & controle , Medula Espinal/efeitos dos fármacos , Superóxidos/toxicidade
12.
PLoS One ; 11(4): e0153015, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27045367

RESUMO

In the present study, the effect and mechanism of action of the flavonoid naringenin were evaluated in superoxide anion donor (KO2)-induced inflammatory pain in mice. Naringenin reduced KO2-induced overt-pain like behavior, mechanical hyperalgesia, and thermal hyperalgesia. The analgesic effect of naringenin depended on the activation of the NO-cGMP-PKG-ATP-sensitive potassium channel (KATP) signaling pathway. Naringenin also reduced KO2-induced neutrophil recruitment (myeloperoxidase activity), tissue oxidative stress, and cytokine production. Furthermore, naringenin downregulated KO2-induced mRNA expression of gp91phox, cyclooxygenase (COX)-2, and preproendothelin-1. Besides, naringenin upregulated KO2-reduced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) mRNA expression coupled with enhanced heme oxygenase (HO-1) mRNA expression. In conclusion, the present study demonstrates that the use of naringenin represents a potential therapeutic approach reducing superoxide anion-driven inflammatory pain. The antinociceptive, anti-inflammatory and antioxidant effects are mediated via activation of the NO-cGMP-PKG-KATP channel signaling involving the induction of Nrf2/HO-1 pathway.


Assuntos
Citocinas/fisiologia , Flavanonas/farmacologia , Inflamação/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Dor/tratamento farmacológico , Transdução de Sinais , Superóxidos/metabolismo , Animais , Comportamento Animal , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Flavanonas/uso terapêutico , Inflamação/etiologia , Masculino , Camundongos , Óxido Nítrico/metabolismo , Dor/etiologia , Canais de Potássio/metabolismo
13.
Neuropharmacology ; 105: 508-519, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26907804

RESUMO

Naringenin is a flavonoid widely consumed by humans that present anti-inflammatory activity and low toxicity. Recently, the analgesic effect of naringenin has been demonstrated in neuropathic pain models. Herein, we tested the analgesic effects of naringenin in several models of inflammatory pain. Mice received treatment with naringenin (16.7-150 mg/kg, per oral), or with the controls anti-inflammatory drugs indomethacin (5 mg/kg, intraperitoneal) or dipyrone (80 mg/kg, intraperitoneal) prior the inflammatory stimuli injection. For acute pain, we used acetic acid- and PBQ-induced visceral pain (abdominal writhings), and formalin-, capsaicin-, and CFA-induced paw flinching and licking. By using an electronic version of von Frey filaments, we also investigated the effects of naringenin in pain intensity to a mechanical stimulus (mechanical hyperalgesia) after carrageenan, capsaicin, CFA, or PGE2 intraplantar injection. Naringenin (50 mg/kg) reduced acute pain behaviors induced by all tested stimuli, including both phases of formalin test, suggesting a direct nociceptor modulatory effect of this compound besides its anti-inflammatory activity. Accordingly, naringenin also inhibited the increased sensitivity to mechanical stimulus induced by carrageenan, capsaicin, and PGE2. Daily treatment with naringenin during 7 days also reduced CFA-induced mechanical hyperalgesia without gastric or hepatic toxicity. The mechanisms of naringenin involve the inhibition of carrageenan-induced oxidative stress, hyperalgesic cytokines (IL-33, TNF-α, and IL-1ß) production and NF-κB activation in the paw skin. Naringenin also activated the analgesic NO-cyclic GMP-PKG-ATP sensitive K(+) channel signaling pathway to inhibit carrageenan-induced mechanical hyperalgesia and neutrophil recruitment. These results suggest that naringenin inhibits both inflammatory pain and neurogenic inflammation.


Assuntos
Analgésicos/farmacologia , Flavanonas/farmacologia , Hiperalgesia/tratamento farmacológico , Dor Visceral/tratamento farmacológico , Animais , Citocinas/metabolismo , Dipirona/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hiperalgesia/metabolismo , Indometacina/farmacologia , Injeções Intraperitoneais , Canais KATP/metabolismo , Fígado/efeitos dos fármacos , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , NF-kappa B/metabolismo , Neutrófilos/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Estômago/efeitos dos fármacos , Dor Visceral/metabolismo
14.
PLoS One ; 11(2): e0149656, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26895409

RESUMO

Pimaradienoic acid (PA; ent-pimara-8(14),15-dien-19-oic acid) is a pimarane diterpene found in plants such as Vigueira arenaria Baker (Asteraceae) in the Brazilian savannas. Although there is evidence on the analgesic and in vitro inhibition of inflammatory signaling pathways, and paw edema by PA, its anti-inflammatory effect deserves further investigation. Thus, the objective of present study was to investigate the anti-inflammatory effect of PA in carrageenan-induced peritoneal and paw inflammation in mice. Firstly, we assessed the effect of PA in carrageenan-induced leukocyte recruitment in the peritoneal cavity and paw edema and myeloperoxidase activity. Next, we investigated the mechanisms involved in the anti-inflammatory effect of PA. The effect of PA on carrageenan-induced oxidative stress in the paw skin and peritoneal cavity was assessed. We also tested the effect of PA on nitric oxide, superoxide anion, and inflammatory cytokine production in the peritoneal cavity. PA inhibited carrageenan-induced recruitment of total leukocytes and neutrophils to the peritoneal cavity in a dose-dependent manner. PA also inhibited carrageenan-induced paw edema and myeloperoxidase activity in the paw skin. The anti-inflammatory mechanism of PA depended on maintaining paw skin antioxidant activity as observed by the levels of reduced glutathione, ability to scavenge the ABTS cation and reduce iron as well as by the inhibition of superoxide anion and nitric oxide production in the peritoneal cavity. Furthermore, PA inhibited carrageenan-induced peritoneal production of inflammatory cytokines TNF-α and IL-1ß. PA presents prominent anti-inflammatory effect in carrageenan-induced inflammation by reducing oxidative stress, nitric oxide, and cytokine production. Therefore, it seems to be a promising anti-inflammatory molecule that merits further investigation.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Asteraceae/química , Quimiotaxia de Leucócito/efeitos dos fármacos , Citocinas/biossíntese , Diterpenos/farmacologia , Óxido Nítrico/biossíntese , Estresse Oxidativo/efeitos dos fármacos , Animais , Brasil , Carragenina/antagonistas & inibidores , Diterpenos/química , Edema , Interleucina-1beta/biossíntese , Masculino , Camundongos , Infiltração de Neutrófilos/efeitos dos fármacos , Cavidade Peritoneal , Peroxidase/metabolismo , Fator de Necrose Tumoral alfa/biossíntese
15.
FASEB J ; 30(1): 54-65, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26310268

RESUMO

Neuropathic pain from injury to the peripheral and CNS represents a major health care issue. We have investigated the role of IL-33/IL-33 receptor (ST2) signaling in experimental models of neuropathic pain in mice. Chronic constriction injury (CCI) of the sciatic nerve induced IL-33 production in the spinal cord. IL-33/citrine reporter mice revealed that oligodendrocytes are the main cells expressing IL-33 within the spinal cord together with a minor expression by neurons, microglia. and astrocytes. CCI-induced mechanical hyperalgesia was reduced in IL-33R (ST2)(-/ -) mice compared with wild-type (WT) mice. Intrathecal treatment of WT mice with soluble IL-33 receptor (IL-33 decoy receptor) markedly reduced CCI-induced hyperalgesia. Consistent with these observations, intrathecal injection of IL-33 enhanced CCI hyperalgesia and induced hyperalgesia in naive mice. IL-33-mediated hyperalgesia during CCI was dependent on a reciprocal relationship with TNF-α and IL-1ß. IL-33-induced hyperalgesia was markedly attenuated by inhibitors of PI3K, mammalian target of rapamycin, MAPKs (p38, ERK, and JNK), NF-κB, and also by the inhibitors of glial cells (microglia and astrocytes). Furthermore, targeting these signaling pathways and cells inhibited IL-33-induced TNF-α and IL-1ß production in the spinal cord. Our study, therefore, reveals an important role of oligodendrocyte-derived IL-33 in neuropathic pain.


Assuntos
Alarminas/metabolismo , Hiperalgesia/metabolismo , Interleucina-33/metabolismo , Neuralgia/metabolismo , Oligodendroglia/metabolismo , Medula Espinal/metabolismo , Animais , Astrócitos/metabolismo , Camundongos Knockout , Microglia/metabolismo , Limiar da Dor/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Medula Espinal/fisiopatologia
16.
Anal Cell Pathol (Amst) ; 2015: 285708, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26351625

RESUMO

Cancer pain directly affects the patient's quality of life. We have previously demonstrated that the subcutaneous administration of the mammary adenocarcinoma known as Ehrlich tumor induces pain in mice. Several studies have shown that the flavonoid quercetin presents important biological effects, including anti-inflammatory, antioxidant, analgesic, and antitumor activity. Therefore, the analgesic effect and mechanisms of quercetin were evaluated in Ehrlich tumor-induced cancer pain in mice. Intraperitoneal (i.p.) treatments with quercetin reduced Ehrlich tumor-induced mechanical and thermal hyperalgesia, but not paw thickness or histological alterations, indicating an analgesic effect without affecting tumor growth. Regarding the analgesic mechanisms of quercetin, it inhibited the production of hyperalgesic cytokines IL-1ß and TNFα and decreased neutrophil recruitment (myeloperoxidase activity) and oxidative stress. Naloxone (opioid receptor antagonist) inhibited quercetin analgesia without interfering with neutrophil recruitment, cytokine production, and oxidative stress. Importantly, cotreatment with morphine and quercetin at doses that were ineffective as single treatment reduced the nociceptive responses. Concluding, quercetin reduces the Ehrlich tumor-induced cancer pain by reducing the production of hyperalgesic cytokines, neutrophil recruitment, and oxidative stress as well as by activating an opioid-dependent analgesic pathway and potentiation of morphine analgesia. Thus, quercetin treatment seems a suitable therapeutic approach for cancer pain that merits further investigation.


Assuntos
Carcinoma de Ehrlich/complicações , Dor/tratamento farmacológico , Dor/etiologia , Quercetina/uso terapêutico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Analgésicos Opioides/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Interleucina-1beta/biossíntese , Masculino , Camundongos , Morfina/farmacologia , Morfina/uso terapêutico , Naloxona/farmacologia , Naloxona/uso terapêutico , Infiltração de Neutrófilos/efeitos dos fármacos , Estresse Oxidativo , Dor/patologia , Quercetina/farmacologia , Pele/patologia , Medula Espinal/patologia , Fator de Necrose Tumoral alfa/biossíntese
17.
Neurosci Lett ; 605: 53-8, 2015 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-26291484

RESUMO

Inhibition of tumor necrosis factor-alpha (TNFα) and superoxide anion production reduces inflammation and pain. The present study investigated whether superoxide anion-induced pain depends on TNFα signaling and the role of superoxide anion in TNFα-induced hyperalgesia to clarify the interrelation between these two mediators in the context of pain. Intraplantar injection of a superoxide anion donor (potassium superoxide) induced mechanical hyperalgesia (0.5-5h after injection), neutrophil recruitment (myeloperoxidase activity), and overt pain-like behaviors (paw flinching, paw licking, and abdominal writhings) in wild-type mice. Tumor necrosis factor receptor 1 deficiency (TNFR1-/-) and treatment of wild-type mice with etanercept (a soluble TNFR2 receptor that inhibits TNFα actions) inhibited superoxide anion-induced pain-like behaviors. TNFR1(-/-) mice were also protected from superoxide anion donor-induced oxidative stress, suggesting the role of this pathway in the maintenance of oxidative stress. Finally, we demonstrated that Apocynin (an NADPH oxidase inhibitor) or Tempol (a superoxide dismutase mimetic) treatment inhibited TNFα-induced paw mechanical hyperalgesia and neutrophil recruitment (myeloperoxidase activity). These results demonstrate that TNFα/TNFR1 signaling is important in superoxide anion-triggered pain and that TNFα/TNFR1 signaling amplifies the oxidative stress triggered by superoxide anion, which contributes to sustaining pain and inflammation.


Assuntos
Dor/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Superóxidos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Etanercepte/farmacologia , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Peroxidação de Lipídeos , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/fisiologia , Estresse Oxidativo , Dor/fisiopatologia , Peroxidase/metabolismo , Estimulação Física , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Tato , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/farmacologia
18.
Naunyn Schmiedebergs Arch Pharmacol ; 388(11): 1211-21, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26246053

RESUMO

Bosentan is a mixed endothelin receptor antagonist widely used to treat patients with pulmonary arterial hypertension, and the emerging literature suggests bosentan as a potent anti-inflammatory drug. Superoxide anion is produced in large amounts during inflammation, stimulates cytokine production, and thus contributes to inflammation and pain. However, it remains to be determined whether endothelin contributes to the inflammatory response triggered by the superoxide anion. The present study investigated the effects of bosentan in a mouse model of inflammation and pain induced by potassium superoxide, a superoxide anion donor. Male Swiss mice were treated with bosentan (10-100 mg/kg) by oral gavage, 1 h before potassium superoxide injection, and the inflammatory response was evaluated locally and at spinal cord (L4-L6) levels. Bosentan (100 mg/kg) inhibited superoxide anion-induced mechanical and thermal hyperalgesia, overt pain-like behavior (abdominal writhings, paw flinching, and licking), paw edema, myeloperoxidase activity (neutrophil marker) in the paw skin, and leukocyte recruitment in the peritoneal cavity. Bosentan also inhibited superoxide anion-induced interleukin-1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α) production, while it enhanced IL-10 production in the paw skin and spinal cord. Bosentan inhibited the reduction of antioxidant capacity (reduced glutathione, ferric reducing antioxidant power, and ABTS radical scavenging ability) induced by the superoxide anion. Finally, we demonstrated that intraplantar injection of potassium superoxide induces the mRNA expression of prepro-endothelin-1 in the paw skin and spinal cord. In conclusion, our results demonstrated that superoxide anion-induced inflammation, pain, cytokine production, and oxidative stress depend on endothelin; therefore, these responses are amenable to bosentan treatment.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Hiperalgesia/tratamento farmacológico , Dor/tratamento farmacológico , Sulfonamidas/uso terapêutico , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Bosentana , Citocinas/imunologia , Antagonistas dos Receptores de Endotelina/farmacologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/imunologia , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Masculino , Camundongos , Dor/induzido quimicamente , Dor/imunologia , Cavidade Peritoneal/citologia , Peroxidase/imunologia , Pele/efeitos dos fármacos , Pele/imunologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Sulfonamidas/farmacologia , Superóxidos
19.
J Nat Prod ; 78(8): 1799-808, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26192250

RESUMO

Vanillic acid (1) is a flavoring agent found in edible plants and fruits. It is an oxidized form of vanillin. Phenolic compounds form a substantial part of plant foods used as antioxidants with beneficial biological activities. These compounds have received considerable attention because of their role in preventing human diseases. Especially, 1 presents antibacterial, antimicrobial, and chemopreventive effects. However, the mechanisms by which 1 exerts its anti-inflammatory effects in vivo are incompletely understood. Thus, the effect of 1 was evaluated in murine models of inflammatory pain. Treatment with 1 inhibited the overt pain-like behavior induced by acetic acid, phenyl-p-benzoquinone, the second phase of the formalin test, and complete Freund's adjuvant (CFA). Treatment with 1 also inhibited carrageenan- and CFA-induced mechanical hyperalgesia, paw edema, myeloperoxidase activity, and N-acetyl-ß-D-glucosaminidase activity. The anti-inflammatory mechanisms of 1 involved the inhibition of oxidative stress, pro-inflammatory cytokine production, and NFκB activation in the carrageenan model. The present study demonstrated 1 presents analgesic and anti-inflammatory effects in a wide range of murine inflammation models, and its mechanisms of action involves antioxidant effects and NFκB-related inhibition of pro-inflammatory cytokine production.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , NF-kappa B/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ácido Vanílico/farmacologia , Animais , Anti-Inflamatórios/química , Antioxidantes/farmacologia , Benzaldeídos/química , Benzoquinonas/farmacologia , Carragenina/efeitos adversos , Citocinas/biossíntese , Modelos Animais de Doenças , Edema/induzido quimicamente , Adjuvante de Freund/farmacologia , Hiperalgesia/tratamento farmacológico , Inflamação/induzido quimicamente , Masculino , Camundongos , Estrutura Molecular , Dor/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Ácido Vanílico/química
20.
Chem Biol Interact ; 237: 9-17, 2015 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-25980587

RESUMO

In response to lipopolysaccharide (LPS), tissue resident macrophages and recruited neutrophils produce inflammatory mediators through activation of Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway. These mediators include inflammatory cytokines and reactive oxygen species that, in turn, sensitize nociceptors and lead to inflammatory pain. Vinpocetine is a nootropic drug widely used to treat cognitive and neurovascular disorders, and more recently its anti-inflammatory properties through inhibition of NF-κB activation have been described. In the present study, we used the intraplantar and intraperitoneal LPS stimulus in mice to investigate the effects of vinpocetine pre-treatment (3, 10, or 30mg/kg by gavage) in hyperalgesia, leukocyte recruitment, oxidative stress, and pro-inflammatory cytokine production (TNF-α, IL-1ß, and IL-33). LPS-induced NF-κB activation and cytokine production were investigated using RAW 264.7 macrophage cell in vitro. Vinpocetine (30mg/kg) significantly reduces hyperalgesia to mechanical and thermal stimuli, and myeloperoxidase (MPO) activity (a neutrophil marker) in the plantar paw skin, and also inhibits neutrophil and mononuclear cell recruitment, superoxide anion and nitric oxide production, oxidative stress, and cytokine production (TNF-α, IL-1ß and IL-33) in the peritoneal cavity. At least in part, these effects seem to be mediated by direct effects of vinpocetine on macrophages, since it inhibited the production of the same cytokines (TNF-α, IL-1ß and IL-33) and the NF-κB activation in LPS-stimulated RAW 264.7 macrophages. Our results suggest that vinpocetine represents an important therapeutic approach to treat inflammation and pain induced by a gram-negative bacterial component by targeting NF-κB activation and NF-κB-related cytokine production in macrophages.


Assuntos
Citocinas/antagonistas & inibidores , Lipopolissacarídeos/toxicidade , NF-kappa B/antagonistas & inibidores , Neutrófilos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Dor/prevenção & controle , Animais , Citocinas/biossíntese , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Dor/induzido quimicamente , Cavidade Peritoneal , Peroxidase/metabolismo , Alcaloides de Vinca/farmacologia
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