RESUMO

OBJECTIVE: The present study aimed to investigate five triazole compounds as P2X7R inhibitors and evaluate their ability to reduce acute inflammation in vivo. MATERIAL: The synthetic compounds were labeled 5e, 8h, 9i, 11, and 12. TREATMENT: We administered 500 ng/kg triazole analogs in vivo, (1-10 µM) in vitro, and 1000 mg/kg for toxicological assays. METHODS: For this, we used in vitro experiments, such as platelet aggregation, in vivo experiments of paw edema and peritonitis in mice, and in silico experiments. RESULTS: The tested substances 5e, 8h, 9i, 11, and 12 produced a significant reduction in paw edema. Molecules 5e, 8h, 9i, 11, and 12 inhibited carrageenan-induced peritonitis. Substances 5e, 8h, 9i, 11, and 12 showed an anticoagulant effect, and 5e at a concentration of 10 µM acted as a procoagulant. All derivatives, except for 11, had pharmacokinetic, physicochemical, and toxicological properties suitable for substances that are candidates for new drugs. In addition, the ADMET risk assessment shows that derivatives 8h, 11, 5e, and 9i have high pharmacological potential. Finally, docking tests indicated that the derivatives have binding energies comparable to the reference antagonist with a competitive inhibition profile. CONCLUSIONS: Together, the results indicate that the molecules tested as antagonist drugs of P2X7R had anti-inflammatory action against the acute inflammatory response.

Assuntos

Hemostáticos , Peritonite , Camundongos , Animais , Hemostáticos/efeitos adversos , Triazóis/efeitos adversos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Edema/induzido quimicamente , Edema/tratamento farmacológico , Carragenina/efeitos adversos , Simulação de Acoplamento Molecular

RESUMO

The aim of this study was to investigate the anti-inflammatory effect of alcoholic extract of Tarantula cubensis alcoholic extract (TCAE) in experimentally induced inflammation in rats. Fifty-four adult Sprague-Dawley male rats were randomly divided into nine groups. Paw edema was induced by 0.2mL subplantar (s.p.) injection of 1% carrageenan (CAR) into the right hind paw. Rats were treated with the nonsteroidal anti-inflammatory drug (NSAID) indomethacin (INDO) (10mg/kg, p.o.) or TCAE at different doses (1, 10 or 100µg/kg) injected s.c. for systemic or s.p. for local anti-inflammatory effect. Saline was used as control. Changes in paw thickness, volume, and weight were calculated as percentages. Formalin-fixed paws were used for histopathological examination. We detected that TCAE applied s.c. at 10µg/kg and 100µg/kg doses resulted in thinner paw thickness, lower paw volume, and lower paw weights four hours after the induction of inflammation when compared with the INDO group (p<0.05). The paw edema inhibitory effect of TCAE applied at a dose of 10µg/kg, s.c. was 68% when compared with the INDO which had an inhibitory effect of 56%. These results were verified with similar histopathological findings. The anti-inflammatory feature of 10µg/kg of TCAE given systematically was similar to the effects of INDO. Our results suggest that TCAE has anti-inflammatory effects by reducing edema and decreasing inflammatory reaction. These results may be attributed to the inhibition of the production of proinflammatory mediators. Thus, TCAE may be considered as a potential anti-inflammatory agent for treating acute inflammatory conditions.

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O objetivo deste estudo foi investigar o efeito anti-inflamatório do extrato alcoólico de Tarantula cubensis (TCAE) na inflamação induzida experimentalmente em ratos. Cinqüenta e quatro ratos Sprague-Dawley adultos machos foram divididos aleatoriamente em nove grupos. O edema da pata foi induzido pela injeção de 0,2mL de subplantar (s.p.) de 1% de carragena (CAR) na pata traseira direita. Ratos foram tratados com o medicamento antiinflamatório não esteróide (NSAID) indometacina (INDO) (10mg/kg, p.o.) ou TCAE em doses diferentes (1, 10 ou 100µg/kg) injetado s.c. para efeito sistêmico ou s.p. para efeito antiinflamatório local. A soro fisiológico foi usado como controle. As mudanças na espessura da pata, volume e peso foram calculadas como porcentagens. As patas fixadas com fórmalina foram usadas para exame histopatológico. Detectamos que o TCAE aplicado s.c. em doses de 10µg/kg e 100µg/kg resultou em menor espessura da pata, menor volume da pata e menor peso da pata quatro horas após a indução da inflamação quando comparado com o grupo INDO (p<0,05). O efeito inibidor do edema da pata de TCAE aplicado na dose de 10µg/kg, s.c. foi de 68% quando comparado com o INDO que teve um efeito inibidor de 56%. Estes resultados foram verificados com resultados histopatológicos semelhantes. A característica anti-inflamatória de 10µg/kg de TCAE dada sistematicamente foi semelhante aos efeitos do INDO. Nossos resultados sugerem que o TCAE tem efeitos anti-inflamatórios reduzindo o edema e diminuindo a reação inflamatória. Estes resultados podem ser atribuídos à inibição da produção de mediadores pró-inflamatórios. Assim, o TCAE pode ser considerado como um agente antiinflamatório potencial para o tratamento de condições inflamatórias agudas.

Assuntos

Animais , Ratos , Tarentula cubensis/uso terapêutico , Edema/terapia , Ratos Sprague-Dawley , Modelos Animais , Inflamação/terapia

RESUMO

Pain and inflammation are symptoms of various diseases, and they can be modulated by different pathways, thus highlighting the importance of investigating the therapeutic effects of novel compounds. Previous studies have shown that isatin-thiosemicarbazone exhibits antitumor, antifungal antibacterial and other biological properties. Based on the wide range of biological effects of these compounds, the aim of the present study was to investigate the central nervous system (CNS) performance, and the anti-nociceptive and anti-inflammatory activity of (Z)-2-(5-nitro-2-oxoindolin-3-ilidene)-N-hydroazinecarbothioamide (PA-Int5) in treated mice. Three doses of PA-Int5 were tested orally (1.0, 2.5 and 5.0 mg/kg) in the nociceptive and inflammatory animal models. Additionally, the potential sedative effects of PA-Int5 (5 mg/kg, oral gavage) were investigated using an open field and rotarod tests, to exclude any possible unspecific effects of the nociceptive assays. Anti-nociceptive activity was assessed using the acetic acid-induced abdominal contortion and formalin tests, whereas anti-inflammatory activity was assessed using a carrageenan-induced paw edema and zymosan-induced air-pouch models. PA-Int5 (5 mg/kg) induced anti-nociceptive activity in the abdominal contortion model. In the formalin test, PA-Int5 (at 2.5 and 5 mg/kg) reduced nociception in the second phase. At the higher dose tested, PA-Int5 did not affect spontaneous locomotion or motor coordination. The data revealed that at all doses tested, the compound significantly reduced paw edema following carrageenan administration. In the zymosan-induced air-pouch model, PA-Int5 potently inhibited leukocyte migration and protein levels at the site of inflammation. When combined, the results revealed, for the first time, that PA-Int5 exhibited anti-nociceptive and anti-inflammatory activities, and highlights its potential, as well that of other derivatives, as novel candidates for pain relief.

RESUMO

Sesquiterpene lactones (SL) are natural bioactive molecules indicated as potential scaffolds for anti-inflammatory and analgesic drug design. However, their anti-inflammatory applicability remains underestimated since the impact of SL on inflammatory nociception and tissue repair are overlooked. Thus, we used an integrated in silico, in vitro and in vivo framework to investigate the impact of tagitinin F (TAG-F) on lipopolysaccharide (LPS)-challenged macrophages, excisional skin wounds, and carrageenan-induced paw edema and mechanical hyperalgesia in mice. RAW 264.7 macrophages in culture were challenged with LPS and treated with TAG-F (5, 10, 50 and 100 µM). The paw of BALB/c mice was injected with carrageenan and treated with 0.5% and 1% TAG-F. Excisional wounds were also produced in BALB/c mice and treated with 0.5% and 1% TAG-F. Our results indicated a consistent concentration-dependent downregulation in 5-lipoxygenase, cyclooxygenase 1 and 2 (COX-1 and COX-2), matrix metalloproteinase 1 and 2 (MMP-1 and MMP-2) activities; as well as attenuation in prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and tumor necrosis factor-α (TNF-α) production in both in vitro and in vivo models. In vivo, TAG-F also attenuated carrageenan-induced paw edema and mechanical hyperalgesia in mice. From the excisional skin wound, TAG-F was still effective in reducing neutrophils and macrophages infiltration and stimulating collagen deposition in the scar tissue, accelerating tissue maturation. Together, our findings indicate that the anti-inflammatory effect of TAG-F is more comprehensive than previously suggested, exerting a significant impact on the control of edema, inflammatory pain and modulating central metabolic processes linked to skin wound healing.

Assuntos

Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Cicatriz/tratamento farmacológico , Edema/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Carragenina , Cicatriz/metabolismo , Colágeno/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Edema/induzido quimicamente , Leucotrieno B4/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7 , Sesquiterpenos/farmacologia , Tato , Fator de Necrose Tumoral alfa/metabolismo

RESUMO

BACKGROUND: Antiproliferative and cytotoxic effects of lidocaine have been reported in tumor cells. However, the use of these drugs is restricted due to their short action with rapid dispersion from the injected site. The complexation of local anesthetics in 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) is able to improve pharmacological features. OBJECTIVE: This study evaluated the antitumor effects of lidocaine and the complex HP-ß-CD-lidocaine (HP-ß-CD-lido). METHODS: In vitro;, human adenocarcinoma (HeLa) and keratinocytes (HaCaT) were exposed to lidocaine formulations and cell viability, proliferation and apoptosis induction were measured. In vivo;, Walker 256 carcinoma cells were subcutaneously injected into the plantar region of the rat right hind paw. The animals were treated with a local application of 5% lidocaine or 5% HP-ß-CD-lido. Doxorubicin (3 mg/Kg/day, intraperitoneal) was used as a positive control. Edema sizes were measured daily and the release of cytokines (TNF-α, IL-1α and CXCL-1) and prostaglandin E2 was evaluated. Histological analysis was also performed. RESULTS: HaCaT IG50 values were 846 µM and 2253 µM for lido and HP-ß-CD-lido, respectively. In HeLa cells, the IG50 was 1765 µM for lido and 2044 µM for HP-ß-CD-lido. Lidocaine formulations significantly reduced the paw edema on day 6 after Walker 256 cells inoculation. However, there were no differences in the release of inflammatory mediators in comparison to the control group. CONCLUSION: Lidocaine formulations were able to reduce the edema in vivo;, without affecting the tumor- induced inflammatory response. The antiproliferative effects of lidocaine formulations may have contributed to tumor reduction.

Assuntos

2-Hidroxipropil-beta-Ciclodextrina/química , Portadores de Fármacos/química , Edema/tratamento farmacológico , Lidocaína/administração & dosagem , Neoplasias/tratamento farmacológico , Animais , Linhagem Celular Tumoral/transplante , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Quimiocina CXCL1/metabolismo , Modelos Animais de Doenças , Composição de Medicamentos/métodos , Ensaios de Seleção de Medicamentos Antitumorais , Edema/diagnóstico , Edema/imunologia , Edema/patologia , Células HaCaT , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Interleucina-1alfa/metabolismo , Lidocaína/farmacocinética , Masculino , Neoplasias/complicações , Neoplasias/imunologia , Neoplasias/patologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/metabolismo

RESUMO

The compound (E)-2-cyano-3-(1H-indol-3-yl)-N-phenylacrylamide (ICMD-01) was designed and developed based on the structures of clinically relevant drugs indomethacin and paracetamol through the molecular hybridization strategy. This derivative was obtained by an amidation reaction between substituted anilines and ethyl 2-cyanoacetate followed by a Knoevenagel-type condensation reaction with indole aldehyde that resulted in both a viable synthesis and satisfactory yield. In order to assess the immunomodulatory and anti-inflammatory activity, in vitro assays were performed in J774 macrophages, and significant inhibitions (p < 0.05) of the production of nitrite and the production of cytokines (IL-1ß and TNFα) in noncytotoxic concentrations were observed. The anti-inflammatory effect was also studied via CFA-induced paw edema in vivo tests and zymosan-induced peritonitis. In the paw edema assay, ICMD01 (50 mg kg-1) showed satisfactory activity, as did the group treated with dexamethasone, reducing edema in 2-6 h. In addition, there was no significant inhibition of PGE2, IL-1ß or TNFα in vivo. Moreover, in the peritonitis assay that assesses leukocyte migration, ICMD-01 exhibited promising results. Therefore, these preliminary studies demonstrate this compound to be a strong candidate for an anti-inflammatory drug together with an improved gastrointestinal safety profile when compared to the conventional anti-inflammatory drugs.

Assuntos

Anti-Inflamatórios/farmacologia , Edema/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Peritonite/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Linhagem Celular , Citocinas , Masculino , Camundongos , Peritonite/induzido quimicamente , Zimosan/toxicidade

RESUMO

ABSTRACT BACKGROUND AND OBJECTIVES: The constant search for bioactive compounds with anti-inflammatory and antinociceptive activities are of interest to research centers. For the characterization of these activities, trials on guinea pigs are necessary. Therefore, the purpose of this study was to demonstrate some methods to evaluate the anti-inflammatory and antinociceptive potential of natural products. CONTENTS: A stimulus is required to evaluate these activities, and the induction of inflammatory or nociceptive process can be by chemical inducers like formaldehyde, carrageenan, among others, or electronic equipment such as the hot plate. For all assays, the baseline and post-dose measurement of the studied compound is always compared with a control group. The planning of the experiment, as well as its conduct in accordance with well-established protocols, are important tools in the success of the work. The tests presented evaluated the antinociceptive and anti-inflammatory activity as well as the mechanisms involved. CONCLUSION: It was possible to evaluate that the tests present in the literature today meet the researcher's need for the elucidation of the anti-inflammatory and antinociceptive activity of new compounds.

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RESUMO JUSTIFICATIVA E OBJETIVOS: A busca constante por compostos bioativos com atividade anti-inflamatória e antinociceptiva são de interesse dos centros de pesquisas. Para a caracterização dessas atividades são necessários ensaios em cobaias. Frente a isso, o objetivo deste estudo foi demonstrar alguns métodos para a avaliação do potencial anti-inflamatório e antinociceptivo de produtos naturais. CONTEÚDO: Para a avaliação dessas atividades é necessário um estímulo, sendo que a indução de processo inflamatório ou nociceptivo pode ser por indutores químicos como formol, carragenina, entre outros, ou ainda, equipamentos eletrônicos como placa quente. Para todos os ensaios, sempre é realizada a mensuração basal e posterior à administração do composto que está sendo estudado em comparação com um grupo controle. O planejamento do experimento, assim como toda a condução conforme protocolos já bem ilustrados, são ferramentas importantes no êxito do trabalho. Os testes apresentados avaliaram atividade antinociceptiva e anti-inflamatória assim como mecanismos envolvidos. CONCLUSÃO: Foi possível avaliar que os testes presentes na literatura hoje, atendem a necessidade do pesquisador na elucidação da atividade anti-inflamatória e atividade antinociceptiva de novos compostos.

RESUMO

The P2X7 receptor (P2X7R) is an ion channel which is activated by interactions with the extracellular ATP molecules. The molecular complex P2X7R/ATP induces conformational changes in the protein subunits, opening a pore in the ion channel macromolecular structure. Currently, the P2X7R has been studied as a potential therapeutic target of anti-inflammatory drugs. Based on this, a series of eight boronic acids (NO) analogs were evaluated on the biologic effect of this pharmacophoric group on the human and murine P2X7R. The boronic acids derivatives NO-01 and NO-12 inhibited in vitro human and murine P2X7R function. These analogs compounds showed effect better than compound BBG and similar to inhibitor A740003 for inhibiting dye uptake, in vitro IL-1ß release and ATP-induced paw edema in vivo. In both, in vitro and in vivo assays the compound NO-01 showed to be the hit compound in the present series of the arylboronic acids analogs. The molecular docking suggests that the NO derivatives bind into the upper body domain of the P2X7 pore and that the main intermolecular interaction with the two most active NO derivatives occur with the residues Phe 95, 103 and 293 by hydrophobic interactions and with Leu97, Gln98 and Ser101 by hydrogen bonds.. These results indicate that the boronic acid derivative NO-01 shows the lead compound characteristics to be used as a scaffold structure to the development of new P2X7R inhibitors with anti-inflammatory action.

Assuntos

Anti-Inflamatórios , Ácidos Borônicos , Antagonistas do Receptor Purinérgico P2X , Receptores Purinérgicos P2X7/metabolismo , Acetamidas/química , Acetamidas/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Ácidos Borônicos/química , Ácidos Borônicos/farmacologia , Células HEK293 , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Antagonistas do Receptor Purinérgico P2X/química , Antagonistas do Receptor Purinérgico P2X/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Receptores Purinérgicos P2X7/genética

RESUMO

Twenty new 2-(1H-pyrazol-1-yl)-1,3,4-thiadiazole analogs were synthetized to develop P2X7 receptor (P2X7R) inhibitors. P2X7R inhibition in vitro was evaluated in mouse peritoneal macrophages, HEK-293 cells transfected with hP2X7R (dye uptake assay), and THP-1 cells (IL-1ß release assay). The 1-(5-phenyl-1,3,4-thiadiazol-2-yl)-1H-pyrazol-5-amine derivatives 9b, 9c, and 9f, and 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-(4-fluorophenyl)-1,3,4-thiadiazole (11c) showed inhibitory effects with IC50 values ranging from 16 to 122 nM for reduced P2X7R-mediated dye uptake and 20 to 300 nM for IL-1ß release. In addition, the in vitro ADMET profile of the four most potent derivatives was determined to be in acceptable ranges concerning metabolic stability and cytotoxicity. Molecular docking and molecular dynamics simulation studies of the molecular complexes human P2X7R/9f and murine P2X7R/9f indicated the putative intermolecular interactions. Compound 9f showed affinity mainly for the Arg268, Lys377, and Asn266 residues. These results suggest that 2-(1H-pyrazol-1-yl)-1,3,4-thiadiazole analogs may be promising novel P2X7R inhibitors with therapeutic potential.

RESUMO

Recent findings have demonstrated new therapeutic functions of cardiotonic steroids, a process that is termed drug repositioning. Despite the confirmed anti-inflammatory effects of cardiotonic steroids, their clinical use has been discouraged due to toxicity related to inhibition of the Na+/K+ ATPase. A novel synthetic compound derived from digoxin, 21­benzylidene digoxin (21­BD), does not inhibit this enzyme. Herein, we evaluated the anti-inflammatory and antinociceptive effects and acute toxicity of 21­BD. Murine (Swiss mice) models of paw oedema induced by carrageenan, acetic acid-induced abdominal writhing, and formalin and acute toxicity tests were used. Oral administration of 21­BD (0.3 mg/kg) showed a significant and prolonged inhibition of paw oedema. Histological analysis demonstrated a reduction in inflammatory cells and expression of inducible nitric oxide synthase (iNOS) in footpads 6 h after administration of carrageenan. 21­BD (0.3 mg/kg) also reduced the levels of tumour necrosis factor (TNF)-α 2 and 4 h after carrageenan. 21­BD demonstrated antinociceptive activity, inhibiting abdominal writhes at all tested doses. However, in the formalin test, 21­BD did not present antinociceptive activity. In the acute toxicity test, 21­BD did not cause symptoms of toxicity or mortality. The present study demonstrated, for the first time, that 21­BD is safe and exhibits a marked anti-inflammatory activity in acute local inflammation. This effect might be a consequence of its ability to inhibit the release of the PMN leucocyte-derived mediators, including TNF-α, and iNOS expression as well as its inhibitory effect on oedema and PMN leucocyte infiltration.

Assuntos

Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Digoxina/análogos & derivados , Analgésicos/química , Animais , Anti-Inflamatórios/química , Carragenina/toxicidade , Digoxina/administração & dosagem , Digoxina/química , Digoxina/farmacologia , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Indometacina/farmacologia , Masculino , Camundongos , Estrutura Molecular , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Testes de Toxicidade , Fator de Necrose Tumoral alfa/metabolismo

RESUMO

BACKGROUND AND AIMS: This study aimed to assess the potential of calcitonin-gene related peptide (CGRP), a neuropeptide released from sensory nerves, to induce oedema in orofacial tissue. EXPERIMENTAL APPROACH: Wistar rats (150-200 g) anesthetized with isoflurane were injected intraorally with CGRP (100 µl; 8-33 pmol) in the right side of the mouth. The contralateral side was injected with the same volume of physiological saline. Increased cheek thickness (in mm), as a measure of oedema formation, was assayed bilaterally with a digital caliper before (T = 0) and up to 24 h following injection of CGRP. Pretreatment with antagonists (CGRP8-37, 10 nmol; pizotifen, 2 mg/kg) was given by intra-oral or subcutaneous injection, 10 or 30 min, respectively, before the inflammatory stimulus. CGRP and CGRP8-37 were also injected into the rat hind paw to induce oedema. Data are presented as the mean (±SEM) difference in thickness between the right and the left sides at each time. RESULTS: Following intra-oral injection, CGRP induced a rapidly developing (5-15 min) and long-lasting (6 h), dose-dependent oedema in the rat cheek, blocked by pre-treatment with CGRP8-37 or pizotifen. CGRP induced a smaller oedematogenic effect in the rat hind paw also blocked by the CGRP antagonist. CGRP (16 pmol) potentiated the oedema induced by co-injected substance P (3.7 nmol) and contributed to the oedema following intraoral injection of carrageenan (100 µg). Injection of CGRP8-37 alone induced an early but short-lasting oedema. CONCLUSION: Local injection of CGRP potently induced oedema in the orofacial tissue of rats which was blocked by a CGRP receptor antagonist. The overall inhibition of carrageenan-induced oedema by CGRP8-37 suggests that endogenous CGRP contributes to an oedematogenic response in orofacial tissues.

Assuntos

Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem , Bochecha/patologia , Edema/induzido quimicamente , Lábio/efeitos dos fármacos , Lábio/patologia , Animais , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Carragenina/administração & dosagem , Inflamação/induzido quimicamente , Masculino , Fragmentos de Peptídeos/administração & dosagem , Ratos Wistar , Substância P/administração & dosagem

Assuntos

Edema/etiologia , Inflamação/etiologia , Periodontite/complicações , Receptor B1 da Bradicinina/imunologia , Perda do Osso Alveolar/etiologia , Perda do Osso Alveolar/imunologia , Perda do Osso Alveolar/patologia , Animais , Chondrus , Modelos Animais de Doenças , Edema/induzido quimicamente , Edema/imunologia , Edema/patologia , Extremidades/patologia , Inflamação/imunologia , Inflamação/patologia , Interleucina-1beta/imunologia , Masculino , Periodontite/imunologia , Periodontite/patologia , Ratos , Ratos Wistar , Receptor B1 da Bradicinina/análise , Fator de Necrose Tumoral alfa/imunologia

RESUMO

Copaiba oil is used as a popular medicine in the Amazonian forest region, especially due to its anti-inflammatory properties. In this paper, we describe the formulation of hydrogel containing copaiba oil nanoemulsions (with positive and negative charges), its skin permeation, and its anti-inflammatory activity in two in vivo models: mouse ear edema and rat paw edema. Three hydrogels were tested (Carbopol®, hydroxyethylcellulose and chitosan), but only Carbopol® and hydroxyethylcellulose hydrogels presented good stability and did not interfere with the nanoemulsions droplet size and polydispersity index. In skin permeation assay, both formulations, positively charged nanoemulsion (PCN) and negatively charged nanoemulsion (NCN), presented a high retention in epidermis (9.76 ± 2.65 µg/g and 7.91 ± 2.46 µg/cm2, respectively) followed by a smaller retention in the dermis (2.43 ± 0.91 and 1.95 ± 0.56 µg/cm2, respectively). They also presented permeation to the receptor fluid (0.67 ± 0.22 and 1.80 ± 0.85 µg/cm2, respectively). In addition, anti-inflammatory effect was observed to NCN and PCN with edema inhibitions of 69 and 67% in mouse ear edema and 32 and 72% in rat paw edema, respectively. Histological cuts showed the decrease of inflammatory factors, such as dermis and epidermis hyperplasia and inflammatory cells infiltration, confirming the anti-inflammatory effect from both copaiba oil nanoemulsions incorporated in hydrogel.

Assuntos

Anti-Inflamatórios/administração & dosagem , Fabaceae/química , Óleos de Plantas/administração & dosagem , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Edema/tratamento farmacológico , Emulsões , Hidrogéis , Masculino , Camundongos , Nanopartículas , Óleos de Plantas/farmacocinética , Óleos de Plantas/uso terapêutico , Ratos , Pele/metabolismo

RESUMO

Seeds of Crotalaria retusa L. are used in popular medicine because of their pharmacological properties. The albumin fraction obtained from its seeds contains lectin, a protein known to have analgesic and anti-inflammatory properties. Thus, albumins extracted from C. retusa were investigated for their anti-inflammatory and antinociceptive effects. The intraperitoneal administration of different doses of albumins (5, 10 or 20mg/kg) significantly inhibited the mice paw edema induced by carrageenan (maximum inhibition rate of 80.9% at four hours, 20mg/kg), and this event was followed by diminishing paw myeloperoxidase measurements. Albumins (20mg/kg) also inhibited neutrophil migration into the peritoneal cavity induced by carrageenan. However, no effect was observed in the dextran-induced paw edema and abdominal contortions induced by acetic acid. Moreover, albumins (20mg/kg) significantly reduced the second (inflammatory) phase of the licking time induced by formalin. The detection of heammaglutinating activity against human erythrocytes in albumins evidences the presence of lectin in seeds of C. retusa. Our data showed that seeds of C. retusa had anti-inflammatory and antinociceptive properties and such activities are probably due to the inhibitory effect on neutrophil migration of lectin present in albumins.

Assuntos

Albuminas/farmacologia , Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Crotalaria/química , Sementes/química , Albuminas/uso terapêutico , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Movimento Celular/efeitos dos fármacos , Fracionamento Químico , Cromatografia de Afinidade , Edema/tratamento farmacológico , Edema/patologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Hemaglutinação/efeitos dos fármacos , Humanos , Lectinas/farmacologia , Masculino , Camundongos , Peritonite/tratamento farmacológico , Peritonite/patologia

RESUMO

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used medications in inflammatory illnesses. However, the gastrointestinal bleeding and toxicity associated with NSAIDs long term use prompted the quest towards investigations for new anti-inflammatory agents. Natural and natural-derived molecules proved its anti-inflammatory efficacy in vitro as well as in vivo. Given this background, the scope of this research involves structural changes of the natural polyphenol (tyrosol) generating two new salicylate derivatives and testing their biological properties, focusing on anti-inflammatory effects assessed in vitro and in vivo assays. The first molecular modification was the introduction of a carboxylic acid group adjacent to the phenol group present in this compound, which creates a new salicylate-like tyrosol. In addition, the acetylation of phenol group in this molecule produced an acetylsalicylate derivative, which may be regarded as aspirin-like natural polyphenol. Interestingly, tyrosol and its novel derivatives attenuated the edema in acute inflammatory response on carrageenan- induced local inflammation in mice. In addition, our results demonstrated that tyrosol and its novel derivatives were able to reduce the chemotaxis of neutrophil assessed in vitro model by chemo attractant (fMLP). Furthermore, only derivative 2 was able to reduce this effect in the acute inflammatory model. In (DPPH)- scavenging activity, tyrosol derivatives demonstrated a minor antioxidant activity, which may suggest that radical scavenging is not a major pathway involved in the anti-inflammatory effects of these derivatives. Salicylate-like tyrosol derivatives are of particular interest for future studies.

Assuntos

Anti-Inflamatórios não Esteroides/farmacologia , Edema/tratamento farmacológico , Inflamação/tratamento farmacológico , Álcool Feniletílico/análogos & derivados , Salicilatos/síntese química , Salicilatos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Carragenina , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Inflamação/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Álcool Feniletílico/síntese química , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Salicilatos/química , Relação Estrutura-Atividade

RESUMO

Abstract Aiming to investigate new therapeutic agents with fewer side effects, the number of studies about natural products has increased. Phenolic compounds comprise a well-studied class of abundant plant-derived compounds, whose anti-inflammatory activity has been described. Isoflavones are phenolic compounds that occur mainly in the Leguminosae family, and can be found in many species, such as Trifolium riograndense Burkart, Leguminosae (clover). In this study an HPLC method was used to determine and quantify four isoflavones (genistein, daidzein, formononetin, and biochanin A) in hydrolyzed leaf, flower, stolon, and root extracts of T. riograndense. In vivo anti-inflammatory activity was investigated using the rat paw edema method and in vitro chemotaxis model with a dry extract from the leaves, which had the highest amount of isoflavones. The major isoflavone found in all parts of the plant was formononetin. The chemotaxis assay revealed that the different concentrations (0.2-50 µg/ml) of the dry extract significantly inhibited neutrophil migration in a concentration-dependent manner (more than 90%). In the rat paw edema test, oral administration of clover extract 100 mg/kg was able to significantly inhibit the edema formation induced by carrageenan. In conclusion, chemical analyses showed that Trifolium riograndense is a plant rich in isoflavones and a new interesting option as isoflavone source. The results of the biological tests taken together show that the extract of T. riograndense has anti-inflammatory effect in rodents.

RESUMO

We have designed a microemulsion (ME) containing Ketoprofen (KET) for anti-inflammatory effect evaluated using the rat paw edema model. The ME was prepared by adding propylene glycol (PG) loaded with 1% KET/water (3:1, w/w), to a mixture of sorbitan monooleate and polysorbate 80 (47.0%) at 3:1 (w/w) and canola oil (38.0%). The physicochemical characterization of KET-loaded ME involved particle size and zeta potential determination, entrapment efficiency, calorimetric analysis, and in vitro drug release. The in vivo anti-inflammatory study employed male Wistar rats. Measurement of the foot volume was performed using a caliper immediately before and 2, 4, and 6 h after injection of Aerosil. KET-loaded ME showed particle size around 20 nm, with zeta potential at -16 mV and entrapment efficiency at 70%. Moreover, KET was converted to the amorphous state when loaded in the formulation and it was shown that the drug was slowly released from the ME. Finally, the in vivo biological activity was similar to that of the commercial gel, but ME better controlled edema at 4 h. These results demonstrated that the ME formulation is an alternative strategy for improving KET skin permeation for anti-inflammatory effect. Furthermore, our findings are promising considering that the developed ME was loaded with only 1% KET, and the formulation was able to keep a similar release profile and in vivo effect compared to the commercial gel with 2.5% KET. Therefore, the KET-loaded developed herein ME is likely to have a decreased side effect compared with that of the commercial gel, but both presented the same efficacy.

Assuntos

Anti-Inflamatórios não Esteroides/administração & dosagem , Cetoprofeno/administração & dosagem , Pele/metabolismo , Animais , Liberação Controlada de Fármacos , Edema/tratamento farmacológico , Emulsões/química , Cetoprofeno/química , Cetoprofeno/farmacocinética , Cetoprofeno/farmacologia , Masculino , Tamanho da Partícula , Ratos , Ratos Wistar , Absorção Cutânea

RESUMO

Camellia sinensis, which is obtained from green tea extract (GTE), has been widely used in therapy owing to the antioxidant, chemoprotective, and anti-inflammatory activities of its chemical components. However, GTE is an unstable compound, and may undergo reactions that lead to a reduction or loss of its effectiveness and even its degradation. Hence, an attractive approach to overcome this problem to protect the GTE is its incorporation into liquid crystalline systems (LCS) that are drug delivery nanostructured systems with different rheological properties, since LCS have both fluid liquid and crystalline solid properties. Therefore, the aim of this study was to develop and characterize GTE-loaded LCS composed of polyoxypropylene (5) polyoxyethylene (20) cetyl alcohol, avocado oil, and water (F25E, F29E, and F32E) with different rheological properties and to determine their anti-inflammatory efficacy. Polarized light microscopy revealed that the formulations F25, F29, and F32 showed hexagonal, cubic, and lamellar liquid crystalline mesophases, respectively. Rheological studies showed that F32 is a viscous Newtonian liquid, while F25 and F29 are dilatant and pseudoplastic non-Newtonian fluids, respectively. All GTE-loaded LCS behaved as pseudoplastic with thixotropy; furthermore, the presence of GTE increased the S values and decreased the n values, especially in F29, indicating that this LCS has the most organized structure. Mechanical and bioadhesive properties of GTE-unloaded and -loaded LCS corroborated the rheological data, showing that F29 had the highest mechanical and bioadhesive values. Finally, in vivo inflammation assay revealed that the less elastic and consistent LCS, F25E and F32E presented statistically the same anti-inflammatory activity compared to the positive control, decreasing significantly the paw edema after 4 h; whereas, the most structured and elastic LCS, F29E, strongly limited the potential effects of GTE. Thereby, the development of drug delivery systems with suitable rheological properties may enhance GTE bioavailability, enabling its administration via the skin for the treatment of inflammation.

RESUMO

Na Região Amazônica o uso do óleo das árvores copaibeiras é tão extenso, que a copaíba se destaca como a planta medicinal mais utilizada e conhecida pela população amazônica. Existem diversas indicações para a utilização do óleo-resina de copaíba com pouco respaldo científico. Avaliar a ação do óleo-resina de copaíba da espécie Copaifera reticulata como antiinflamatório em modelos experimentais de reação inflamatória aguda foi o objetivo desta pesquisa. Para isso, foram utilizados 4 grupos de 7 camundongos da linhagem Swiss Webster, que receberam tratamento veiculado com o ultrassom, e o óleo-resina extraído de árvore da espécie Copaífera reticulata. O modelo de inflamação aguda bolsa de ar (air pouch) induzida por carragenina foi utilizado para avaliar o efeito anti-inflamatório do óleo-resina de copaíba (in natura). As análises ocorreram no exsudato que foi avaliado quanto ao conteúdo total de proteínas, número total de leucócitos e análise celular. Para análise estatística foi eleito o teste de Kruskal-Wallis com nível de significância alfa = 0,05. As células totais e as mononucleares não mostraram diferenças estatisticamente significantes entre si nem em relação ao grupo copaíba. A comparação do nível de proteínas apresentou diferença significativa (p-valor < 0,01) entre o grupo controle (0,2608 ± 0,1557) e o grupo tratado por carragenina (0,597 ± 0,152). Foi observada diferença real (1,4 neutrófilos) entre os grupos carragenina (2,0079 ± 1,5231) e o grupo copaíba (0,6063 ± 0,32). Conclui-se que a atividade anti-inflamatória do óleo-resina é potencialmente importante como fonte de princípios ativos e que o ultrassom proporcionou a facilitação e aceleração da penetração transcutânea do óleo-resina de copaíba, favorecendo o seu uso tópico. (AU)

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In the Amazon region the use of oil of copaibeira trees is so extensive that the copal stands out as the most known medicinal plant used by Amazonian population. There are several indications for the use oleoresin of copaiba with little scientific backing. The aim of this study was to evaluate the effects of oleoresin of copaiba species Copaifera reticulata as antiinflammatory in experimental models of acute inflammatory reaction. For this, we used 28 mice of Swiss Webster strain, who received treatment with ultrasound aired, and oleoresin extracted from Copaifera reticulata. The model of acute inflammation air pouch induced by carrageenan was used to evaluate the anti-inflammatory effect of oleoresin of copaiba (fresh). The analysis occurred in the exudate analyzed for total protein content, total number of leukocytes and cell analysis. For statistical analysis was elected the Kruskal-Wallis test with significance level alpha = 0.05. Total cells and mononuclear cells showed no statistically significant differences among themselves or in relation to the group copal. The comparison of protein level showed a significant difference (p-value < 0.01 *), saline was lower (0.2608 ± 0.1557) than carrageenan (0.597 ± 0.152). Real difference was observed (1.4 neutrophils) between groups carrageenan (2.0079 ± 1.5231) and the group copaíba (0.6063 ± 0:32). We concluded that the antiinflammatory activity of the oleoresin is potentially important as a source of active ingredients and provided that ultrasound facilitation and acceleration of transcutaneous penetration of the copaiba oil, favoring its topical use. (AU)

Assuntos

Animais , Masculino , Camundongos , Anti-Inflamatórios , Fabaceae , Edema , Compostos Fitoquímicos , Ultrassom

RESUMO

BACKGROUND: Many fruits have been used as nutraceuticals because the presence of bioactive molecules that play biological activities. OBJECTIVE: The present study was designed to compare the anti-inflammatory and antioxidant effects of methanolic extracts of Lycium barbarum (GOJI), Vaccinium macrocarpon (CRAN) and Vaccinium myrtillus (BLUE). MATERIALS AND METHODS: Mices were treated with extracts (50 and 200 mg/kg, p.o.), twice a day through 10 days. Phytochemical analysis was performed by high-performance liquid chromatography. Antioxidant activity was determine by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, reducing power, lipid peroxidation thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and catalase (CAT) activity. Anti-inflammatory activity was evaluated by paw edema followed by determination of myeloperoxidase (MPO) and TBARS. RESULTS: High amount of phenolic compounds, including rutin, were identified in all berries extracts. However, quercetin was observed only in BLUE and CRAN. GOJI presents higher scavenging activity of DPPH radical and reducing power than BLUE and CRAN. The extracts improved antioxidant status in liver; BLUE showed the largest reduction (75.3%) in TBARS when compared to CRAN (70.7%) and GOJI (65.3%). Nonetheless, CAT activity was lower in BLUE group. However, hepatic concentrations of GSH were higher in animals treated with GOJI rather than CRAN and BLUE. Despite all fruits caused a remarkable reduction in paw edema and TBARS, only BLUE and CRAN were able to reduce MPO. CONCLUSION: These results suggest that quercetin, rutin, or other phenolic compound found in these berry fruits extracts could produce an anti-inflammatory response based on modulation of oxidative stress in paw edema model. SUMMARY: Within fruits broadly consumed because of its nutraceuticals properties include, Lycium barbarum (Goji berry), Vaccinium myrtillus (Blueberry or Bilberry) and Vaccinium macrocarpon (Cranberry)The objectives of this study were the investigation and comparison of chemical composition, antioxidant activity "in vitro" and "in vivo" and anti inflammatory property of berry fruits bought dry form.In summary, two main findings can be addressed with this study: (1) Berry fruits presented antioxidant and anti inflammatory activities "in vitro" and "in vivo"; (2) the extracts of GOJI, CRAN, and BLUE modulate the inflammatory process by different mechanisms.