Galantamine anti-colitic effect: Role of alpha-7 nicotinic acetylcholine receptor in modulating Jak/STAT3, NF-κB/HMGB1/RAGE and p-AKT/Bcl-2 pathways

Abstract

Vagal stimulation controls systemic inflammation and modulates the immune response in different inflammatory conditions, including inflammatory bowel diseases (IBD). The released acetylcholine binds to alpha-7 nicotinic acetylcholine receptor (α7 nAChR) to suppress pro-inflammatory cytokines. This provides a new range of potential therapeutic approaches for controlling inflammatory responses. The present study aimed to assess whether galantamine (Galan) anti-inflammatory action involves α7 nAChR in a 2,4,6-trinitrobenzene sulfonic acid (TNBS) model of colitis and to estimate its possible molecular pathways. Rats were assigned into normal, TNBS, sulfasalazine (Sulfz), Galan treated (10 mg/kg), methyllycaconitine (MLA; 5.6 mg/kg), and MLA + Galan groups. Drugs were administered orally once per day (11 days) and colitis was induced on the 8th day. Galan reduced the TNBS-induced ulceration, colon mass index, colonic MDA, neutrophils adhesion and infiltration (ICAM-1/MPO), inflammatory mediators (NF-κB, TNF-α, HMGB1, and RAGE), while increased the anti-apoptotic pathway (p-Akt/Bcl-2). Mechanistic study revealed that Galan increased the anti-inflammatory cytokine IL-10, phosphorylated Jak2, while reduced the inflammation controller SOCS3. However, combining MLA with Galan abrogated the beneficial anti-inflammatory/anti-apoptotic signals. The results of the present study indicate that Galan anti-inflammatory/-apoptotic/ -oxidant effects originate from the stimulation of the peripheral α7 nAChR, with the involvement of the Jak2/SOCS3 signaling pathway.

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

“…In addition, stimulation of α7nAChR induces STAT3 activation and subsequent protection of macrophages from endoplasmic reticulum stress-induced apoptosis, which affects the activity of the M2-type macrophage subset ( 15 ). Furthermore, Wazea et al ( 16 ) showed that the anti-atherogenic role of α7nAChR was due to attenuation of macrophage oxidative stress. In patients with CD, an inflammatory macrophage population present in the intestine produces large amounts of pro-inflammatory cytokines, including interleukin (IL)-23, tissue necrosis factor-α (TNF-α) and IL-6 ( 17 ).…”

Prophylactic Effect of Opuntia ficus indica Fruit Peel Extract against Irradiation-Induced Colon Injury in Rats

“…Indeed, NF-κB plays a major role in the regulation of the inflammatory process. Additionally, inhibition of NF-κB reduces TNF-α and ICAM-1 to delay leukocyte migration with the consequent activation of MPO [34]. The reduction in TNF-α levels by OFI extract may be explained partly by inhibition of the translocation of NF-κB [35].…”

Activation of α7 Nicotinic Acetylcholine Receptor Ameliorates Zymosan-Induced Acute Kidney Injury in BALB/c Mice

“…As previously reported, GAL, the α7 nAChR agonist, enhanced the cholinergic anti-inflammatory pathway (CAP) 3 that collaborates between the nervous and the innate immune systems 4 . Previous reports of several inflammatory disorders as diabetes 5 , rheumatoid arthritis 6 , and colitis 7 proved the anti-inflammatory properties of GAL that are mostly mediated via the activation of the α7 nAChR 2 , 5 , 6 . Of note, one of the main mechanistic pathways by which this receptor exerts its anti-inflammatory efficacy is through the janus kinase2/ signal transducer and activator of transcription3, as well as their feedback regulator suppressor of cytokine signaling 3 (JAK2/ STAT3/ SOCS3) signaling pathway.…”

“…Of note, one of the main mechanistic pathways by which this receptor exerts its anti-inflammatory efficacy is through the janus kinase2/ signal transducer and activator of transcription3, as well as their feedback regulator suppressor of cytokine signaling 3 (JAK2/ STAT3/ SOCS3) signaling pathway. Such pathway plays a role in regulating IL-6 and the transcriptional factor nuclear factor- kappa B (NF-κB) 7 . Moreover, NF-κB/ STAT3/ SOCS3 pathway inhibition by α7 nAChR showed a promising effect against experimental asthma 8 .…”

“…Moreover, it mediates cytokine release and tissue damage via acting as a ligand on toll like receptor (TLR) 19 . Activation of this protein is characterized by the translocation of the transcription factor NF-κB, which in turn increases its gene expression in a vicious inflammatory cycle 7 . Consequently, ZYM-induced kidney damage and HMGB-1 engenders the challenge for newly potential therapeutic targets to modulate such organs damage.…”