Curcuma longa extract protects against 5-fluorouracil-induced oral mucositis in hamsters

Abstract Curcumin, contained at Turmeric (Curcumalonga), can exert many beneficial pleiotropic activities in the gastrointestinal tract. This study evaluated the antioxidant and anti-inflammatory activity of C. longa on 5-fluorouracil (5-FU)-induced oral mucositis (OM) in hamsters. Phytochemical analysis of crude C. longa extract (CLE) was performed to detect the presence of curcumin by TLC and HPLC. Golden Syrian hamsters were orally pre-treated with CLE (5, 50, or 100mg/kg). Cheek pouch samples were subjected to macroscopic and histopathological evaluation. ELISA was performed to quantify the inflammatory cytokines IL-1ß and TNF-α. Superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA) levels were assessed by ultraviolet-visible spectroscopy analysis. Behavior analysis was conducted by the open field test. Curcumin content in the CLE was 0.55%m/m ± 0.0161 (2.84%). The group treated with 5mg/kg CLE showed healing evidence with macroscopic absence of ulceration (p<0.05) and microscopic aspect of re-epithelialization, discrete inflammatory infiltrate and absence of edema. Treatment with 5mg/kg CLE significantly increased GSH levels, and reduced MDA levels and SOD activity (p˂0.05), and decreased IL-1ß (p˂0.05) and TNF-α (p˂0.01) levels. A significant reduction in walking distance, ambulation, speed, and rearing was observed for motor activity. Curcumin reduced oxidative stress, inflammation, and motor activity in hamsters with 5-FU-induced OM.

Avaliação das atividades anti-inflamatórias e antioxidantes da gliclazida em modelo experimental de mucosite oral induzida por 5-fluorouracil / Evaluation of the anti-inflammatory and antioxidant activities of gliclazide in an experimental model of oral mucositis induced by 5-fluorouracil

A mucosite oral (MO) é uma inflamação aguda da mucosa oral, sequela mais importante dos tratamentos de radioterapia ou/e quimioterapia. As lesões na cavidade oral são graves, dolorosas e podem levar a sepse e morte. Não existe um protocolo único de prevenção e cura para MO. Na perspectiva de encontrar terapias farmacológicas para prevenir MO, propomos a investigação do efeito pleiotrópico do medicamento comercial gliclazida, um anti-diabético de ação secundária anti-inflamatória e antioxidante nunca estudada na MO. Este estudo teve como objetivo avaliar o efeito da gliclazida em um modelo MO experimental induzido por 5-fluorouracil. Hamsters machos foram pré-tratados com gliclazida oral (1, 5 ou 10mg/kg) por 10 dias. As amostras das mucosas dos animais foram submetidas à análise macroscópica, histopatológica e imuno-histoquímica (COX2, iNOS, MMP-2, NFκB P65, GPx) e imunofluorescência (P-selectina). Os níveis de IL-1ß e TNF-α, a atividade de mieloperoxidase (MPO) e os níveis de malondialdeído (MDA) foram investigados por análise espectroscópica ultravioleta-visível. A expressão protéica de NFκB NLS P50 foram analisados por western blotting. O grupo tratado com gliclazida na dose de 10 mg / kg apresentou melhores resultados como ; presença de eritema, ausência de erosão e de ulceração da mucosa com escore de 1 (1-2) (p <0,01) nos achados clínicos. Os dados histopatológicos do grupo tratado com gliclazida 10 mg / kg mostraram reepitelização, discreto infiltrado inflamatório mononuclear, úlceras com escore de 1 (1-1) (p <0,01). O tratamento com gliclazida 10 mg/kg reduziram os níveis de atividade de MPO (p <0,001), MDA (p <0,001) e NFκB NLS P50 (p <0,05), resultando em baixa imunocoloração para Cox-2, iNOS (p <0,05) , NFκB P65 (p <0,05) e imunorreacção negativa para MMP-2 (p <0,001).Para Gpx, a coloração foi menos intensa no grupo GLI 10-FUT em comparação com 5FUT/solução salina (p <0,05). A Imunofluorescência revelou diminuição dos níveis de P-selectina (p <0,001) após o tratamento com gliclazida 10 mg/kg (p <0,05). A gliclazida na dose de 10mg/kg atenuou a severidade da MO e reduziu o estresse oxidativo e a inflamação na MO induzida pelo 5-FU em hamsters (AU).

Oral mucositis (OM) is acute inflammation of the oral mucosa, the most important sequelae from radiotherapy and/or chemotherapy treatments. The lesions in the oral cavity are severe and painful, and can lead to sepsis and death. There is no single protocol for preventing or curing OM. From the perspective of finding pharmacological therapies to prevent OM, we propose an investigation of the pleiotropic effect of commercial drugs, among them gliclazide, an anti-diabetic with anti-inflammatory and anti-oxidant side action which has never studied regarding OM. This study aimed to evaluate the effect of gliclazide on an experimental OM model induced by 5-fluorouracil. Male hamsters were pretreated with oral gliclazide (1, 5 or 10 mg/kg) for 10 days. The mucosal samples of the animals were submitted to histopathological and immunohistochemical analysis (COX2, iNOS, MMP-2, NFκB P65, GPx) and immunofluorescence (P-selectin). Levels of IL-1ß and TNF-α, myeloperoxidase activity (MPO) and malondialdehyde levels (MDA) were investigated by ultraviolet-visible spectroscopic analysis. Protein expression of NFkB NLS P50 was analyzed by western blotting. The group treated with gliclazide at a dose of 10 mg/kg presented erythema, absence of erosion and mucosal ulceration with a score of 1 (1-2) (p <0.01) in the clinical findings. The histopathological data of the gliclazide 10 mg/kg group showed reepithelialization, a discrete mononuclear inflammatory infiltrate, and ulcers with a score of 1 (1-1) (p <0.01). Treatment with 10 mg/kg gliclazide reduced the activity levels of MPO (p <0.001), MDA (p <0.001) and NFκB NLS P50 (p <0.05), resulting in low immunostaining for Cox-2, iNOS (p <0.05), NFκB P65 (p <0.05) and negative immunoreaction for MMP-2. For Gpx, staining was restored in the GLI 10-FUT group compared to 5FUT/saline (p <0.05). Immunofluorescence showed a decrease in P-selectin levels (p <0.001) after treatment with 10 mg/kg gliclazide (p <0.05). Furthermore, 10 mg/kg gliclazide attenuated OM severity and reduced oxidative stress, and 5-FU induced OM in hamsters (AU).