α7 Nicotinic Agonist AR-R17779 Protects Mice against 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis in a Spleen-Dependent Way

Abstract

The existence of a cholinergic anti-inflammatory pathway negatively modulating the inflammatory and immune responses in various clinical conditions and experimental models has long been postulated. In particular, the protective involvement of the vagus nerve and of nicotinic Ach receptors (nAChRs) has been proposed in intestinal inflammation and repeatedly investigated in DSS- and TNBS-induced colitis. However, the role of α7 nAChRs stimulation is still controversial and the potential contribution of α4β2 nAChRs has never been explored in this experimental condition. Our aims were therefore to pharmacologically investigate the role played by both α7 and α4β2 nAChRs in the modulation of the local and systemic inflammatory responses activated in TNBS-induced colitis in mice and to assess the involvement of the spleen in nicotinic responses. To this end, TNBS-exposed mice were sub-acutely treated with various subcutaneous doses of highly selective agonists (AR-R17779 and TC-2403) and antagonists (methyllycaconitine and dihydro-β-erythroidine) of α7 and α4β2 nAChRs, respectively, or with sulfasalazine 50 mg/kg per os and clinical and inflammatory responses were evaluated by means of biochemical, histological and flow cytometry assays. α4β2 ligands evoked weak and contradictory effects, while α7 nAChR agonist AR-R17779 emerged as the most beneficial treatment, able to attenuate several local markers of colitis severity and to revert the rise in splenic T-cells and in colonic inflammatory cytokines levels induced by haptenization. After splenectomy, AR-R17779 lost its protective effects, demonstrating for the first time that, in TNBS-model of experimental colitis, the anti-inflammatory effect of exogenous α7 nAChR stimulation is strictly spleen-dependent. Our findings showed that the selective α7 nAChRs agonist AR-R17779 exerted beneficial effects in a model of intestinal inflammation characterized by activation of the adaptive immune system and that the spleen is essential to mediate this cholinergic protection.

Combined administration of SHP2 inhibitor SHP099 and the α7nAChR agonist PNU282987 protect mice against DSS‑induced colitis

“…Several studies have indicated that activating α7nAChR can alleviate colonic inflammation to a certain degree ( 18 , 19 ). The present study demonstrated that macrophage-specific expression of α7nAChR was induced in inflamed colons of DSS-induced colitis in mice.…”

“…This work demonstrates that α7nAChR serves a crucial role in the regulation of macrophage activation and is suggestive of a potential role for macrophage α7nAChR in inflammatory diseases such as colitis. Indeed, some studies suggest that α7nAChR plays a negative role in the progression of colitis ( 18 , 19 ). However, treatment with pharmacological agonists of α7nAChR in colitis induced intolerable side effects in an experimental mouse model, and large doses of such agonists may have disruptive effects on colon integrity and induce anxiety-like behavior ( 20 , 21 ).…”

Effect of Electroacupuncture at Zusanli (ST36) on Sepsis Induced by Cecal Ligation Puncture and Its Relevance to Spleen

“…Immediately afterward, vessel disconnection around the spleen was performed with vessel clamp, No.0 operation silk thread, and scissors. Finally, we removed the spleen and sutured the abdominal musculature and skin [ 28 ].…”

“…Then, a stimulation at an intensity of 2 V (load voltage) and a frequency of 3 Hz was given for 15 minutes using the Electronic Acupuncture Treatment Instrument (96805- I Type, Xinsheng Industrial Limited Liability Company, Qingdao, China). For GTS21 (a specific agonist of α 7nAchR; ab120560, Abcam, England) administration, liquid medicine was injected to CLP rats intraperitoneally with a dose of 4 mg/kg/d for two days [ 28 ].…”

Targeting the Eph/Ephrin System as Anti-Inflammatory Strategy in IBD

“…The length of colon and its weight were measured to assess deposition of fibrotic material and muscular contraction elicited by colitis induction; weight/length ratio was calculated to assess colon thickness, according to previously published criteria (Grandi et al, 2017).…”