Research Article: Therapeutic effect of adenosine on experimentally induced acute ulcerative colitis model in rats1

Date Published: February 14, 2020

Publisher: Sociedade Brasileira para o Desenvolvimento da Pesquisa em Cirurgia

Author(s): Gulcin Ercan, Gurkan Yigitturk, Oytun Erbas.

http://doi.org/10.1590/s0102-865020190120000004

Abstract

To examine the therapeutic effect of external adenosine on an acetic acid-induced acute ulcerative colitis model in rats.

Thirty male mature rats were divided into three groups as control, acute colitis (AC) and AC+adenosine group (AC+AD). AC was induced by rectal administration of 4% acetic acid (AA). 5mg/kg/day adenosine was performed i.p for 4 weeks to AC+AD group. Rectum and colon were excised for microscopic and histopathological histopathologic evaluations, and immunohistochemical analysis of nuclear factor kappa B (NF-kB). Blood samples were collected for biochemical detection of TNF-α, Pentraxin-3 and malondialdehyde (MDA) levels.

AC group had generalized hyperemia and hemorrhage with increased macroscopic and histopathological scores compared with control (P <0.0001) while adenosine treatment decreased these scores significantly (P <0.001), with reduced distribution of disrupted epithelium, leukocyte infiltrates, and focal hemorrhage. AC group showed significantly increased immunoexpression of NF-kB in rectum, plasma and tissue levels of TNF-α, plasma Pentraxin-3 and MDA levels (P <0.0001) while adenosine reduced these levels (P < 0.05). Adenosine appears to promote healing of colon and rectum exposed to AA-induced AC, suggesting a boosting effect of adenosine on the intestinal immune system to cure ulcerative colitis.

Partial Text

Ulcerative colitis is a chronic inflammatory disease of the gastrointestinal tract. Its etiology involves the basic clinical symptoms of rectal bleeding, diarrhea, weight loss and abdominal pain, and other signs include anemia, fever, joint pain, damage to mucus membranes, renal calculi, and osteoporosis1,2. Although there are several environmental, genetic, and immunological factors which play essential roles in the pathogenesis of ulcerative colitis2,3, the underlying etiology and pathogenesis remains essentially unknown.

All animal studies were strictly conformed to the animal experiment guidelines of the Ethics Committee for Animal Care of Ege University. All procedures were performed according to the Animal Experimentation Ethics Committee under protocol number 2012-004.

All animals (n=30) in this 4 week-study survived at the end of procedures and there was no need to exclude none due to any inflammation or any alteration in feeding or weighing or complication of application by acetic acid or anesthesia protocol.

Released by cells into the extracellular space during hypoxia, ischemia, or exercise, the nucleoside adenosine is a potent key regulatory molecule to balance the cellular oxygen supply and demand during the metabolic stress11. During the acute inflammation process, neutrophils release the nuclear DNA to trap the pathogens, providing a rich source for extracellular nucleotides and nucleosides. Nucleosides are also supplied luminally from dietary sources. Therefore, under a variety of pathological and nonpathological conditions, a large number of adenosine molecules may accumulate in the extracellular space in the vicinity of both the apical and basolateral surfaces of intestinal epithelial cells12. Since endogenously generated adenosine is suggested to play a role in the regulation of inflammation in the intestine, until now, the attempts to enhance the adenosine signaling during experimental colitis have exerted many beneficial results13. Aiming to support these results in this experimental study, we showed that the long-term adenosine treatment could ameliorate AA-induced colitis ulcerative pathologies in the colon and rectum of rats. The therapeutic effect of adenosine on experimentally induced colitis was reflected in its ability to decrease the AA-induced hyperemia and hemorrhage, disruption of intestinal epithelium, infiltration of leukocytes into colon and rectum, AA-increased NF-kB immunoexpression, and AA-elevated TNF-α in both plasma and rectum tissues, MDA and PTX3 levels in plasma.

The findings of the present study reflect the high potential and remarkable therapeutic effects of adenosine as a new therapeutic strategy in inflammatory intestinal diseases. Adenosine signaling represents impactful levers to be tackled to improve the control of mucosal inflammation. Still, there are some issues that need to be examined, such as the clinical implication of adenosine in humans. Although this experimental study exerts substantial results, overall clinical studies for these novel concepts are still lacking. Therefore, further mechanism and molecular studies are needed to shed new light at the underlying mechanism of adenosine in the inflammatory diseases.

 

Source:

http://doi.org/10.1590/s0102-865020190120000004

 

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