RESUMO
The misuse of anabolic androgenic steroid associated or not with physical workouts disrupts gastrointestinal (GI) function homeostasis. Our goal was to investigate the effects of nandrolone decanoate (ND) and moderate swimming on the GI transit of solid meals, GI motor contractility, and intestinal histology in rats. Male Wistar rats were allocated to four groups that received intramuscular injections of ND (5.0 mg/kg) or vehicle (60.0 µL) and were submitted or not to swimming sessions (60 min, 5% body weight overload) for 4 weeks. Gastric emptying, intestinal transit, in vitro GI contractility, intestinal morphometry, and duodenal mucosal mast cells were evaluated in all experimental groups. ND treatment accelerated gastric emptying, slowed small intestine transit time, enhanced gastric carbachol-mediated reactivity, decreased crypt depth and villus height, reduced mucosal thickness, and increased the circular and longitudinal muscle layer thickness of the duodenum in sedentary rats. Moderate exercise accelerated intestinal transit time and reduced submucosa thickness. In vehicle-treated animals, a strong negative correlation was found between intestinal transit and mucosal mast cells, which was reversed by ND treatment. Combining ND treatment and swimming accelerated gastric emptying, increased duodenal cholinergic reactivity, inhibited the sodium nitroprusside relaxing response, increased the number of duodenal mast cells, decreased villus height, and increased the thickness of all muscle layers. ND changed the morphological and functional properties of the GI tract over time, with intense dysmotility, especially in sedentary animals, but moderate exercise seemed to have played a compensatory role in these harmful effects in the gut.
Assuntos
Anabolizantes , Duodeno , Motilidade Gastrointestinal , Decanoato de Nandrolona , Nandrolona , Condicionamento Físico Animal , Ratos Wistar , Animais , Masculino , Decanoato de Nandrolona/farmacologia , Duodeno/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Anabolizantes/farmacologia , Nandrolona/farmacologia , Nandrolona/análogos & derivados , Mastócitos/efeitos dos fármacos , Ratos , Natação , Esvaziamento Gástrico/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacosRESUMO
Background: Tyrosine kinase inhibitors (TKIs) may sensitize neoplasms to conventional antineoplastic agents, however such studies are scarse in the veterinary literature and there is no in vivo study about this subject. Although the literature recommend consensual about the use of masitinib for unresectable or metastatic MCTs, the potential of tumour sensitization to chemotherapeutic agents exerted by the drug is poorly explored in veterinary medicine. The objective of this paper was to report, for the first time, the sensitization of 2 canine mast cell tumours (MCTs) to lomustine, with the use of 2 tyrosine kinase inhibitors: masitinib and toceranib. Cases: Two dogs were referred due tumour recurrence in the left pelvic limb (dog 1), and unilateral mass in the right nasal mucocutaneous region (dog 2). The first case was a 8-year-old female Pinscher, and the second case refers to a 8-year-old male mixed-breed dog. Fine needle aspiration of both lesions was performed, and the cytological analysis were compatible with high grade canine MCT. In the first case, it was started a chemotherapeutic treatment with intravenous vinblastine (2 mg/m² ), associated with prednisolone (40 mg/m2 , every 24 h for 7 days), followed by 25 mg/m2 every 24 h, for more 30 days, tramadol (4 mg/kg every 8 h, until new recommendations) and gabapentin (3 mg/kg every 12 h, until new recommendations). However, there was no objective response, and vinblastine was substituted by lomustine (60 mg/m2 every 21 days), however there was also no response after 2 doses. After masitinib importation, the same was started at 12.5 mg/kg orally every 24 h, but there was also no objective response. However, after new lomustine administration the lesion showed complete remission. The second dog initiated its treatment with toceranib, recently licensed in Brazil, at a dosage of 2.7 mg/kg every 48 h, and after 30 days, there was partial remission. However, the remaining lesion still deemed unresectable, and systemic chemotherapy with lomustine (50 mg/m2 ) was initiated along with continuous toceranib. After 3 weeks of the first chemotherapy complete remission was noted and a second dose was administered. Once the patient remained in complete clinical remission, only toceranib was maintained at the same dose. After 11 months using the toceranib, there was sign of disease recurrence and lomustine was re-initiated resulting in complete remission. Discussion: The TKIs masitinib and toceranib might be considered the first-line therapy for unresectable and/or metastatic canine MCT, but also for those cases with confirmed internal tandem duplications in the exon 11 of the c-KIT protooncogene. Masitinib appears to be more selective than others TKI, such as toceranib, imatinib, dasatinib and sunitinib, because it causes weak inhibition of BCR/ABL (breakpoint cluster region-Abelson), Fms (macrophage colony-stimulating factor receptor), Flt-3 (FMS-like tyrosine kinase-3) and VEGFR (vascular endothelial growth factor receptor), which may partially explains its increased safety and lower risk of cardiotoxicity. In the first case, the animal has been treated with lomustine associated to masitinib and showed a progression-free interval of 33 days, however, the response reported may have been lower, due previously exposition to chemotherapeutic agents, which might compromise the response to TKI. The second case, with the association of lomustine and toceranib, was followed up for 365 days, presenting only one recurrence in the final third of the follow-up, however, with subsequent new complete remission. Sensitization of canine MCT to lomustine with TKIs increases the therapeutic possibilities for this neoplasm, mainly in patients with advanced stage and high-grade tumours.
Assuntos
Animais , Cães , Proteínas Tirosina Quinases/antagonistas & inibidores , Mastocitoma/tratamento farmacológico , Lomustina/análise , Mastócitos/efeitos dos fármacosRESUMO
Mast cells (MCs) are main effector cells in allergic inflammation and after activation, they release stored (histamine, heparin, proteases) and newly synthesized (lipid mediators and cytokines) substances. In the gastrointestinal tract the largest MC population is located in the lamina propria and submucosa whereas several signals such as the cytokine IL-4, seem to increase the granule content and to stimulate a remarkable expansion of intestinal MCs. The broad range of MC-derived bioactive molecules may explain their involvement in many different allergic disorders of the gastrointestinal tract. Annexin A1 (AnxA1) is a 37 KDa glucocorticoid induced monomeric protein selectively distributed in certain tissues. Its activity can be reproduced by mimetic peptides of the N-terminal portion, such as Ac2-26, that share the same receptor FPR-L1. Although previous reports demonstrated that AnxA1 inhibits MC degranulation in murine models, the effects of exogenous peptide Ac2-26 on intestinal MCs or the biological functions of the Ac2-26/FPR2 system in human MCs have been poorly studied. To determine the effects of Ac2-26 on the function of MCs toward the possibility of AnxA1-based therapeutics, we treated WT and IL-4 knockout mice with peptide Ac2-26, and we examined the spontaneous and compound 48/80 stimulated colonic MC degranulation and cytokine production. Moreover, in vitro, using human mast cell line HMC-1 we demonstrated that exogenous AnxA1 peptide is capable of interfering with the HMC-1 degranulation in a direct pathway through formyl peptide receptors (FPRs). We envisage that our results can provide therapeutic strategies to reduce the release of MC mediators in inflammatory allergic processes.
Assuntos
Anexina A1/farmacologia , Degranulação Celular/efeitos dos fármacos , Colo/efeitos dos fármacos , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Mastócitos/efeitos dos fármacos , Peptídeos/farmacologia , Animais , Linhagem Celular , Colo/imunologia , Colo/metabolismo , Humanos , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Mastócitos/imunologia , Mastócitos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Formil Peptídeo/metabolismo , Técnicas de Cultura de TecidosRESUMO
Degeneration of motor neurons, glial cell reactivity, and vascular alterations in the CNS are important neuropathological features of amyotrophic lateral sclerosis (ALS). Immune cells trafficking from the blood also infiltrate the affected CNS parenchyma and contribute to neuroinflammation. Mast cells (MCs) are hematopoietic-derived immune cells whose precursors differentiate upon migration into tissues. Upon activation, MCs undergo degranulation with the ability to increase vascular permeability, orchestrate neuroinflammation and modulate the neuroimmune response. However, the prevalence, pathological significance, and pharmacology of MCs in the CNS of ALS patients remain largely unknown. In autopsy ALS spinal cords, we identified for the first time that MCs express c-Kit together with chymase, tryptase, and Cox-2 and display granular or degranulating morphology, as compared with scarce MCs in control cords. In ALS, MCs were mainly found in the niche between spinal motor neuron somas and nearby microvascular elements, and they displayed remarkable pathological abnormalities. Similarly, MCs accumulated in the motor neuron-vascular niche of ALS murine models, in the vicinity of astrocytes and motor neurons expressing the c-Kit ligand stem cell factor (SCF), suggesting an SCF/c-Kit-dependent mechanism of MC differentiation from precursors. Mechanistically, we provide evidence that fully differentiated MCs in cell cultures can be generated from the murine ALS spinal cord tissue, further supporting the presence of c-Kit+ MC precursors. Moreover, intravenous administration of bone marrow-derived c-Kit+ MC precursors infiltrated the spinal cord in ALS mice but not in controls, consistent with aberrant trafficking through a defective microvasculature. Pharmacological inhibition of c-Kit with masitinib in ALS mice reduced the MC number and the influx of MC precursors from the periphery. Our results suggest a previously unknown pathogenic mechanism triggered by MCs in the ALS motor neuron-vascular niche that might be targeted pharmacologically.
Assuntos
Esclerose Lateral Amiotrófica/imunologia , Mastócitos/imunologia , Microvasos/patologia , Neurônios Motores/patologia , Doenças Neuroinflamatórias/imunologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Medula Espinal/imunologia , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Benzamidas/farmacologia , Estudos de Casos e Controles , Quimases/metabolismo , Ciclo-Oxigenase 2/metabolismo , Feminino , Humanos , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos , Microvasos/metabolismo , Pessoa de Meia-Idade , Neurônios Motores/metabolismo , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Piridinas/farmacologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , Fator de Células-Tronco/metabolismo , Tiazóis/farmacologia , Triptases/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Dilodendron bipinnatum (Sapindaceae) stem bark decoction and macerate were used to treat uterine inflammation, pain in general, dermatitis and bone fractures. These homemade preparations also have diuretic, stimulant, expectorants and sedative effects and are effective in treating worm infections in the Brazilian Pantanal population. Our previous research confirmed the anti-inflammatory activity of the hydroethanolic extract of inner stem bark of D. bipinnatum (HEDb). AIM: This work aimed to investigate the efficacy of HEDb in ameliorating experimental colitis in rats and to elucidate the possible mechanisms involved in the anti-ulcerative colitis properties of HEDb in rats and Caco-2 cell line. MATERIALS AND METHODS: The effects on cell viability, IL-8 and TNF-α in human colon adenocarcinoma (Caco-2) were determined by flow cytometer and ELISA. Wistar rats (n = 6-7) were orally gavaged with, vehicle (0.9% saline), HEDb at doses of 20, 100 or 500 mg/kg, or mesalazine at a dose of 500 mg/kg, at 48, 24 and 1 h prior to the administration of trinitrobenzene sulfonic acid via rectal administration to induce colitis. The anti-inflammatory effects of HEDb were assessed macroscopically, by myeloperoxidase (MPO) activity and for glutathione (GSH) concentration in the colon. Additionally, colonic histopathological analyses of UC severity were conducted by different staining methods (H&E, PAS and toluidine blue). Pro-inflammatory cytokines TNF-α and IL-1ß were quantified in colonic tissue by ELISA and colonic expressions of COX-2 and IL-17 were analyzed by western blotting. RESULTS: HEDb was shown to be non-cytotoxic with mean viability of 80% in Caco-2 cells. HEDb pre-treatments of 1, 5 or 20 µg/mL significantly reduced TNF-α production in Caco-2 cells by 21.8% (p < 0.05), 60.5 and 82.1% (p < 0.001) respectively following LPS treatment compared to LPS alone. However, no change in IL-8 production was observed. HEDb pre-treatment of rats subjected to TNBS significantly (p < 0.001) reduced colonic lesion score. Higher doses (100 and 500 mg/kg) caused a sharp downregulation of haemorrhagic damage, leukocyte infiltration, edema and restoration of mucus production. Moreover, mast cell degranulation was inhibited. Colonic MPO activity was reduced following all doses of HEDb, reaching 51.1% ± 1.51 (p < 0.05) with the highest dose. GSH concentration was restored by 58% and 70% following 100 and 500 mg/kg of HEDb, respectively. The oral treatment of HEDb at doses 20, 100 and 500 mg/kg decreased the concentrations of TNF-α and IL-1ß at all doses in comparison to vehicle treated control. In addition, HEDb inhibited the COX-2 and IL-17 expressions with maximal effect at 500 mg/kg (60.3% and 65% respectively; p < 0.001). In all trials, the effect of HEDb at all doses being 20, 100 and 500 mg/kg was statistically comparable to mesalazine (500 mg/kg). CONCLUSIONS: HEDb reduces colonic damage in the TNBS colitis model and relieves oxidative and inflammatory events, at least in part, by increasing mucus production, reducing leukocyte migration and reducing TNF-α (in vivo and in vitro), IL-1ß, IL-17 and COX-2 expression. Therefore, HEDb requires further investigation as a candidate for treating IBD.
Assuntos
Antioxidantes/farmacologia , Colite Ulcerativa/prevenção & controle , Muco/metabolismo , Casca de Planta/química , Extratos Vegetais/farmacologia , Sapindaceae/química , Animais , Antioxidantes/química , Antioxidantes/uso terapêutico , Brasil , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Edema/induzido quimicamente , Edema/prevenção & controle , Glutationa/metabolismo , Humanos , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Lipopolissacarídeos/toxicidade , Mastócitos/efeitos dos fármacos , Peroxidase/metabolismo , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Ratos Wistar , Ácido Trinitrobenzenossulfônico/toxicidade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The main objectives of this study were to evaluate the chemical constitution and allergenic potential of red propolis extract (RPE). They were evaluated, using high performance liquid chromatography (HPLC) and the release of ß-hexosaminidase, respectively. A plethora of biologically active polyphenols and the absence of allergic responses were evinced. RPE inhibited the release of ß-hexosaminidase, suggesting that the extract does not stimulate allergic responses. Additionally, the physicochemical properties and antibacterial activity of hydrogel membranes loaded with RPE were analyzed. Bio-polymeric hydrogel membranes (M) were obtained using 5% carboxymethylcellulose (M1 and M2), 1.0% of citric acid (M3) and 10% RPE (for all). Their characterization was performed using thermal analysis, Fourier transform infrared (FTIR), total phenolic content, phenol release test and, antioxidant activity through 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) and Ferric Reducing Antioxidant Power (FRAP). The latter appointed to the similar antioxidant capacity of the M1, M2 and M3. The degradation profiles showed higher thermostability to M3, followed by M2 and M1. The incorporation of RPE into the matrices and the crosslinking of M3 were evinced by FTIR. There were differences in the release of phenolic compounds, with a higher release related to M1 and lower in the strongly crosslinked M3. The degradation profiles showed higher thermostability to M3, followed by M2 and M1. The antibacterial activity of the membranes was determined using the disc diffusion assay, in comparison with controls, obtained in the same way, without RPE. The membranes elicited antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis, with superior performance over M3. The hydrogel membranes loaded with RPE promote a physical barrier against bacterial skin infections and may be applied in the wound healing process.
Assuntos
Própole/química , Administração Tópica , Alérgenos/química , Animais , Antibacterianos/administração & dosagem , Antibacterianos/química , Antibacterianos/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/química , Antioxidantes/farmacologia , Bandagens , Materiais Biocompatíveis/administração & dosagem , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Biopolímeros/administração & dosagem , Biopolímeros/química , Biopolímeros/farmacologia , Brasil , Linhagem Celular , Fenômenos Químicos , Cromatografia Líquida de Alta Pressão , Composição de Medicamentos , Estabilidade de Medicamentos , Humanos , Hidrogéis , Técnicas In Vitro , Mastócitos/efeitos dos fármacos , Mastócitos/enzimologia , Mastócitos/imunologia , Membranas Artificiais , Fenóis/química , Própole/administração & dosagem , Própole/farmacologia , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos , Termogravimetria , beta-N-Acetil-Hexosaminidases/metabolismoRESUMO
Glycomacropeptide (GMP) is a bioactive peptide derived from milk κ-casein with immune-modulatory and anti-inflammatory properties. Food allergy (FA) is an adverse immune reaction with a broad spectrum of manifestations. Allergen intake induces persistent intestinal inflammation and tissue damage. In this study, the anti-allergic activity of GMP was evaluated using a rat ovalbumin (OVA)-induced FA model with gastrointestinal manifestation. Rats were orally GMP treated from 3 days prior and during FA development. The severity of food anaphylaxis and diarrheal episodes, antibody production and histamine level were measured. Histopathological changes, inflammation and predominant cytokine profile at intestine were analyzed. Oral GMP intake decreased clinical signs and diarrhea severity induced by allergen, with a significant reduction in intestinal edema and expression level of IL-1ß and TNF-α. Prophylaxis with GMP also diminished serum anti-OVA IgE and IgG1, and histamine levels. GMP treatment markedly decreased eosinophil infiltration, mast cell and goblet cell hyperplasia, total IgE expression in intestine, and prevented histological changes in villi, crypts and internal muscularis layer. The treatment effectively suppressed IL-5, IL-13 and GATA3 expression and skewed the intestinal cytokine profile toward type 1 and regulatory. These results suggest that GMP may protect against FA through down-regulating the type 2 inflammatory response.
Assuntos
Antialérgicos/uso terapêutico , Caseínas/farmacologia , Regulação para Baixo/efeitos dos fármacos , Hipersensibilidade Alimentar/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Alérgenos/imunologia , Anafilaxia/tratamento farmacológico , Anafilaxia/prevenção & controle , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/fisiopatologia , Fator de Transcrição GATA3 , Interleucina-13 , Interleucina-1beta/metabolismo , Interleucina-5 , Intestinos , Masculino , Mastócitos/efeitos dos fármacos , Ovalbumina/imunologia , Fragmentos de Peptídeos/metabolismo , Ratos , Ratos WistarRESUMO
Existing evidence suggests that the local anaesthetic mexiletine can be beneficial for patients with asthma. However, caution is required since anaesthesia of the airways inhibits protective bronchodilator neuronal reflexes, limiting applications in conditions of hyperirritable airways. Here, we describe the synthesis of a new series of mexiletine analogues, which were screened for reduced activity in Na+ channels and improved smooth muscle relaxant effects, that were evaluated using the patch-clamp technique and an isolated tracheal organ bath, respectively. JME-173 (1-(4-bromo-3,5-dimethylphenoxy)propan-2-amine) was the most effective among the four mexiletine analogues investigated. JME-173 was then studied in vivo using a murine model of lung inflammation induced by cigarette smoke (CS) and in vitro using neutrophil chemotaxis and mast cell degranulation assays. Finally, the JME-173 pharmacokinetic profile was assessed using HPLC-MS/MS bioanalytical method. JME-173 directly inhibited IL-8 (CXCL8)- and FMLP-induced human neutrophil chemotaxis and allergen-induced mast cell degranulation. After oral administration 1 h before CS exposure, JME-173 (50 mg/kg) strongly reduced the increased number of macrophages and neutrophils recovered in the bronchoalveolar effluent without altering lymphocyte counts. Pharmacokinetic experiments of JME-173 (10 mg/kg, orally) showed values of maximum concentration (Cmax), maximum time (Tmax), area under the blood concentration-time curve (AUC0-t) and area under the blood concentration-time curve from 0-Inf (AUC0-inf) of 163.3 ± 38.3 ng/mL, 1.2 ± 0.3 h, 729.4 ± 118.3 ng*h/ml and 868.9 ± 117.1 ng*h/ml (means ± S.E.M.), respectively. Collectively, these findings suggest that JME-173 has the potential to be an effective oral treatment for diseases associated with bronchoconstriction and inflammation.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Mexiletina/análogos & derivados , Mexiletina/farmacologia , Parassimpatolíticos/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/efeitos dos fármacos , Animais , Área Sob a Curva , Líquido da Lavagem Broncoalveolar/citologia , Degranulação Celular/efeitos dos fármacos , Humanos , Masculino , Mastócitos/efeitos dos fármacos , Camundongos , Infiltração de Neutrófilos/efeitos dos fármacos , Técnicas de Patch-Clamp , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Ratos , Ratos Wistar , Fumaça , Relação Estrutura-Atividade , Produtos do TabacoRESUMO
INTRODUCTION: Mast cells are involved in not only inducing, but also maintaining neurogenic inflammation and neuropathic pain. In previous work, we have demonstrated that dehydroleucodine, xanthatin and 3-benzyloxymethyl-5H-furan-2-one inhibit rat peritoneal and human LAD2 mast cell degranulation induced by compound 48/80 and calcium ionophore A23187. However, the effect of these molecules on neuropeptide-induced mast cell activation has not been studied so far. OBJECTIVE: The aim of this study was to determine whether dehydroleucodine, xanthatin, and 3-benzyloxymethyl-5H-furan-2-one inhibit neuropeptide-induced mast cell activation. METHODS: This work is based on in vitro simulation of a neurogenic inflammation scenario involving neuropeptides and mast cells, to subsequently analyze potential therapeutic strategies for neuropathic pain. RESULTS: Neuromedin-N did not stimulate mast cell serotonin release but substance P and neurotensin did induce serotonin release from peritoneal mast cells in a dose-dependent manner. Mast cell serotonin release induced by substance P and neurotensin was inhibited by dehydroleucodine and xanthatin, but not by 3-benzyloxymethyl-5H-furan-2-one. The inhibitory potency of dehydroleucodine and xanthatin was higher than that obtained with the reference compounds, ketotifen and sodium chromoglycate, when mast cells were preincubated with dehydroleucodine before substance P incubation, and with dehydroleucodine or xanthatin before neurotensin incubation. CONCLUSIONS: These results are the first strong evidence supporting the hypothesis that dehydroleucodine and xanthatin inhibit substance P- and neurotensin-induced serotonin release from rat peritoneal mast cells. Our findings suggest, additionally, that these α,ß-unsaturated lactones could be of value in future pharmacological research related to inappropriate mast cell activation conditions such as neurogenic inflammation and neuropathic pain.
Assuntos
Lactonas/farmacologia , Mastócitos/efeitos dos fármacos , Inflamação Neurogênica/metabolismo , Neurotensina/farmacologia , Fragmentos de Peptídeos/farmacologia , Serotonina/metabolismo , Substância P/farmacologia , Animais , Células Cultivadas , Mastócitos/metabolismo , Ratos WistarRESUMO
Mast cell activation through the high-affinity IgE receptor (FcεRI) plays a central role in allergic reactions. FcεRI-mediated activation triggers multiple signaling pathways leading to degranulation and synthesis of different inflammatory mediators. IgE-mediated mast cell activation can be modulated by different molecules, including several drugs. Herein, we investigated the immunomodulatory activity of the histone deacetylase inhibitor valproic acid (VPA) on IgE-mediated mast cell activation. To this end, bone marrow-derived mast cells (BMMC) were sensitized with IgE and treated with VPA followed by FcεRI cross-linking. The results indicated that VPA reduced mast cell IgE-dependent degranulation and cytokine release. VPA also induced a significant reduction in the cell surface expression of FcεRI and CD117, but not other mast cell surface molecules. Interestingly, VPA treatment inhibited the phosphorylation of PLCγ2, a key signaling molecule involved in IgE-mediated degranulation and cytokine secretion. However, VPA did not affect the phosphorylation of other key components of the FcεRI signaling pathway, such as Syk, Akt, ERK1/2, or p38. Altogether, our data demonstrate that VPA affects PLCγ2 phosphorylation, which in turn decreases IgE-mediated mast cell activation. These results suggest that VPA might be a key modulator of allergic reactions and might be a promising therapeutic candidate.