Abstract
The co-administration of 3α-hydroxymasticadienoic acid (3α-OH MDA) and diligustilide (DLG) generates a synergist gastroprotective effect on indomethacin-induced gastric damage. However, the related protective activities of the compounds alone (or in combination) remain unclear. In the present study, we evaluated the anti-inflammatory and antioxidative activities, as well as the potential modulation of important gasotransmitters of each compound individually and in combination using the indomethacin-induced gastric damage model. Male Wistar rats were treated orally with the 3α-OH MDA, DLG, or their combination (at a fixed ratio of 1:1, 1:3, and 3:1) 30 min before the generation of gastric mucosal lesions with indomethacin (30 mg/kg, p.o.). Three hours later, the gastric injury (mm2) was determined. Results from these experiments indicate, in addition to maintaining basal levels of PGE2, the gastroprotective effect of the pre-treatment with 3α-OH MDA (70%), DLG (81%), and their combination (72%) which was accompanied by significant decreases in leukocyte recruitment, as well as decreases in TNF-α and LTB4 gastric levels (p < 0.05). We also found that the pre-treatment maintains the basal antioxidant enzyme activities (SOD) and gastric NO and H2S production even in the presence of indomethacin (p < 0.05). In conclusion, when 3α-OH MDA-DLG is given at a 1:1 combination ratio, the gastroprotective effect and the inflammatory, antioxidant, and gaso-modulation properties are not different from those of treatments using the maximum doses of each compound, revealing that this combination produces promising results for the treatment of gastric ulcers.
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Acknowledgments
E. A. Pineda-Peña acknowledges Programa de Becas Postdoctorales DGAPA-UNAM 2018-2019 for postdoctoral fellowship. The authors acknowledge BcS Itzel Karina Vega-Aguilar and BcS Dulce Guadalupe Meza-Perez from Universidad Nacional Autónoma de México for their technical assistance in this project.
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The authors acknowledge the support provided by the Grants PAIP 5000-9143, from Facultad de Química, DGAPA-UNAM IN213418 from Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México, and CONACYT project A1-S-9698 from Consejo Nacional de Ciencia y Tecnologia (CONACYT).
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EP performed the experiments and data analysis and wrote the article. AO, JV, and JL helped with the data analysis and contributed to the correction of the manuscript. JT contributed to the correction of the manuscript. AC developed part of the experimental design and contributed to the correction of the manuscript, and AN designed and supervised the entire project. All authors read and approved the manuscript.
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The experiments, care, and handling of the animals were conducted in accordance with the Mexican official guidelines for laboratory animals (NOM-062-ZOO-1999) and international norms. The protocol of this study was approved by the Institutional Committee for the use and care of laboratory animals (CICUAL) from the Facultad de Química UNAM (file number: OFICIO/FQ/CICUAL/321/18 and date of approval: 24 August 2018).
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Pineda-Peña, E.A., Orona-Ortiz, A., Velázquez-Moyado, J.A. et al. Anti-inflammatory, antioxidant, and gaso-protective mechanism of 3α-hydroxymasticadienoic acid and diligustilide combination on indomethacin gastric damage. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1501–1513 (2020). https://doi.org/10.1007/s00210-020-01857-7
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DOI: https://doi.org/10.1007/s00210-020-01857-7