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1.
Life Sci ; 229: 139-148, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31085246

RESUMO

Citral (CIT) is a monoterpene formed by the geranial and neral stereoisomers. CIT is the major compound of Cymbopogon citratus essential oil, commonly known as "lemongrass", and has demonstrated potential antihyperalgesic, anti-nociceptive and anti-inflammatory effects. However, CIT shows high volatility, low solubility in water and consequent low bioavailability, which limits its use. Therefore, the aim of this study was to evaluate cell viability, anti-hyperalgesic and anti-inflammatory effects of inclusion complexes of CIT on ß-cyclodextrin (ß-CD) and hydroxypropyl-ß-cyclodextrin (HP-ß-CD). Initially, physical mixture (PM) and freeze-dried inclusion (FD) complexes of CIT/ß-CD and CIT/HP-ß-CD were obtained in the molar ratio (1:1). The samples were characterized by DSC, TG/DTG, FT-IR, XRD, SEM and the complexation efficiency were performed by HPLC. Cell viability assay was performed by rezasurin reduction technique in J774 macrophages cell line. The motor activity through rota rod apparatus, mechanical hyperalgesia and pleurisy induced by carrageenan were evaluated in mice. The complexation of CIT was evidenced with ß-CD and HP-ß-CD by the characterization techniques analyzed. The complexation efficiency of CIT/ß-CD and CIT/HP-ß-CD were 78.6% and 71.7%, respectively. The CIT, CIT/ß-CD and CIT/HP-ß-CD showed cell viability in macrophages and did not interfere in the motor activity of mice. Besides that, the samples demonstrated antihyperalgesic and anti-inflammatory activity due to the reduction in total leukocytes and TNF-α levels. However, CIT/ß-CD has better pharmacological effects among the three samples evaluated. Therefore, CIT/ß-CD has potential for the development of products to treat inflammatory and pain reactions.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/farmacologia , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Monoterpenos/farmacologia , beta-Ciclodextrinas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Carragenina/toxicidade , Quimioterapia Combinada , Hiperalgesia/induzido quimicamente , Hiperalgesia/patologia , Inflamação/induzido quimicamente , Inflamação/patologia , Masculino , Camundongos
2.
PLoS One ; 14(5): e0217209, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31125368

RESUMO

BACKGROUND: Recently, attention has been focused on the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the mechanism of and as a treatment target for neuropathic and inflammatory pain. Ivabradine, a blocker of HCN channels, was demonstrated to have an effect on neuropathic pain in an animal model. Therefore, in the present study, we evaluated the effect of ivabradine on inflammatory pain, and under the hypothesis that ivabradine can directly influence inflammatory responses, we investigated its effect in in vivo and in vitro studies. METHODS: After approval from our institution, we studied male Sprague-Dawley rats aged 8 weeks. Peripheral inflammation was induced by the subcutaneous injection of carrageenan into the hindpaw of rats. The paw-withdrawal threshold (pain threshold) was evaluated by applying mechanical stimulation to the injected site with von Frey filaments. Ivabradine was subcutaneously injected, combined with carrageenan, and its effect on the pain threshold was evaluated. In addition, we evaluated the effects of ivabradine on the accumulation of leukocytes and TNF-alpha expression in the injected area of rats. Furthermore, we investigated the effects of ivabradine on LPS-stimulated production of TNF-alpha in incubated mouse macrophage-like cells. RESULTS: The addition of ivabradine to carrageenan increased the pain threshold lowered by carrageenan injection. Both lamotrigine and forskolin, activators of HCN channels, significantly reversed the inhibitory effect of ivabradine on the pain threshold. Ivabradine inhibited the carrageenan-induced accumulation of leukocytes and TNF-alpha expression in the injected area. Furthermore, ivabradine significantly inhibited LPS-stimulated production of TNF-alpha in the incubated cells. CONCLUSION: The results of the present study demonstrated that locally injected ivabradine is effective against carrageenan-induced inflammatory pain via HCN channels. Its effect was considered to involve not only an action on peripheral nerves but also an anti-inflammatory effect.


Assuntos
Fármacos Cardiovasculares/farmacologia , Carragenina/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Inflamação/prevenção & controle , Ivabradina/farmacologia , Dor/prevenção & controle , Canais de Potássio/metabolismo , Animais , Fármacos Cardiovasculares/administração & dosagem , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Ivabradina/administração & dosagem , Masculino , Dor/induzido quimicamente , Dor/metabolismo , Dor/patologia , Canais de Potássio/genética , Ratos , Ratos Sprague-Dawley
3.
Biomed Pharmacother ; 115: 108882, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31029001

RESUMO

In the current work, the phytochemical composition of a leaf methanol extract from Albizia anthelmintica was thoroughly investigated. The antioxidant, anti-inflammatory, analgesic, and antipyretic activities of the extract were investigated. In the carrageenan induced hind paw edema bioassay; the extract significantly reduced the edema thickness in rats and diminished the leukocyte migration to the peritoneal cavity in mice. The extract exhibited central and peripheral anti-nociceptive effects; it significantly decreased the number of acetic acid induced writhes and prolonged the latency time in the hot plate test. The extract showed a substantial antipyretic activity as it decreased significantly the elevated rectal temperature in mice after intraperitoneal injection of Brewer's yeast. Molecular docking of some major compounds in the extract to COX-1, COX-2 and 5-LOX, enzymes involved in the inflammation cascade, revealed appreciable interactions with the conserved amino acid residues in these target proteins. These findings were confirmed with in vitro enzyme inhibitory assays in which the extract showed IC50 values of 4.11, 0.054, and 1.74 µg/mL towards COX-1, COX-2 and 5-LOX, respectively. The extract displayed solid antioxidant properties as well with a TAC value of 35.13 U/L and EC50of 5.36 µg/mL in DPPH assay. These findings suggested that Albizia anthelmintica is a good antioxidant with potential therapeutic efficacy for treating inflammation, pain and related oxidative stress disorders.


Assuntos
Albizzia/química , Analgésicos/farmacologia , Antioxidantes/farmacologia , Dor/tratamento farmacológico , Extratos Vegetais/farmacologia , Folhas de Planta/química , Analgésicos/química , Animais , Anti-Inflamatórios , Antioxidantes/química , Antipiréticos , Carragenina/toxicidade , Cromatografia Líquida , Diclofenaco/farmacologia , Glucosídeos/química , Camundongos , Simulação de Acoplamento Molecular , Nalbufina/farmacologia , Extratos Vegetais/química , Prostaglandina-Endoperóxido Sintases/química , Prostaglandina-Endoperóxido Sintases/metabolismo , Distribuição Aleatória , Ratos , Espectrometria de Massas em Tandem/métodos , Leveduras
4.
Biomed Pharmacother ; 113: 108721, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30856538

RESUMO

Kalanchoe brasiliensis and Kalanchoe pinnata are used interchangeably in traditional medicine in the treatment of wound healing. In this context, the objective of the present study was to evaluate the local anti-inflammatory activity of a topical formulation containing aqueous extract of both species. The in vivo model used was ear edema induced by croton oil and paw edema induced by carrageenan. The Swiss mice treatments use formulations containing aqueous extract at different concentrations (1.25%, 2.5%, and 5%) or dexamethasone (1 mg/g), all administered topically and immediately after edema induction. The treatment with formulations containing aqueous extract of both species reduced ear and paw edema, besides that, the decrease in edema was evidenced by reduction of myeloperoxidase activity, IL-1ß, and TNF-α levels and increase IL-10 levels. In conclusion, the two species showed local anti-inflammatory activity; however K. brasiliensis showed a better result in both edematogenic models since it had activity in the lowest concentration.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Kalanchoe/química , Extratos Vegetais/farmacologia , Administração Cutânea , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/isolamento & purificação , Carragenina/toxicidade , Óleo de Cróton/toxicidade , Dexametasona/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Edema/patologia , Feminino , Inflamação/patologia , Interleucina-1beta/metabolismo , Masculino , Camundongos , Peroxidase/metabolismo , Extratos Vegetais/administração & dosagem , Folhas de Planta , Fator de Necrose Tumoral alfa/metabolismo , Água/química
5.
J Ethnopharmacol ; 236: 401-411, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30703495

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Holigarna caustica (Dennst.) is commonly used in traditional medicine to treat a variety of painful conditions such as eye irritation, inflammation, arthritis, skin diseases, cuts and wounds. AIM OF THE STUDY: The present study was undertaken to investigate the anti-nociceptive and anti-inflammatory activities of the methanol extract of H. caustica leaves and to elucidate its possible mechanism(s) of action. MATERIALS AND METHODS: Fresh leaves of H. caustica were collected, dried, and extracted with methanol (MEHC). MEHC was subjected to activity testing, using chemical-induced (acetic acid and formalin test) and heat-induced (hot plate and tail immersion test) pain models. To determine the possible mechanism behind the anti-nociceptive activity of MEHC, the opioid antagonist naltrexone was used to evaluate the involvement of opioid receptors in the case of formalin, hot plate and tail immersion tests, while the involvement of the cGMP and ATP-sensitive K+ channel pathways were assessed using methylene blue and glibenclamide respectively, in the acetic acid-induced writhing test. In parallel, the carrageenan-induced paw oedema model was used to determine the anti-inflammatory potential of the extract. Exploratory and motor behaviours were evaluated by the open-field test. Various bioactive compounds potentially responsible for the anti-nociceptive and anti-inflammatory activities were ascertained using GC-MS analysis. RESULTS: MEHC showed strong, significant and dose-dependent anti-nociceptive activity in all chemical-induced and heat-induced pain models at all experimental doses. The association of opioid receptors with the observed anti-nociceptive effects was confirmed by using naltrexone. The cGMP and ATP-sensitive K+ channel pathway was also shown to be involved in the anti-nociceptive activity of MEHC. In addition, MEHC exhibited a dose-dependent inhibition of inflammatory oedema induced by carrageenan. MEHC was not connected with changes in either the locomotor activity or motor responses of mice. In a GC-MS analysis, 40 compounds were identified, among which twelve are documented bioactive compounds with potent analgesic and anti-inflammatory properties. CONCLUSIONS: Our current study revealed that MEHC possesses strong central and peripheral anti-nociceptive as well as anti-inflammatory activity. It may also be concluded that both opioid receptors as well as the cGMP and ATP-sensitive K+ channel pathway are involved in the anti-nociceptive mechanism of MEHC. This study rationalizes the ethnomedicinal use of H. caustica leaves in various painful conditions.


Assuntos
Anacardiaceae/química , Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Edema/tratamento farmacológico , Dor/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Analgésicos/isolamento & purificação , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/uso terapêutico , Bangladesh , Carragenina/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Feminino , Humanos , Canais KATP/metabolismo , Masculino , Medicina Tradicional , Metanol/química , Camundongos , Nociceptividade/efeitos dos fármacos , Dor/etiologia , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Receptores Opioides/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Phytomedicine ; 57: 9-17, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30668327

RESUMO

BACKGROUND: It is well known that medicinal plants and their products are relevant candidates for the treatment of inflammatory conditions. Ethyl p-coumarate is a phenylpropanoid that has similar structure to others anti-inflammatory and antioxidant substances. However, these activities have never been tested. PURPOSE: The aim of this study was to investigate the effect of ethyl p-coumarate on inflammatory and oxidative stress parameters. STUDY DESIGN: This is an experimental study to evaluate the anti-inflammatory and antioxidant activities of ethyl p-coumarate in acute and chronic models of inflammation. METHODS: The anti-inflammatory effect of ethyl p-coumarate was evaluated in Swiss mice by carrageenan-induced paw edema model (1%, 50 µl), followed by histological analysis, and edema induced by compound 48/80 (12 µg/paw), histamine (100  µg/paw), serotonin (100 µg/paw) and prostaglandin E2 (3 nmol/paw) in comparison to indomethacin treatment (10 mg/kg, p.o.). In addition, peritonitis was induced by carrageenan (500 µg/cavity) to neutrophil and total leukocytes counting, myeloperoxidase (MPO), interleukin 6 (IL-6) and 8 (IL-8), nitrite (NO2-), glutathione (GSH) and malondialdehyde (MDA) measurements. The arthritis model was induced with Freund's complete adjuvant (id. 0.1 ml) in female Wistar rats, with measurement of joint diameter and X-ray. Changes in gastric tissue of Swiss mice were analyzed in comparison to indomethacin (20  mg/kg, p.o.). RESULTS: After treatment with ethyl p-coumarate, the animals had no apparent toxic effects, and significantly inhibited paw edema induced by edematogenic agents, neutrophil (p < 0.001) and total leukocyte (p < 0.001) migration, MPO (p < 0.01), IL-6 (p < 0.05) and IL-8 (p < 0.5), MDA (p < 0.5), GSH (p < 0.5), NO2- (p < 0.001), joint thickness and bones changes. Furthermore, were not observed significant formation of gastric lesions. CONCLUSION: Taken together, these results suggest that ethyl p-coumarate exhibits anti-inflammatory activity through the inhibition of inflammatory mediators and leukocyte migration without causing gastric lesions.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ácidos Cumáricos/farmacologia , Inflamação/tratamento farmacológico , Neutrófilos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Carragenina/toxicidade , Movimento Celular/efeitos dos fármacos , Doença Crônica , Edema/induzido quimicamente , Edema/tratamento farmacológico , Feminino , Adjuvante de Freund/toxicidade , Inflamação/patologia , Masculino , Camundongos , Neutrófilos/metabolismo , Neutrófilos/patologia , Peritonite/induzido quimicamente , Peritonite/tratamento farmacológico , Ratos Wistar
7.
Phytomedicine ; 54: 169-181, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30668366

RESUMO

BACKGROUND: Different processing conditions alter the ginseng bioactive compounds, promoting or reducing its anti-inflammatory effects. We compared black ginseng (BG) - that have been steamed 5 times - with red ginseng (RG). HYPOTHESIS/ PURPOSE: To compare the anti-inflammatory activities and the anti-nociceptive properties of RG and BG. METHODS: Nitric Oxide (NO) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay, quantitative Reverse Transcriptase-Polymerase Chain Reaction (qRT-PCR), western blot, xylene-induced ear edema, carrageenan-induced paw edema RESULTS: The ginsenoside contents were confirmed using high-performance liquid chromatography (HPLC) and has been altered through increased processing. The highest concentration of these extracts inhibited NO production to near-basal levels in lipopolysaccharide (LPS)-stimulated RAW 264.7 without exhibiting cytotoxicity. Pro-inflammatory cytokine expression at the mRNA level was investigated using qRT-PCR. Comparatively, BG exhibited better inhibition of pro-inflammatory mediators, iNOS and COX-2 and pro-inflammatory cytokines, IL-1ß, IL-6 and TNF-α. Protein expression was determined using western blot analysis and BG exhibited stronger inhibition. Xylene-induced ear edema model in mice and carrageenan-induced paw edema in rats were carried out and tested with the effects of ginseng as well as dexamethasone and indomethacin - commonly used drugs. BG is a more potent anti-inflammatory agent, possesses anti-nociceptive properties, and has a strong potency comparable to the NSAIDs. CONCLUSION: BG has more potent anti-inflammatory and anti-nociceptive effects due to the change in ginsenoside component with increased processing.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Edema/tratamento farmacológico , Panax/química , Extratos Vegetais/farmacologia , Animais , Carragenina/toxicidade , Ciclo-Oxigenase 2/metabolismo , Citocinas/genética , Citocinas/metabolismo , Edema/induzido quimicamente , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley
8.
Phytomedicine ; 55: 191-199, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668429

RESUMO

BACKGROUND: Veratrum, hellebore is an important plant species of the Liliaceae family and jervine is the characteristic steroidal alkaloid constituent of Veratrum album. PURPOSE: In the current study, anti-inflammatory and antioxidant effects of jervine isolated from NH4OH-benzene extract of V. album rhizomes were investigated on CAR induced paw edema in rats. METHODS/STUDY DESIGN: In inflammatory study, 50, 100, 200 and 400  mg/kg doses of jervine, 25  mg/kg doses of DIC and IND were orally administered, and the volume of the foots were measured up to their knee arthrosis by plethismometer. After one hour of the oral administration of the all treatments, 0.1 ml of CAR solution (1%) was injected into the foot of the all rat groups and the volume of the foots were measured during 5 h after CAR injection. GPx, SOD, GR, MPO, CAT enzymes activities and GSH, LPO levels of the supernatants of paw homogenates and inflammation biomarkers such as TNF-α and IL-1ß in the rats serums were also estimated. RESULTS: According to the present results, jervine exerted 50.4-73.5% anti-inflammatory effects in carrageenan induced paw edema. Inflammation biomarkers such as TNF-α, IL-1ß and MPO that increased by CAR injection were suppressed by the administrations of all doses of jervine, IND and DIC. In all paw tissues, LPO levels as indicator of oxidative tissue damage were found to be high in CAR-treated group and it was found to be decreased in all doses of jervine. CONCLUSION: Jervine, DIC and IND reduced the negative effects of CAR due to increasing effects on the SOD, CAT, GSH, GPx and GR antioxidants.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Alcaloides de Veratrum/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Antioxidantes/metabolismo , Carragenina/toxicidade , Avaliação Pré-Clínica de Medicamentos/métodos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Enzimas/metabolismo , Inflamação/tratamento farmacológico , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Extratos Vegetais/química , Ratos Sprague-Dawley , Rizoma/química , Fator de Necrose Tumoral alfa/metabolismo , Veratrum/química , Alcaloides de Veratrum/administração & dosagem , Alcaloides de Veratrum/isolamento & purificação
9.
Pain ; 160(1): 102-116, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30169421

RESUMO

Neuropathic pain is one of the most important types of chronic pain. It is caused by neuronal damage. Clinical and experimental studies suggest a critical role for neuroimmune interactions in the development of neuropathic pain. In this article, we have shown that the cytoplasmic receptor Nod-like receptor-2, NOD2, and its adaptor-signaling molecule RIPK2 participate in the development of neuropathic pain after peripheral nerve injury (spared nerve injury model). The activation of NOD2 signaling in peripheral macrophage mediates the development of neuropathic pain through the production of pronociceptive cytokines (tumor necrosis factor and IL-1ß). This study found that peripheral nerve injury promoted a systemic increase in the NOD2 ligand. These results highlight a previously undetermined role for NOD2 signaling in the development of neuropathic pain, suggesting a new potential target for preventing neuropathic pain.


Assuntos
Macrófagos/metabolismo , Neuralgia/patologia , Neuralgia/fisiopatologia , Proteína Adaptadora de Sinalização NOD2/metabolismo , Animais , Transplante de Medula Óssea , Carragenina/toxicidade , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/terapia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Minociclina/uso terapêutico , Neuralgia/genética , Neuralgia/cirurgia , Fármacos Neuroprotetores/uso terapêutico , Proteína Adaptadora de Sinalização NOD2/genética , RNA Interferente Pequeno/uso terapêutico , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Xantinas/uso terapêutico
10.
Crit Rev Food Sci Nutr ; 59(19): 3054-3073, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29902080

RESUMO

Carrageenan (CGN) is a common food additive that has been widely used for decades as a gelling, thickening and stabilizing agent. Carrageenan has been proven safe for human consumption; however, there has been significant confusion in the literature between CGN and the products of intentional acid-hydrolysis of CGN, which are degraded CGN (d-CGN) and poligeenan (PGN). In part, this confusion was due to the nomenclature used in early studies on CGN, where poligeenan was referred to as "degraded carrageenan" (d-CGN) and "degraded carrageenan" was simply referred to as carrageenan. Although this nomenclature has been corrected, confusion still exists resulting in misinterpretation of data and the subsequent dissemination of incorrect information regarding the safe dietary use of CGN. The lack of understanding of the molecular weight distribution of CGN has further exacerbated the issue. The significant differences in chemistry, manufacture, and protein reactivity of CGN versus d-CGN and PGN are reviewed, in addition to the in vivo toxicological profiles of CGN, d-CGN, and PGN. As CGN cannot be hydrolyzed to PGN in vivo, concerns over the use of CGN as a food additive are unfounded, particularly since current studies support the lack of oncogenic and tumorigenic activity of CGN in humans.


Assuntos
Carragenina/química , Aditivos Alimentares/química , Polissacarídeos/química , Animais , Carragenina/toxicidade , Aditivos Alimentares/toxicidade , Humanos , Polissacarídeos/toxicidade
11.
J Ethnopharmacol ; 234: 216-224, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30552992

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Emex spinosa (L.) Campd. (E. spinosa) locally known as "hillaioua" has always been used in folk medicine for the treatment of inflammation and pain. It is still being exploited by pharmaceutical companies for its potential remedial effects. AIM OF THE STUDY: In this study, the effects of E. spinosa (L.) Campd. against acute inflammation, pain and oxidative damage were evaluated. MATERIALS AND METHODS: Total phenols and flavonoids were evaluated. Anti-inflammatory and analgesic activities the E. spinosa ethyl acetate fractions of the aerial (Es EtOAc-AP) and underground (Es EtOAc-R) parts were assessed on carrageenan-induced paw oedema (100 mg/kg BW) and acetic acid-induced writhing response (50, 100 and 150 mg/kg BW), respectively. The E. spinosa fractions effects on oxidative stress markers and inflammatory parameters were determined. Gas chromatography-mass spectrometry (GC-MS) analysis was performed to identify various chemical components. RESULTS: The ethyl acetate fractions were shown to be the most active thanks to their phenolic and flavonoid contents richness. Intraperitoneal administration of E. spinosa ethyl acetate fractions at 100 mg/kg BW, one hour before carrageenan injection, significantly inhibited the oedema formation by 89.31% and 97.7% for the aerial and underground parts respectively when compared to the reference drug "dexamethasone" (51.9%). Besides, a significant increase (p ≤ 0.001) of the dermal antioxidant enzymes (the superoxide dismutase (SOD)), catalase (CAT) and glutathione peroxidase (GPx) was observed five hours after carrageenan administration. The best restoration was obtained with Es EtOAc-R (82.04%, 93.55% and 93.55% respectively for SOD, CAT and GPx activities). Moreover, EtOAc-fractions treated mice proved their ability to restore both of CRP and fibrinogen (p < 0.001). In addition, E. spinosa EtOAc-fractions attenuated abdominal contractions (p < 0.05) by 71.69% and 82.41% for the aerial part and roots respectively at 150 mg/kg BW against 100% for dichlofenac sodium used as standard drug. The phytochemical analysis of Es EtOAc-AP and Es EtOAc-R by GC-MS may explain the obtained results. The analysis of the fractions demonstrated the presence of palmitic and linoleic acids known for their anti-inflammatory and analgesic capacities. CONCLUSIONS: These findings explain the traditional use of E. spinosa in folk medicine and suggest that E. spinosa fractions could be a promising herbal drug.


Assuntos
Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Rumex/química , Acetatos/química , Analgésicos/administração & dosagem , Analgésicos/isolamento & purificação , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Carragenina/toxicidade , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Edema/patologia , Cromatografia Gasosa-Espectrometria de Massas , Inflamação/patologia , Masculino , Medicina Tradicional/métodos , Camundongos , Dor/tratamento farmacológico , Dor/patologia , Extratos Vegetais/administração & dosagem
12.
Carbohydr Polym ; 206: 362-370, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30553333

RESUMO

A smart wound dressing based on carrageenan (κC), locust bean gum (LBG), and cranberry extract (CB) for monitoring bacterial wound infections was developed and characterized using UV-vis spectroscopy, FT-IR, and SEM. The mechanical, swelling, cytotoxic and pH sensor properties were also investigated. UV-vis spectra demonstrated that the obtained κC:LBG:CB hydrogel film exhibited a visible change of colors as it was immersed in PBS solution pH 5.0, 7.3 and 9.0. The spectra of FT-IR suggested that chemical interactions had occurred between κC and CB extract. The obtained κC:LBG:CB hydrogel film exhibited adequate mechanical properties and a swelling behavior dependent on pH. Cytotoxicity tests indicated that κC:LBG:CB hydrogel film had dose-dependent cytotoxicity against NIH 3T3 fibroblast cells. The in vitro studies using Staphylococcus aureus and Pseudomonas aeruginosa demonstrated that the color changes of the κC:LBG:CB hydrogel film could be observed by naked eyes, confirming the potential use of the obtained hydrogel film as a visual system for monitoring bacterial wound infections.


Assuntos
Infecções Bacterianas/diagnóstico , Bandagens , Hidrogéis/química , Indicadores e Reagentes/farmacologia , Extratos Vegetais/farmacologia , Infecção dos Ferimentos/diagnóstico , Animais , Antocianinas/química , Antocianinas/farmacologia , Antocianinas/toxicidade , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/toxicidade , Carragenina/química , Carragenina/toxicidade , Cor , Módulo de Elasticidade , Galactanos/química , Galactanos/toxicidade , Hidrogéis/toxicidade , Concentração de Íons de Hidrogênio , Indicadores e Reagentes/química , Indicadores e Reagentes/toxicidade , Mananas/química , Mananas/toxicidade , Camundongos , Células NIH 3T3 , Extratos Vegetais/química , Extratos Vegetais/toxicidade , Gomas Vegetais/química , Gomas Vegetais/toxicidade , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Resistência à Tração , Vaccinium macrocarpon/química
13.
Folia Med (Plovdiv) ; 60(2): 270-274, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30355818

RESUMO

BACKGROUND: Persisting inflammatory stimuli cause chronic inflammation recognized as the major factor contributing to the development of a number of diseases. One group of drugs used in the treatment of chronic inflammation is the group of non-steroidal anti-inflammatory drugs and, more specifically, the selective COX-2 inhibitors (coxibs). However, most of the coxibs were withdrawn from the market in view of their safety profile. In the present study, 2-[3-Acetyl-5-(4-chlorophenyl)- 2-methyl-pyrrol-1-yl]-4-methylsulfanyl-butyric acid (compound 3e), an Npyrrolylcarboxylic acid derivative structurally related to celecoxib, is evaluated for anti-inflammatory activity after single and multiple (14 days) administration using an animal inflammation model. AIM: To evaluate the anti-inflammatory properties of 2-[3-Acetyl-5-(4-chlorophenyl)-2-methyl-pyrrol-1-yl]-4-methylsulfanyl-butyric acid (compound 3e) after single and multiple (14 days) administration using an animal inflammation model. MATERIALS AND METHODS: Forty Wistar rats were allocated into 5 groups (n=8) treated with saline (controls), diclofenac (25 mg/kg b.w.), compound 3e (10, 20 and 40 mg/kg b.w.) intraperitoneally. The volume of the right hind paw of the animals of all groups is measured prior to treatment and two, three and four hours after administration of carrageenan using a plethysmometer (Ugo Basile, Italy). The percentage of paw edema is calculated using the Trinus formula. RESULTS: In a single administration, compound 3e in doses of 10 and 20 mg/kg b.w. did not inhibit paw edema, while a dose of 40 mg/kg b.w. significantly inhibited carrageenan-induced paw edema at 2 hours in comparison with the control group. After continuous administration, compound 3e in doses of 10, 20 and 40 mg/kg b.w. significantly reduced paw edema at 2, 3, and 4 hours compared to animals treated with saline. CONCLUSIONS: Compound 3e shows anti-inflammatory properties similar to those of diclofenac after continuous administration.


Assuntos
Anti-Inflamatórios/farmacologia , Butiratos/farmacologia , , Pirróis/farmacologia , Animais , Butiratos/química , Carragenina/toxicidade , Diclofenaco/farmacologia , Edema/induzido quimicamente , Membro Posterior , Inflamação/induzido quimicamente , Pirróis/química , Ratos
14.
Int Immunopharmacol ; 65: 174-181, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30316075

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
15.
Pharmacol Rep ; 70(6): 1139-1145, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30317129

RESUMO

BACKGROUND: Skeletal muscle inflammation is strongly associated with pain and may impair regeneration and functional recovery after injury. Since anti-inflammatory and antinociceptive effects have been described for the inclusion complex of carvacrol and ß-cyclodextrin (ßCD-carvacrol), this study investigated the effects of ßCD-carvacrol in a model of acute skeletal muscle inflammation. METHODS: Muscle injury was induced in male Wistar rats by injection of 3% carrageenan in the gastrocnemius muscle. Rats were orally pretreated with saline (vehicle) or ßCD-carvacrol (20, 40, 80 and 180 mg/kg) one hour before administration of carrageenan. RESULTS: The injection of carrageenan in the gastrocnemius muscle increased tissue myeloperoxidase (MPO) activity (p < 0.001), edema (p < 0.001) and the levels of tumoral necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, macrophage inflammatory protein (MIP-2), but not IL-10 levels. Also, it increased mechanical hyperalgesia and decreased the grip force of animals. Pretreatment with ßCD-carvacrol (80 or 160 mg/kg) significantly decreased muscle MPO activity and edema 24 h after injury in comparison to vehicle-pretreated group. Animals pretreated with ßCD-carvacrol (160 mg/kg) presented significantly lower levels of IL-1ß, IL-6 and MIP-2 and higher levels of IL-10 six hours after induction and lower levels of TNF-α and MIP-2 after 24 h when compared to the vehicle group. Pretreatment with ßCD-carvacrol also reduced mechanical hyperalgesia and limited the decrease of grip force (80 or 160 mg/kg; p < 0.001) 6 and 24 h after injury. CONCLUSION: These results show that ßCD-carvacrol reduces inflammation and nociception in a model of acute injury to skeletal muscles.


Assuntos
Mediadores da Inflamação/metabolismo , Monoterpenos/administração & dosagem , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Nociceptividade/efeitos dos fármacos , beta-Ciclodextrinas/administração & dosagem , Animais , Carragenina/toxicidade , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Força da Mão/fisiologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/antagonistas & inibidores , Masculino , Nociceptividade/fisiologia , Ratos , Ratos Wistar
16.
Pain ; 159(12): 2630-2640, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30169420

RESUMO

Oxytocin (OT), known for its neurohormonal effects around birth, has recently been suggested for being a critical determinant in neurodevelopmental disorders. This hypothalamic neuropeptide exerts a potent analgesic effect through an action on the nociceptive system. This endogenous control of pain has an important adaptive value but might be altered by early life stress, possibly contributing to its long-term consequences on pain responses and associated comorbidities. We tested this hypothesis using a rat model of neonatal maternal separation (NMS) known to induce long-term consequences on several brain functions including chronic stress, anxiety, altered social behavior, and visceral hypersensitivity. We found that adult rats with a history of NMS were hypersensitive to noxious mechanical/thermal hot stimuli and to inflammatory pain. We failed to observe OT receptor-mediated stress-induced analgesia and OT antihyperalgesia after carrageenan inflammation. These alterations were partially rescued if NMS pups were treated by intraperitoneal daily injection during NMS with OT or its downstream second messenger allopregnanolone. The involvement of epigenetic changes in these alterations was confirmed since neonatal treatment with the histone deacetylase inhibitor SAHA, not only normalized nociceptive sensitivities but also restored OT receptor-mediated stress-induced analgesia and the endogenous antihyperalgesia in inflamed NMS rats. There is growing evidence in the literature that early life stress might impair the nociceptive system ontogeny and function. This study suggests that these alterations might be restored while stimulating OT receptor signaling or histone deacetylase inhibitors, using molecules that are currently available or part of clinical trials for other pathologies.


Assuntos
Analgésicos/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Hipersensibilidade/tratamento farmacológico , Privação Materna , Ocitocina/uso terapêutico , Limiar da Dor/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Carragenina/toxicidade , Feminino , Inibidores de Histona Desacetilases/uso terapêutico , Hipersensibilidade/patologia , Masculino , Nociceptividade/efeitos dos fármacos , Dor/tratamento farmacológico , Células do Corno Posterior/efeitos dos fármacos , Gravidez , Pregnanolona/uso terapêutico , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Vasotocina/análogos & derivados , Vasotocina/farmacologia , Vorinostat/uso terapêutico
17.
Psychopharmacology (Berl) ; 235(11): 3259-3271, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30225659

RESUMO

RATIONALE: Cannabidiol (CBD), a non-intoxicating component of cannabis, or the psychoactive Δ9-tetrahydrocannabiol (THC), shows anti-hyperalgesia and anti-inflammatory properties. OBJECTIVES: The present study evaluates the anti-inflammatory and anti-hyperalgesia effects of CBD's potent acidic precursor, cannabidiolic acid (CBDA), in a rodent model of carrageenan-induced acute inflammation in the rat hind paw, when administered systemically (intraperitoneal, i.p.) or orally before and/or after carrageenan. In addition, we assess the effects of oral administration of THC or CBDA, their mechanism of action, and the efficacy of combined ineffective doses of THC and CBDA in this model. Finally, we compare the efficacy of CBD and CBDA. RESULTS: CBDA given i.p. 60 min prior to carrageenan (but not 60 min after carrageenan) produced dose-dependent anti-hyperalgesia and anti-inflammatory effects. In addition, THC or CBDA given by oral gavage 60 min prior to carrageenan produced anti-hyperalgesia effects, and THC reduced inflammation. The anti-hyperalgesia effects of THC were blocked by SR141716 (a cannabinoid 1 receptor antagonist), while CBDA's effects were blocked by AMG9810 (a transient receptor potential cation channel subfamily V member 1 antagonist). In comparison to CBDA, an equivalent low dose of CBD did not reduce hyperalgesia, suggesting that CBDA is more potent than CBD for this indication. Interestingly, when ineffective doses of CBDA or THC alone were combined, this combination produced an anti-hyperalgesia effect and reduced inflammation. CONCLUSION: CBDA or THC alone, as well as very low doses of combined CBDA and THC, has anti-inflammatory and anti-hyperalgesia effects in this animal model of acute inflammation.


Assuntos
Canabinoides/administração & dosagem , Modelos Animais de Doenças , Dronabinol/administração & dosagem , Edema/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Dor/tratamento farmacológico , Administração Oral , Analgésicos não Entorpecentes , Animais , Carragenina/toxicidade , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Hiperalgesia/induzido quimicamente , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Dor/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
18.
Pain Res Manag ; 2018: 4838413, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30073041

RESUMO

Plants provide an alternative source to manage different human disorders due to various metabolites. The aim of this study is to investigate the phytochemical constituents of the methanolic extracts of Euphorbia retusa and to evaluate their antioxidant, anti-inflammatory, and analgesic activities. The phytochemical results obtained by HPLC and by chemical assay reactions have revealed the richness of the methanolic extract of E. retusa in active compounds, in particular polyphenols, flavonoids, and tannins. The methanolic extract shows significant antioxidant activities in vitro, in the DPPH and the FRAP assays. The antinociceptive activity was evaluated using acetic acid and hot-plate models of pain in mice. The anti-inflammatory activity was evaluated by carrageenan-induced paw edema. Oral pretreatment with the methanolic extract of E. retusa (200 mg/kg) exhibited a significant inhibition of pain induced either by acetic acid or by the heating plate and in a manner comparable to the standard drug paracetamol. E. retusa significantly reduced paw edema starting from the 3rd hour after carrageenan administration by increasing the activity of antioxidant enzymes (SOD, CAT, and GPx) in liver and paw tissues and decreasing the levels of MDA. These results may confirm the interesting potential of this plant as a treatment of various inflammatory and pain diseases.


Assuntos
Euphorbia/química , Inflamação/tratamento farmacológico , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ácido Acético/toxicidade , Analgésicos/química , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Carragenina/toxicidade , Catalase/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Inflamação/induzido quimicamente , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Nitroazul de Tetrazólio/metabolismo , Medição da Dor , Superóxido Dismutase/metabolismo , Tiazolidinedionas/metabolismo
19.
J Med Chem ; 61(17): 7929-7941, 2018 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-30095904

RESUMO

Here, we report analgesic and anti-inflammatory activity of a series of compounds obtained by appending 4-aminophenylmorpholin-3-one and acyclic, cyclic, or heterocyclic moieties on 1,3,5-triazine. The structures of compounds 4b and 6b are optimized for the best inhibition of COX-2 with IC50 values of 0.06 and 0.08 µM, respectively, and selectivity over COX-1 of 166 and >125, respectively. At the dose of 5 mg kg-1, these compounds significantly reduced acetic acid induced writhings, and their ED50 values were found to be 2.2 and 1.9 mg kg-1, respectively. Besides the cell-based and animal-based experiments showing the modes of action of these compounds targeting COX-2, the interaction behavior of 4b with COX-2 was also characterized, with physicochemical experiments including ITC, NMR, UV-vis, and molecular-modeling studies. Characteristically, these compounds interact with R120, Y355, and W385, the residues responsible for holding the substrate and mediating the process of electron transfer during the metabolic phase of the enzyme.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Descoberta de Drogas , Hiperalgesia/prevenção & controle , Inflamação/prevenção & controle , Dor/prevenção & controle , Triazinas/química , Analgésicos/química , Analgésicos/farmacologia , Animais , Carragenina/toxicidade , Ciclo-Oxigenase 2/química , Feminino , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/enzimologia , Inflamação/induzido quimicamente , Inflamação/enzimologia , Masculino , Camundongos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Dor/induzido quimicamente , Dor/enzimologia , Relação Estrutura-Atividade
20.
Georgian Med News ; (279): 196-200, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30035746

RESUMO

With changing lifestyle and dietary transition, there is an increase in intake of processed and packaged foods which tend to have a number of food additives. This has increased our consumption of these chemical substances. One of such additives is carrageenan (CGN) - E407. This paper reports the effect of 0.5 % carrageenan solution consumption on the main indices of endogenous intoxication in rats. Experimental studies were conducted on 48 non-linear, male, white rats weighing 180-200 g. The experimental animals had free access to 0.5% carrageenan solution (Sigma-Aldrich, USA) in drinking water. Control group of animals received pure water. Syndrome of endogenous intoxication was evaluated using measurement of the middle mass molecules contents in blood serum. We have found that even the minimal intake of carrageenan, triggers the mechanisms of endogenous intoxication in rats, starting in 2 weeks of consumption. 1 month consumption of carrageenan with drinking water in concentration of 0.5% is associated with significant increase in endogenous intoxication, manifested by increased contents of middle mass molecules (both the chain amino acids and the aromatic amino acids) in blood serum. From these facts, one may conclude that although carrageenan has been used widely in food as an emulsifier, a stabilizer, and a thickener for more than 50 years, some questions of its safety are still opened.


Assuntos
Carragenina/toxicidade , Aditivos Alimentares/toxicidade , Aminoácidos/sangue , Aminoácidos/química , Animais , Masculino , Peso Molecular , Ratos , Soluções
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