Intestinal mucositis was induced by the administration of 5‐FU in a single dose of 450mg/kg on the first day of the protocol in Swiss mice, and groups of animals that received dosages of angico branco were treated between the second and the fifth day, culminating in euthanasia and removal of intestinal segments for further analysis. Initially, through histopathological and morphometric findings, the severity of mucositis was demonstrated in this study, through aspects related to tissue architecture, focusing on the reduction and vacuolization of intestinal villi, crypt necrosis, infiltration of inflammatory cells, loss of inflammation cell architecture, decreased villus/crypt ratio, caused in the group of animals that received the 5‐FU dose. However, the group of animals that were treated with angico branco gum at a dose of 400mg/kg, after induction of intestinal mucositis, attenuation of these deleterious effects promoted by 5‐FU was observed, among which we can mention: less inflammatory infiltrate, maintenance of cellular architecture, attenuation of villus shortening and crypt depth, decrease of crypt necrosis, also evidenced by the better villus/crypt ratio. These effects, however, were not seen in the ileum. Treatment with white angelic gum at doses of 100 mg/kg; 200 mg/kg and 400 mg/kg promoted a statistically significant reduction (p <0.05) in the number of mast cells when confronted with the 5‐FU group in the duodenum and jejunum. In contrast, treatment with white angico gum reversed the mastocytosis observed by the increase in mast cell count in the intestinal segments of animals submitted to mucositis. In addition, the saline group did not show an increase in mast cells when compared to the group with 5‐FU. Studies that evaluated the role of mast cells in mucositis also revealed the participation of these substances in the course of intestinal mucositis (PEREIRA JUNIOR, 2017; MIRANDA, 2018). The study by Nogueira et al. (2017) also demonstrated a significant increase in the number of total and degranulated mast cells in the intestinal segments of animals subjected to irinotecan‐induced intestinal mucositis, with a release of pro‐inflammatory mediators in the inflammatory condition. Through the results found in this study it can be concluded that the gum of angico reduced the mast cell count and preserved the number of goblet cells after induction of intestinal mucositis induced by 5‐FU in mice. White angico gum reduces the mast cell count in the duodenum, jejunum of mice subjected to intestinal mucositis induced by 5‐FU.
The enzyme nitric oxide synthase (iNOS) is responsible for the synthesis of NO which is complemented by the conversion of L‐arginine and oxygen to L‐citrulline and NO. There are three forms of NOS identified: nitric oxide endothelial synthase (eNOS) found in the vascular endothelium, the neuronal nitric oxide synthase (nNOS) that regulates neuronal transmission, and inducible nitric oxide, first identified in macrophages. The first two are constitutive, and the last is related to tissue damage and present in inflammation and cell apoptosis (LIAUDET; SORIANO; SZABÓ, 2000; DAVIS et al., 2001). The mechanism of action of NO can occur in two ways: when there is interaction directly with the molecule of the target system and when there is a reaction with intermediates of reactive oxygen species, which can lead to the formation of reactive nitrogen species (RNA) such as peroxynitrite. (FANG, 1997; DAVIS et al., 2001; VALKO et al., 2007). Intestinal mucositis was induced in mice with the administration of 5 FU, according to the methodology described by Carneiro‐Filho et al. (2004), adapted. The treatment was done using three doses of angico branco gum (100, 200, 400 mg/kg) one day after i.p. of 5‐FU, the choice of doses being based on the study by Santos et al. (2013). The other groups received saline. Suppression of NO is an essential indicator for the development of an anti‐inflammatory agent, since NO is a mediator of inflammation derived from pro‐inflammatory cytokines and produced in various inflammatory conditions resulting from cytokine cytotoxicity (KHAN et al., 2015; TOSUN et al., 2014; CHUN et al., 2012). It has also been shown that NO negatively regulates the expression of adhesion molecules in the vascular endothelium, thus decreasing neutrophil trafficking in inflamed tissues (LEITÃO et al., 2006). When investigating the possible involvement of nitric oxide in the protective effect of white angico gum on morphometric and histopathological changes in mice submitted to intestinal mucositis by 5‐FU, it was evaluated that the administration of L‐NAME with white angico gum, as well as the separate administration of the two compounds prevented the villus shortening caused by 5‐FU, and increased the villus/crypt ratio. Thus, it can be said that both individual, and acting synergistically blocked the effects of NO and, consequently, can be used to treat intestinal mucositis. In conclusion, we observed that the angico gum at a concentration of 400 mg/kg had a protective effect on the intestinal mucosa, after inducing injury by chemotherapy, by decreasing the immunostaining for the enzyme iNOS, demonstrating the role of antiinflammatory. GAB = 400mg/kg white angico gum. Values were expressed as mean ± SEM of the percentage of the immunostained area for INOS.
Intestinal homeostasis has often been referred to as a state of controlled inflammation, in which pro‐ and anti‐inflammatory factors function in a synchronous manner. In this context, intestinal mucositis can be deemed as an inflammatory pathophysiological process, which results in morphological and physiological changes in the intestinal mucosa of the gastrointestinal tract. Its emergence is due to the administration of antineoplastic agents, such as 5‐fluorouracil (5‐FU), an antimetabolite, during cancer therapy (1). With high rates of morbidity and mortality, mucositis still represents an obstacle in the treatment of cancer due to the lack of an effective treatment. Numerous studies have explored natural products and secondary metabolites from medicinal plants such as natural gums to find compounds having pharmacological activity against various human health disorders. Angico (Anadenanthera colubrina (Vell.)) is a plant of the Fabaceae family prevalent in the Brazilian ecosystems of the Cerrado and Caatinga (4). Angico has been reported to possess medicinal properties for the treatment of diarrhea, cough, bronchitis, and inflammation (5). Secondary metabolites such as steroids, flavonoids, terpenes, andphenolic derivatives can be extracted from the bark of A. colubrina (6) that can function as antioxidants, antimicrobials, and anti‐inflammatory, anti‐proliferative, antiallergic, antithrombotic, and antiviral agents (7). In the present study, we aimed to evaluate the effect of AG on experimental intestinal mucositis induced by 5‐FU. Swiss mice were randomly divided into nine groups: Saline, 5‐FU, AG‐100, AG‐400, Celecoxib (CLX), CLX + AG‐400, L‐NAME, L‐Arginine, and AG + L‐NAME. The animals were euthanized, then, blood and segments of the small intestine were collected to evaluate histopathological, levels of malondialdehyde (MDA) and Nitrite/Nitrate (NOx), leukocytes, mast and goblet cell counts, and immunohistochemical analysis of induced nitric oxide synthase (iNOS) and cyclooxygenase‐2 (COX‐2). AG prevents morphofunctional changes in experimental intestinal mucositis due to 5‐FU by attenuating inflammation, oxidative stress, tissue damage, mastocytosis, and leukopenia. These results suggest that the NO and COX‐2 pathways are possible mechanisms mediating the protective effect of AG on intestinal mucositis induced by antineoplastic chemotherapeutic agents such as 5‐FU.
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