Table 4.
Antagonists of selective acetylcholine receptors (AChRs).
| Antagonists | Cholinergic effects | Effect on immune status | Experimental models |
|---|---|---|---|
| Selective to nicotinic receptors | |||
| Hexamethonium | Nicotinic receptor blocker | Hexamethonium blockade of peripheral nAChR increases neutrophil migration and mechanical hyperalgesia in the RA model (207). It suppresses stress-induced mast cell activation and inhibits elevated PGE2 levels after exposure to stress (208). | – |
| α-Bungarotoxin (α –BTX) | Bind to nAChRs in an irreversible antagonistic manner, blocking ACh’s activity at the post-synaptic membrane, inhibiting channel opening and ion flow, and cause paralysis (209). | α –BTX treatment to T cells activated by sub-optimal PHA concentrations causes blockade of α7-nAChR that enhance T cell proliferation (210). | – |
| Mecamylamine | To neutralize the effects of nicotine, it is used as a competitive non-selective (α3β4, α4β2, α3β2, and α7) nAChR antagonist | Mecamylamine reverses the ant-inflammatory role of nicotine in the nAChR-mediated cholinergic pathway. | Mecamylamine is licensed for the treatment of hypertension. It attenuates all of the nicotine and cigarettes symptoms, including seizures, rendering it an important pharmacotherapy for tobacco addiction (211). |
| Dihydro-beta-erythroidine | Selective α4β2-nAChR antagonist (161). | – | – |
| Dextromethorphan (DXM) | α3β4-nAChR, α4β2-nAChR, and α7-nAChR antagonist in the cholinergic pathway (212). Also, It is a selective antagonism of N-methyl-d-aspartate receptors and/or show interaction with opiate receptors (213). | DXM decreases the expression of CD40, CD80, CD86, MHC class I, and MHC class II in both murine BMDCs and human monocyte-driven DCs upon LPS challenge. DXM pre-treatment results in dose-dependent substantial reductions in TNF-α, IL-6, IL-12, and ROS production. It inhibits the ability of LPS-stimulated BMDCs to promote ovalbumin-specific T cell proliferation by downregulating MAPK and NF-κB pathways (214). DXM is neuroprotective in cerebral ischemia models, spinal cord injury, PD, and epilepsy by downregulating NADPH oxidase, thus, reducing superoxide free radicals and intracellular (ROS) (215, 216). It prevents immune cell filtration, inhibits NOX2 activity, and has an anti-inflammatory effect in EAE (217). Proinflammatory cytokines (TNF-α, IL-6, and IL-17A) expression levels decrease in CIA mice and RA patients. In collagen-reactive CD4+ T cells, DXM reduced the production of anti-CII IgG, IFN-γ, and IL-17A (218). | DXM is under development for the treatment of depression, AD, ALS, and neuropathic pain (219–220). |
| Methyllycaconatine (MLA) | α7-nAChR antagonist | MLA (2.4 mg/kg per day) treatment in acute viral myocarditis increases the frequency of Th1 and Th17 cells, lowers the frequency of Th2 and Treg cells in the spleen. It also increases proinflammatory cytokines, cellular infiltration, and severity of myocardium lesions in viral myocarditis (221). | – |
| N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI) | Selective α6β2-nAChR antagonist (222). Nicotine-evoked dopamine activation and nicotine reinforcement are mediated by α6β2-nAChRs expressed by dopaminergic neurons. bPiDI blocks nicotine’s effects on these receptors, making them therapeutic targets for nicotine addiction (223). | ||
| α-conotoxins | Specific to α3β2-nAChR, α9α10-nAChR, and α3β4-nAChR (224). | α-conotoxins (5.5 μM) increases IL-10 production in Tregs and decreased IL-17 production in T cells (225). In PMA-activated macrophages, α-conotoxins upregulate the TNF-α and IL-6 in a concentration-dependent manner (226). | – |
| SR16584 | High affinity for α3β4-nAChR and 10 nM for α4β2-nAChR (227, 228). | – | – |
| 18-methoxycoronaridine (18-MC) | Highly selective α3β4-nAChR antagonist (229). | – | – |
| AT-1001 | High-affinity and selective to α3β4-nAChR (230). | – | In humans with Th1-mediated celiac disease, it plays a therapeutic role by inhibiting cell permeability (231). |
| MG 624 | α7-nAChR antagonist (232). | – | – |
| Selective to muscarinic receptors | |||
| Atropine | A nonspecific antagonist that competitively inhibits acetylcholine (ACh) at postganglionic muscarinic sites and CNS (232). Abolish the effect of vagus nerve stimulation. | Prior to the LPS-induced activation of the inflammatory response, atropine decreases TNF-α and raises IL-10 plasma levels without affecting IL-6 production. This reduction in TNF-α improved the rate of survival from endotoxic shock in mice (233). Suppresses T cell proliferation and proinflammatory cytokine production in turpentine-induced inflammation. In reaction to the potent neutrophil/macrophage chemoattractant fMLP, atropine therapy decreases both chemokinesis and chemotaxis of PBMCs (234, 235). | – |
| Hyoscyamine | Non-competitively inhibits acetylcholine (ACh). | In the acute lung injury model in rats, hyoscyamine derivatives cause substantial reductions in TNF-α, IL-6, IL-1, and p38MAPK, NFB, and AP1 activation, as well as TLR4 expression (236). | – |
| Scopolamine hydrobromide | A non-selective muscarinic acetylcholine receptor (mAChR). | Scopolamine hydrobromide treatment shows upregulation of TLR3, TLR7, TLR8, and cytokines such as IL-4 and IL-10 (237). Mice treated with scopolamine show an increased density of CD4+, CD11c+, and CD11b+ cells. And also show elevated levels of IL-1β, IL-2, IL-6, IL-12Rβ1, IL-17A, IL-17R, IFN-γ, and TNF-α transcripts (238). | Used for treatment of motion sickness, and GI obstruction (239, 240) |
| Gallamine Triethiodide | Non-competitive inhibition by altering the affinity of the agonist for its binding site. | – | – |
| VU0255035 | Selective M1 mAChR antagonist | – | – |
| Pirenzepine | Selective M1 mAChR selective antagonist. | – | Used in peptic ulcers and also reduces muscle spasms (241, 242). |
| Methoctramine | Selective M2 mAChR antagonist | Methoctramine increases the high-frequency component of heart rate variability and inhibits systemic TNF−α release by activating muscarinic receptors (182). Methoctramine abolishes the ACh-elicited anti-apoptotic property and reduces the TNF-α-activated apoptotic pathway via EGFR-PI3K signaling in cardiomyocytes (243). |
– |
| AF-DX 384 | Selective M2 mAChR and M4 mAChR antagonist. | – | – |
| Darifenacin | Selective M3 mAChR antagonist | – | Effectively used for the treatment of overactive bladder disorder (244). |
| 4-diphenylacetoxy-N-(2-chloroethyl)-piperidine (4-DAMP mustard) | Selective M1/M3 mAChR antagonist. | 4-DAMP abolishes mAChR-mediated immunoglobulin class switching to IgG in B cells. It inhibits the production of IL-6 and the maturation of B cells into IgG-producing plasma cells (245). M3 mAChR-mediated IL-8 expression in regulating inflammatory response via PKC/NF-κB signaling axis is completely antagonized by 4-DAMP (246). It also inhibits human T cell growth by inhibiting M1 mAChR-mediated expression of both IL-2 and IL-2R (179). | – |
| Tropicamide | M4 mAChR antagonist responsible for increased phosphorylation of AMPA receptor. |
– | Inhibiting cholinergic stimulation responses, producing dilation of the pupil and relaxation of the ciliary muscle in ophthalmic surgery (247). |