Comparative effects of nonpeptide tachykinin receptor antagonists on experimental gut inflammation in rats and guinea-pigs

doi:10.1016/S0024-3205(98)00271-9

Life Sciences

Volume 63, Issue 4, 19 June 1998, Pages 293-304

https://doi.org/10.1016/S0024-3205(98)00271-9 Get rights and content

Abstract

Previous studies have shown tachykinins implicated in gut inflammation. The aim of this work was to evaluate the effect of treatments with tachykinin NK1, NK2, and NK3 selective receptor antagonists on the development of gut inflammation induced by trinitrobenzenesulfonic acid (TNBS) in rats and guinea-pigs. On day 0, rats and guinea-pigs received an intraluminal instillation of TNBS/ethanol (40 $mg kg$ ). Each group was daily treated with intraperitoneally injected NK1 (SR 140333; 0.3 mg/kg/day), NK2 (SR 48968; 5 mg/kg/day), or NK3 (SR 142801; 1, 5, or 10 mg/kg/day) receptor antagonists or their vehicle. On day 4, inflammatory levels were evaluated by measuring gut permeability, myeloperoxidase activity, macro- and microscopic damage scores. In TNBS treated rats, daily administration of SR 140333 (0.3 mg/kg/day) and SR 48968 (5 mg/kg/day) reduced colonic inflammation. In TNBS treated guinea-pigs, daily administration of SR 48968 (5 mg/kg/day) and SR 142801 (at 5 and 10 mg/kg/day) attenuated significantly ileal injury. These results suggest that non-peptide tachykinin receptor antagonists are potent anti-inflammatory agents on gut inflammation in rats and guinea-pigs. However, their activity depends upon the animal species and type of receptor considered.

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Tachykinin Antagonists Reverse Ischemia/Reperfusion Gastrointestinal Motility Impairment in Rats
2020, Journal of Surgical Research
Citation Excerpt :
The present study does not provide the insights to elucidate the molecular mechanism of the beneficial effects of pretreatment with NK1-3 antagonists in gut I/R injury. One can speculate that the potent antinociceptive and anti-inflammatory activities of NK1-3 blockers played a role in the observed phenomenon.24,26-29 The model of I/R injury using the SMA clamping and unclamping is well accepted and easily implemented.
Supraceliac aortic clamping and unclamping produces ischemia-reperfusion (I/R) injury of the splanchnic organs. The protective effects of tachykinin receptor antagonists, SR140333 (NK₁ receptor), SR48968 (NK₂ receptor), and SB222200 (NK₃ receptor), against I/R-induced inhibition of intestinal motility were tested in rats.
The intestinal transit of Evans blue was measured in untreated rats and animals subjected to skin incision, I/R (1 h superior mesenteric artery occlusion followed by 24 h reperfusion) or sham operation. Surgical procedures were conducted under diethyl ether anesthesia.
The gastrointestinal transit has not been markedly affected in rats, which were anesthetized or subjected to skin incision in comparison with untreated animals. In contrast, a sham operation and I/R have significantly reduced the intestinal motility. Pretreatment with NK_1-3 blockers (SR140333 [3-30 μg/kg]; SR48968 [3-100 μg/kg]; and SB222200 [10-100 μg/kg]) reversed dose dependently the effects of I/R to the level observed after sham operation only. A combination of NK₁+NK₂+NK₃ inhibitors exerted an additive effect compared with NK₁ and NK₂ antagonists used as single agents. Similarly, combined NK₁+NK₂ were more effective than NK₂ alone. Sham operation and I/R have shifted the in vitro carbachol concentration–response curves to the right in comparison with untreated animals, a phenomenon partially reversed by NK₁-NK₃ pretreatment.
Single-agent and combined treatment with NK_1-3 antagonists markedly attenuated the gastrointestinal dysmotility evoked by I/R injury. The pretreatment with NK₃ blocker proved to be the most active in this experimental setting.
Communication Between Enteric Neurons, Glia, and Nociceptors Underlies the Effects of Tachykinins on Neuroinflammation
2018, Cellular and Molecular Gastroenterology and Hepatology
Citation Excerpt :
In support, our results show an up-regulation of TAC1 mRNA during acute colitis and a trending decrease in both NKA and SP immunoreactivity. Prior studies have indicated that NK2Rs contribute to gut inflammation in animal models because NK2R antagonism with SR 48698 prevented weight loss and reduced macroscopic damage during TNBS colitis in rats and guinea pigs.60 In this study, we did not observe a significant effect of GR 159897 on the initial inflammatory insult, but GR 159897 did enhance the recovery from inflammation as reflected by animal weight.
Tachykinins are involved in physiological and pathophysiological mechanisms in the gastrointestinal tract. The major sources of tachykinins in the gut are intrinsic enteric neurons in the enteric nervous system and extrinsic nerve fibers from the dorsal root and vagal ganglia. Although tachykinins are important mediators in the enteric nervous system, how they contribute to neuroinflammation through effects on neurons and glia is not fully understood. Here, we tested the hypothesis that tachykinins contribute to enteric neuroinflammation through mechanisms that involve intercellular neuron-glia signaling.
We used immunohistochemistry and quantitative real-time polymerase chain reaction, and studied cellular activity using transient-receptor potential vanilloid-1 (TRPV1)^tm1^(cre)Bbm/J::Polr2a^{tm1(CAG-GCaMP5g,-tdTomato)Tvrd} and Sox10CreER^T2::Polr2a^{tm1(CAG-GCaMP5g,-tdTomato)Tvrd} mice or Fluo-4. We used the 2,4-di-nitrobenzene sulfonic acid (DNBS) model of colitis to study neuroinflammation, glial reactivity, and neurogenic contractility. We used Sox10::CreER^T2+/-/Rpl22^tm1.1Psam/J mice to selectively study glial transcriptional changes.
Tachykinins are expressed predominantly by intrinsic neuronal varicosities whereas neurokinin-2 receptors (NK2Rs) are expressed predominantly by enteric neurons and TRPV1-positive neuronal varicosities. Stimulation of NK2Rs drives responses in neuronal varicosities that are propagated to enteric glia and neurons. Antagonizing NK2R signaling enhanced recovery from colitis and prevented the development of reactive gliosis, neuroinflammation, and enhanced neuronal contractions. Inflammation drove changes in enteric glial gene expression and function, and antagonizing NK2R signaling mitigated these changes. Neurokinin A–induced neurodegeneration requires glial connexin-43 hemichannel activity.
Our results show that tachykinins drive enteric neuroinflammation through a multicellular cascade involving enteric neurons, TRPV1-positive neuronal varicosities, and enteric glia. Therapies targeting components of this pathway could broadly benefit the treatment of dysmotility and pain after acute inflammation in the intestine.
Neuronal Regulation of Mucosal Immune Responses
2015, Mucosal Immunology: Fourth Edition
In this chapter, the current understanding of how innate mucosal immunity can be influenced by the neuronal system will be highlighted, and the cell types and receptors documented to play a role in this interaction discussed. We will focus on the direct neuronal regulatory mechanisms, notwithstanding current advances regarding the role of gut microbes, including gastrointestinal commensals and pathogens, in modulating communication in the gut–brain axis. These aspects of gut–brain communication will be discussed elsewhere.
Opposite effects of substance P and calcitonin gene-related peptide in oxazolone colitis
2012, Digestive and Liver Disease
Citation Excerpt :
Both CGRP and SP appear to act as important messengers between the nervous and immune systems [9]. Pharmacological blocking of the SP high-affinity receptor NK-1 using CP and SR14033 showed anti-inflammatory effects in rat models of TNBS and DSS colitis [2,3,6]. However, another NK-1 antagonist was ineffective [4,7].
Extrinsic sensory neurons play a crucial role in aberrant immune responses in colitis. The activation of peptidergic sensory nerve fibres is accompanied by a release of the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP). SP levels increase whilst CGRP levels decrease in colon specimens from patients with inflammatory bowel disease; thus suggesting the pro- and anti-inflammatory roles, respectively, of these neuropeptides.
Oxazolone (4-ethoxymethylene-2-phenyl-2-oxazolin-5-one) colitis was induced in wild-type (WT), SP and CGRP knockout (^−/−) mice. CGRP^−/− mice were treated with the neurokinin 1-receptor antagonist CP-96345 (CP). The permeability of the mouse colon was evaluated by Evans Blue uptake. Cytokines produced by colonic lamina propria mononuclear cells were measured by ELISA.
Colons of WT, CGRP^−/− and SP^−/− mice showed similar tissue architecture and permeability. SP^−/− mice were protected against oxazolone colitis, whereas CGRP^−/− showed increased susceptibility to colitis compared to WT mice. SP^−/− and CP-treated CGRP^−/− mice showed no significant body weight loss during the period of sickness in contrast to untreated CGRP^−/− and WT mice. Decreased production of IL-4, IL-5, and IL-13 by colonic lamina propria mononuclear cells of the protected SP^−/− mice confirms the crucial role of these cytokines in oxazolone colitis.
We demonstrate that the neuropeptides CGRP and SP exert opposing effects in oxazolone colitis and provide further evidence for a prominent neuroimmune association in the gut.
TRPA1 and substance P mediate colitis in mice
2011, Gastroenterology
Citation Excerpt :
Such an oxidation product is stable and could contribute to sustaining the activation/sensitization of the receptor channel if applied to the Cys residues in TRPA1. The released neuropeptides are candidate mediators for linking the sensory neurons to the immune system and generating inflammation.17–23 We used null mutant mouse strains and generated a double-knockout line for CGRP and SP to study both mechanistically different colitis models (Figure 6).
The neuropeptides calcitonin gene-related peptide (CGRP) and substance P, and calcium channels, which control their release from extrinsic sensory neurons, have important roles in experimental colitis. We investigated the mechanisms of colitis in 2 different models, the involvement of the irritant receptor transient receptor potential of the ankyrin type-1 (TRPA1), and the effects of CGRP and substance P.
We used calcium-imaging, patch-clamp, and neuropeptide-release assays to evaluate the effects of 2,4,6-trinitrobenzene-sulfonic-acid (TNBS) and dextran-sulfate-sodium-salt on neurons. Colitis was induced in wild-type, knockout, and desensitized mice.
TNBS induced TRPA1-dependent release of colonic substance P and CGRP, influx of Ca2+, and sustained ionic inward currents in colonic sensory neurons and transfected HEK293t cells. Analysis of mutant forms of TRPA1 revealed that TNBS bound covalently to cysteine (and lysine) residues in the cytoplasmic N-terminus. A stable sulfinic acid transformation of the cysteine-SH group, shown by mass spectrometry, might contribute to sustained sensitization of TRPA1. Mice with colitis had increased colonic neuropeptide release, mediated by TRPA1. Endogenous products of inflammatory lipid peroxidation also induced TRPA1-dependent release of colonic neuropeptides; levels of 4-hydroxy-trans-2-nonenal increased in each model of colitis. Colitis induction by TNBS or dextran-sulfate-sodium-salt was inhibited or reduced in TRPA1−/− mice and by 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopro-pylphenyl)-acetamide, a pharmacologic inhibitor of TRPA1. Substance P had a proinflammatory effect that was dominant over CGRP, based on studies of knockout mice. Ablation of extrinsic sensory neurons prevented or attenuated TNBS-induced release of neuropeptides and both forms of colitis.
Neuroimmune interactions control intestinal inflammation. Activation and sensitization of TRPA1 and release of substance P induce and maintain colitis in mice.
Protection from DNBS-induced colitis by the tachykinin NK<inf>1</inf> receptor antagonist SR140333 in rats
2009, European Journal of Pharmacology
Inflammation is known to be associated with changes in tachykinin expression both in human and animal models: substance P and NK₁ receptor expression are increased in patients with inflammatory bowel disease, and similar changes are reported in experimental models of inflammation. We investigated the effect of the tachykinin NK₁ receptor antagonist SR140333 (10 mg/kg orally) on 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis in rats. Colonic damage was assessed by means of macroscopic and microscopic scores, myeloperoxidase activity (MPO) and TNF-α tissue levels on day 6 after induction of colitis. An enzyme immunoassay technique was used to measure colonic substance P levels. DNBS administration impaired body weight gain and markedly increased all inflammatory parameters as well as colonic tissue levels of substance P. Treatment with SR140333 significantly counteracted the impairment in body weight gain, decreased macroscopic and histological scores and reduced colonic myeloperoxidase activity and TNF-α tissue levels. Colonic tissue levels of substance P were also reduced by SR140333, although this effect did not reach statistical significance. In conclusion, treatment with SR140333 protects from DNBS-induced colitis in rats. These results suggest a role for NK₁ receptors and substance P in the development of intestinal inflammation and indicate tachykinin receptors as a potential pharmacological target in the treatment of inflammatory bowel disease.

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Comparative effects of nonpeptide tachykinin receptor antagonists on experimental gut inflammation in rats and guinea-pigs

Abstract

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Gastroenterology

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