Nitrergic Enteric Neurons in Health and Disease—Focus on Animal Models

Abstract

Nitrergic enteric neurons are key players of the descending inhibitory reflex of intestinal peristalsis, therefore loss or damage of these neurons can contribute to developing gastrointestinal motility disturbances suffered by patients worldwide. There is accumulating evidence that the vulnerability of nitrergic enteric neurons to neuropathy is strictly region-specific and that the two main enteric plexuses display different nitrergic neuronal damage. Alterations both in the proportion of the nitrergic subpopulation and in the total number of enteric neurons suggest that modification of the neurochemical character or neuronal death occurs in the investigated gut segments. This review aims to summarize the gastrointestinal region and/or plexus-dependent pathological changes in the number of nitric oxide synthase (NOS)-containing neurons, the NO release and the cellular and subcellular expression of different NOS isoforms. Additionally, some of the underlying mechanisms associated with the nitrergic pathway in the background of different diseases, e.g., type 1 diabetes, chronic alcoholism, intestinal inflammation or ischaemia, will be discussed.

Involvement of Enteric Glia in Small Intestine Neuromuscular Dysfunction of Toll-Like Receptor 4-Deficient Mice

“…In the ENS, the major inhibitory NANC neurotransmitter is endogenous NO that can be generated by the three different enzymes, nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS). More than 90% of the total NOS in the small intestine is nNOS, expressed by nitrergic neurons, mostly distributed in the myenteric plexus, which act as inhibitory interneurons or inhibitory motoneurons [42]. However, iNOS isoform is also constitutively present and accounts for less than 10% of the total enteric NOS activity whereas eNOS isoform is barely detectable [42,43].…”

“…More than 90% of the total NOS in the small intestine is nNOS, expressed by nitrergic neurons, mostly distributed in the myenteric plexus, which act as inhibitory interneurons or inhibitory motoneurons [42]. However, iNOS isoform is also constitutively present and accounts for less than 10% of the total enteric NOS activity whereas eNOS isoform is barely detectable [42,43]. In case of inflammation, the induction of iNOS produces a large amount of NO in epithelial and immune cells as well as in neurons and EGCs of the ENS, determining altered epithelial function and water and ion transport dysregulation with consequent intestinal dysmotility [24,33,34,42,[44][45][46].…”

“…However, iNOS isoform is also constitutively present and accounts for less than 10% of the total enteric NOS activity whereas eNOS isoform is barely detectable [42,43]. In case of inflammation, the induction of iNOS produces a large amount of NO in epithelial and immune cells as well as in neurons and EGCs of the ENS, determining altered epithelial function and water and ion transport dysregulation with consequent intestinal dysmotility [24,33,34,42,[44][45][46]. Indeed, we have recently shown that, in NANC conditions, isolated ileal segments from TLR4 −/− mice display increased EFS-mediated relaxations associated with a proportional increase of nNOS + neurons and an increase of both iNOS activity and immunoreactivity, whereas in WT mice the inhibitory tone was mainly dependent on nNOS-mediated NO production [29].…”

Peer Review #3 of "Homeoprotein OTX1 and OTX2 involvement in rat myenteric neuron adaptation after DNBS-induced colitis (v0.1)"

“…After I/R, NO derived from iNOS promoted OTX1 up-regulation more, while nNOS more closely related to OTX2 upregulation. During gut inflammation and I/R injury, iNOS and nNOS have different roles on enteric neuronal homeostasis, retaining a neurodamaging and neuroprotective role, respectively (Rivera et al, 2012;Filpa et al, 2017;Bódi et al, 2019). Activation of the inducible isoform and downregulation of nNOS, are correlated with derangement of the neuromuscular function and slowing of the gastrointestinal transit (Rivera et al, 2012;Giaroni et al, 2013;Filpa et al, 2015).…”

PDTC Alleviates Depressive Symptoms and Colon Tissue Injury via Inhibiting NO Overproduction in CUMS Rats

“…NO is synthesized by neuronal NO synthase (nNOS), endothelial NOS (eNOS), and iNOS in the different cell types, and all of the NOS isoforms are present in mRNA and protein in the enteric neurons (Bagyanszki et al, 2011). iNOS-derived NO is released in large quantities during inflammation, which may be cytotoxic to enteric neurons (Bodi et al, 2019). However, few studies have addressed the effects of the iNOS/NO pathway in the spinal cord on GI function under stress conditions.…”