Kynurenines and intestinal neurotransmission: the role of N-methyl-d-aspartate receptors

Abstract

Gastrointestinal neuroprotection involves the net effect of many mechanisms which protect the enteral nervous system and its cells from death, dysfunction or degeneration. Neuroprotection is also a therapeutic strategy, aimed at slowing or halting the progression of primary neuronal loss following acute or chronic diseases. The neuroprotective properties of a compound clearly have implications for an understanding of the mechanism of dysfunctions and for therapeutic approaches in a number of gastrointestinal diseases.This paper focused on the roles of glutamate and N-methyl-D-aspartate (NMDA) receptors in the intrinsic neuronal control of gastrointestinal motility; the consequences of inflammation on gastrointestinal motility changes; and the involvement of tryptophan metabolites (especially kynurenic acid) in the regulatory function of the enteral nervous system and the modulation of the inflammatory response. Common features in the mechanisms of action, illustrative evidence from animal models, and experimental neuroprotective therapies making use of the currently available possibilities are also discussed.Overall, the evidence suggests that gastrointestinal neuroprotection against inflammation and glutamate-induced neurotoxicity may be mediated synergistically through the blockade of NMDA receptors and the inhibition of neuronal nitric oxide synthase activity and xanthine oxidoreductase-dependent superoxide production. These components are likewise significant factors in the pathomechanism of gastrointestinal inflammatory diseases and inflammation-linked motility alterations. Inhibition of the enteric NMDA receptors by kynurenic acid or its analogues may provide a novel option via which to influence intestinal hypermotility and inflammatory processes simultaneously.

Targeted Deletion of Kynurenine 3-Monooxygenase in Mice

“…Related to their role(s) in physiology, peripheral and central KP metabolites have recently received considerable attention as potential agents in human diseases ranging from cancer (61) to intestinal syndromes (62) and disorders of the endocrine (63), immune (64,65), and central nervous systems (20, 66 -69). Causal connections have been postulated either because genetic or biochemical KP abnormalities were found in specimens obtained from patients, as in schizophrenia (70 -76), or because studies in animals had predicted etiologically significant links.…”

Kynurenine pathway metabolism and the microbiota-gut-brain axis

“…Less is understood regarding the functions of kynurenic acid and quinolinic acid in the GI tract; however, both appear to be involved in immunoregulation (Keszthelyi et al, 2009). Interestingly, kynurenic acid may have anti-inflammatory properties in the GI tract (Kaszaki et al, 2012), and has been shown, in-vitro, to inhibit the proliferation of colon cancer cells (Walczak et al, 2014). **************************Insert Figure 2 Here****************************** 6.…”

Migraine, Neurogenic Inflammation, Drug Development - Pharmacochemical Aspects

“…N-methyl-D-aspartate (NMDA) receptor consists of three subunits (NR1, NR2, and NR3) and is activated by Glu and glycine. Glycine is essential for NMDA receptor function with the glycine binding site being located on the NR1 subunit [129,130]. In higher (micromolar/millimolar) doses, KYNA acts on the strychnine-insensitive glycine binding site of the NMDA receptor [130].…”