RESUMO
OBJECTIVES: Epiisopiloturine (EPI) and epiisopilosine (EPIIS) are side products in the pharmaceutical industry. The present study aimed to investigate the anti-inflammatory potential of the alkaloids EPI and EPIIS in human neutrophils and mechanical hyperalgesia in mice. METHODS: Neutrophils (5 × 106 cells/ml) incubated with EPI and EPIIS and stimulated by the addition of N-formyl-methionyl-leucyl-phenylalanine or phorbol 12-myristate-13-acetate. The release of myeloperoxidase (MPO), reactive oxygen species (ROS) production, calcium influx, gene expression of NF-κB and pro-inflammatory cytokines production were evaluated. It was also investigated the effect these alkaloids on carrageenan-induced mechanical hyperalgesia model in mice. KEY FINDINGS: We demonstrated that both EPI and EPIIS inhibited the degranulation of activated neutrophils. This effect was accompanied by the reduction in ROS, the prevention of the increase in intracellular Ca2+ and decrease in the density of cytosolic NF-κB, and inhibition of TNF-α and IL-6 production. Evaluating hypernociception in mice, EPI and EPIIS inhibited carrageenan-induced inflammatory hypernociception and reduced MPO levels. CONCLUSIONS: The results obtained suggest EPI and EPIIS not only inhibit neutrophils functions in vitro, but also exhibits anti-inflammatory properties in vivo, acting through the modulation of the activation and/or accumulation of neutrophils in the inflammatory focus. Thus, EPI and EPIIS possess promising anti-inflammatory therapeutic potential.
Assuntos
4-Butirolactona/análogos & derivados , Alcaloides/farmacologia , Anti-Inflamatórios/farmacologia , Imidazóis/farmacologia , Neutrófilos/efeitos dos fármacos , 4-Butirolactona/farmacologia , Animais , Cálcio/metabolismo , Humanos , Hiperalgesia/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , N-Formilmetionina Leucil-Fenilalanina , NF-kappa B/metabolismo , Neutrófilos/metabolismo , Peroxidase/efeitos dos fármacos , Peroxidase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Acetato de Tetradecanoilforbol , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Contact dermatitis produces an inflammatory reaction primarily via stimulation of keratinocytes and cells of the immune system, which promote the release of cytokines, reactive oxygen species (ROS), and other chemical mediators. Eugenol (EUG, phenylpropanoid of essential oils) has attracted attention due to its anti-inflammatory properties, as well as antioxidant effect. On the other hand, it is volatile and insoluble and is a skin irritant. In this case, nanostructured systems have been successfully employed as a drug carrier for skin diseases since they improve both biological and pharmaceutical properties of active compounds. The cytotoxic, antioxidant, and anti-inflammatory effects of EUG were assessed in human neutrophils and keratinocytes. Additionally, polymeric nanocarries (NCEUG) were prepared to improve the chemical and irritant characteristics of EUG. EUG presented apparent safety and antioxidant and anti-inflammatory effects on human neutrophils, but presented cytotoxic effects on keratinocytes. However, the nanocapsules were able to reduce its cytotoxicity. An in vivo experiment of irritant contact dermatitis (ICD) in mice induced by TPA showed that NCEUG reduced significantly the ear edema in mice when compared to the EUG solution, as well as the leukocyte infiltration and IL-6 level, possibly due to better skin permeation and irritancy blockage. These findings suggest that EUG is a promising bioactive molecule, and its nanoencapsulation seems to be an interesting approach for the treatment of ICD.
