Kynurenic acid inhibits intestinal hypermotility and xanthine oxidase activity during experimental colon obstruction in dogs

Abstract

Kynurenic acid (KynA), an endogenous antagonist of N-methyl-d-aspartate (NMDA) glutamate receptors, protects the central nervous system in excitotoxic neurological diseases. We hypothesized that the inhibition of enteric glutamate receptors by KynA may influence dysmotility in the gastrointestinal tract. Group 1 of healthy dogs served as the sham-operated control, in group 2, the animals were treated with KynA, while in groups 3 and 4 mechanical colon obstruction was maintained for 7 h. Group 4 was treated with KynA at the onset of ileus. Hemodynamics and motility changes were monitored, and the activities of xanthine oxidoreductase (XOR) and myeloperoxidase (MPO) were determined from tissue samples. Colon obstruction induced a hyperdynamic circulatory reaction, significantly elevated the motility index and increased the mucosal leucocyte accumulation and the XOR activity. The KynA treatment augmented the tone of the colon, permanently decreased the motility index of the giant colonic contractions and reduced the increases in XOR and MPO activities. These effects were concomitant with the in vitro inhibition of XOR activity. In conclusion, KynA antagonizes the obstruction-induced motility responses and XOR activation in the colon. Inhibition of enteric NMDA receptors may provide an option to influence intestinal hypermotility and inflammatory changes.

Oxygen metabolism and barrier regulation in the intestinal mucosa

“…Notably, HIF regulates the generation of extracellular adenosine via upregulation of CD39 and CD73 and this increase in adenosine enhances antiinflammatory signaling through binding of the HIF-inducible adenosine A2B receptor (75). Another example is the tryptophan metabolite kynurenate, which exerts antiinflammatory properties by inhibiting xanthine oxidase, resulting in decreased production of ROS during hypoxic stress (76). Likewise, glutamate, methionine, and threonine appear to improve colonic mucosal regeneration after insult (77).…”

Kynurenic acid enhances expression of p21 Waf1/Cip1 in colon cancer HT-29 cells

“…The highest concentration was reported in honeybee products and some fresh vegetables including broccoli and potato [22]. Although the role of KYNA in the gastrointestinal tract is still not fully elucidated, previous studies revealed its involvement in a complex duodenal mucosa protection system [5][6][7], modulation of intestinal motility, and inflammatory response in experimental colonic obstruction in dogs [9] and experimental colitis in rats [23]. Moreover, taking into consideration that KYNA supported the growth of probiotic bacteria in vitro, its potential role in the regulation of bacterial growth in the digestive system is suggested [3].…”

The in vitro effect of kynurenic acid on the rainbow trout (Oncorhynchus mykiss) leukocyte and splenocyte activity

“…However, the literature contains reports verifying the antioxidant activity of KYNA, both in in vitro experiments and in animal organisms, leading to a reduced synthesis of reactive oxygen species (ROS) and even to a considerable decrease in the intensity of respiratory burst of the peripheral blood phagocytes (Moroni et al 2007, Kaszaki et al 2008, Lugo-Huitron et al 2011, Małac-zewska et al 2014. However, if the ROS scavenging properties of KYNA were to be responsible for the observed effect, then similar changes in the oxidative burst should be observable in a broader range of concentrations of this acid.…”

“…Its anti-inflammatory effect stems from the effect on the GPR35 receptor. It is known that this receptor is not activated until KYNA reaches higher than physiological, micromole concentrations (Fallarini et al 2010, Mándi andVécsei 2012), and the major effect of its activation is the depressed synthesis of pro-inflammatory cytokines, nitrogen oxide and reactive oxygen species in immune cells (Maes et al 2007, Moroni et al 2007, Kaszaki et al 2008, Lugo-Huitron et al 2011, Tiszlavicz et al 2011, Małaczewska et al 2014. The above findings stimulate an interest in kynurenic acid as a potential immunomodulator, which could find applications in correcting the immune response of an organism, especially in the course of systemic disorders.…”