Selective α7 nicotinic acetylcholine receptor agonists worsen disease in experimental colitis

Snoek, Susanne A.; Verstege, Marleen I.; Zanden, Esmerij P. van der; Deeks, Nigel; Bulmer, D; Skynner, Michael J.; Lee, Kevin; Velde, Anje A. te; Boeckxstaens, Guy E.; Jonge, Wouter J. de

doi:10.1111/j.1476-5381.2010.00699.x

Cited by 80 publications

(77 citation statements)

References 49 publications

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“…Similarly, impaired survival was also observed after nicotine treatment in septic peritonitis induced by intraperitoneal injection of E coli or fecal contamination. 60 61 Also in a model of colitis, selective α7nAChR agonists were reported to worsen disease, 62 again illustrating that dampening cytokine production is not always beneficial to the host, especially in infectious conditions.…”

Section: Clinical Significance Of the Cholinergic Anti-inflammatory Pmentioning

confidence: 99%

“…Although both agonists reduced NF-κB transcriptional activity, IL-6 and TNF release by activated peritoneal macrophages, clinical parameters (body weight, colon weight and length), IL-6 and IL-17 levels were not augmented in vivo in two different colitis models; that is, DSS and TNBS-induced colitis. 62 Most likely, the protective effect of α7nAChR activation against excessive inflammation and collateral tissue damage compromises the host defence against the increased exposure to intraluminal microbiota following mucosal damage, suggesting that care should be taken when using these compounds in patients with IBD.…”

Section: Inflammatory Bowel Diseasementioning

confidence: 99%

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The vagal innervation of the gut and immune homeostasis

Matteoli

Gomez‐Pinilla

Giovangiulio

et al. 2015

Autonomic Neuroscience

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The central nervous system interacts dynamically with the immune system to modulate inflammation through humoral and neural pathways. Recently, in animal models of sepsis, the vagus nerve (VN) has been proposed to play a crucial role in the regulation of the immune response, also referred to as the cholinergic anti-inflammatory pathway. The VN, through release of acetylcholine, dampens immune cell activation by interacting with α-7 nicotinic acetylcholine receptors. Recent evidence suggests that the vagal innervation of the gastrointestinal tract also plays a major role controlling intestinal immune activation. Indeed, VN electrical stimulation potently reduces intestinal inflammation restoring intestinal homeostasis, whereas vagotomy has the reverse effect. In this review, we will discuss the current understanding concerning the mechanisms and effects involved in the cholinergic anti-inflammatory pathway in the gastrointestinal tract. Deeper investigation on this counter-regulatory neuroimmune mechanism will provide new insights in the cross-talk between the nervous and immune system leading to the identification of new therapeutic targets to treat intestinal immune disease.

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Section: Clinical Significance Of the Cholinergic Anti-inflammatory Pmentioning

confidence: 99%

Section: Inflammatory Bowel Diseasementioning

confidence: 99%

The vagal innervation of the gut and immune homeostasis

Matteoli

Gomez‐Pinilla

Giovangiulio

et al. 2015

Autonomic Neuroscience

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“…However, chronic i.p. injection of nicotine (0.25 and 2.50 mmol/kg) in DSS-induced colitis in mice failed to decrease clinical signs of inflammation, colonic TNF levels, and histologic features of the disease (Snoek et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Novel Insights on the Effect of Nicotine in a Murine Colitis Model

AlSharari

Akbarali

Abdullah

et al. 2012

J Pharmacol Exp Ther

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Studies showed that nicotine has a positive influence on symptoms of ulcerative colitis. In the present study, we explored the effect of nicotine treatment using different routes of administration in the dextran sodium sulfate (DSS) colitis mouse model. We also investigated the effects of cotinine, a major metabolite of nicotine, in the model. C57BL6 adult male mice were given DSS solution freely in the drinking water for seven consecutive days, and tap water was given thereafter. Disease severity, length of the colon, colon tissue histology, and inflammatory markers, including colonic myeloperoxidase activity and colonic tumor necrosis factor-a levels, were evaluated. The effect of nicotine and cotinine treatments via various different routes of administration were examined the DSS model. In addition, we measured the plasma levels of nicotine and cotinine in our treatment protocols. Administration of low, but not high, doses of oral nicotine in DSS-treated mice resulted in a significant decrease in disease severity, histologic damage scores, as well as colonic level of tumor necrosis factor-a. However, the anti-inflammatory effect of nicotine was not seen after chronic s.c. or minipump infusion of the drug. Differences in plasma levels of nicotine and cotinine do not seem to account for this lack of effect. Finally, oral cotinine alone failed to show a significant effect in the DSS model of colitis. These results highlight that dose and route of administration play a critical role in the protective effect of nicotine in the DSS mouse colitis model.

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“…As a result, the secretion of ACh was reduced and colonic mucosal damage was alleviated through a 'nicotinic anti-inflammatory pathway' dependent on the α7-nicotinic acetylcholine receptor (α7nAChR) [40][41][42] . Our research showed that the discharge frequency of the vagus was decreased after chemical stimulation of the PVN, indicating that the vagus pathway played a critical role in the protective effect.…”

Section: Discussionmentioning

confidence: 99%

Glutamate microinjection into the hypothalamic paraventricular nucleus attenuates ulcerative colitis in rats

Zhang

Fei

et al. 2013

Acta Pharmacol Sin

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Aim: To investigate the effects of glutamate microinjection into hypothalamic paraventricular nucleus (PVN) on ulcerative colitis (UC) in rats and to explore the relevant mechanisms. Methods: 2,4,6-Trinitrobenzenesulfonic acid (100 mg/kg in 50% ethanol) was instilled into the colon of adult male SD rats to induce UC. A colonic damage score (CDS) was used to indicate the severity of the colonic mucosal damage. The pathological changes in the colonic mucosa were evaluated using immunohistochemistry, Western blotting, biochemical analyses or ELISA. Ten minutes before UC induction, drugs were microinjected into the relevant nuclei in rat brain to produce chemical stimulation or chemical lesion.Results: Microinjection of glutamate (3, 6 and 12 µg) into the PVN dose-dependently decreased the CDS in UC rats. This protective effect was eliminated after kainic acid (0.3 µg) was microinjected into PVN or into the nucleus tractus solitarius (NTS) that caused chemical lesion of these nuclei. This protective effect was also prevented when the AVP-V 1 receptor antagonist DPVDAV (200 ng) was microinjected into the NTS. The discharge frequency of the vagus was markedly decreased following microinjection of glutamate into the PVN. Microinjection of glutamate into the PVN in UC rats significantly increased the cell proliferation and anti-oxidant levels, and decreased the apoptosis and Bax and caspase 3 expression levels and reduced the pro-inflammatory factors in the colonic mucosa. Conclusion: The activation of hypothalamic PVN exerts protective effects against UC, which is mediated by the NTS and vagus. The effects may be achieved via anti-oxidative, anti-apoptotic, and anti-inflammatory factors.

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Selective α7 nicotinic acetylcholine receptor agonists worsen disease in experimental colitis

Cited by 80 publications

References 49 publications

The vagal innervation of the gut and immune homeostasis

The vagal innervation of the gut and immune homeostasis

Novel Insights on the Effect of Nicotine in a Murine Colitis Model

Glutamate microinjection into the hypothalamic paraventricular nucleus attenuates ulcerative colitis in rats

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