Abstract
Intestinal mucositis is a frequent side effect of chemotherapy with 5-fluorouracil, characterized by a gastrointestinal inflammatory process. Epiisopiloturine is an imidazole alkaloid from Pilocarpus microphyllus Stapf ex Wardlew., Rutaceae, considered promising due to its high economic potential, since it is a by-product from the isolation of pilocarpine. In addition, this drug has antioxidant and anti-inflammatory activities. This study aimed to investigate the effects of epiisopiloturine on 5-fluorouracil-induced intestinal mucositis. After extraction, epiisopiloturine was characterized by the application of chromatographic, spectroscopic, and thermal methods. In the in vivo study, the animals received a single 5-fluorouracil dose (450 mg/kg, i.p.) and, from the second to the fifth day, were treated with epiisopiloturine (0.1, 1 or 10 mg/kg, i.p.). After euthanasia, the intestinal samples were removed for evaluation of morphometric and histopathological scores, the number of mast cells, goblet cells, circulating leukocytes, and the concentration of malondialdehyde and glutathione. Finally, we evaluated the expression of cyclooxygenase-2 by immunohistochemistry. Epiisopiloturine presented anti-inflammatory action through the reduction of inflammation indicators and oxidative stress. Epiisopiloturine also preserved the number of circulating leukocytes, contributed to the recovery of the tissue architecture, and restored the number of goblet cells in the small intestine. Thus, our findings suggest that epiisopiloturine protects the intestinal mucosa through inhibition of COX-2.
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Acknowledgements
The authors also thank Universidade Federal do Ceará, Universidade Federal do Piauí and Núcleo de Ensino e Pesquisa em Microscopia e Processamento de Imagens.
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This work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
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MLLB: animal experiments, leukocyte count, morphometric analysis oxidative evaluation, and writing of original draft. MSC and MENPR: Epiisopiloturine characterization and writing of original draft. CSMR: immunohistochemistry and histological slides. HBP, JALM, and LCV: animal experiments, leukocyte count, weight loss evaluation, and malondialdehyde and glutathione evaluation. GACB and RFCL: histopathological scores, resources, editing, and review. LMCV: epiisopiloturine isolation, resources, and writing and review. JVRM and GSC: conceptualization, supervision, and writing, review and editing. All authors have read and approved the final version of the manuscript.
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Barbosa, M.L.L., Campelo, M.d.S., Pimenta, H.B. et al. Epiisopiloturine from Pilocarpus microphyllus Leaves Reduces Intestinal Mucositis Through Cyclooxygenase-2 Pathway. Rev. Bras. Farmacogn. 32, 942–952 (2022). https://doi.org/10.1007/s43450-022-00324-z
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DOI: https://doi.org/10.1007/s43450-022-00324-z