Table 2.
Modulators of the AChE enzyme.
| Molecules | Cholinergic effect | Effect on immune status | Applications |
|---|---|---|---|
| GAL (Galantamine) | Weak competitive and reversible ChEI also allosterically modulates nicotinic acetylcholine receptors. | Treg suppressive activity is enhanced post GAL incubation (77). GAL sensitizes microglial α7-nAChRs and induces Ca2+ influx signaling cascades that stimulate Aβ phagocytosis in the AD model (78) GAL resulted in reduced mucosal inflammation associated with decrease MHC II levels and proinflammatory cytokine secretion by splenic CD11c⁺ cells (79). | Improves cognitive function in AD and dementia (80). |
| Rivastigmine | Rivastigmine inhibits both AChE and BChE in CNS. It preferentially inhibits the G1 enzymatic form of AChE, predominantly found in AD patients. | Rivastigmine significantly decreases nitric oxide release, IL-1β, IL-6, and TNF-α from stimulated macrophages (81). In the EAE model, it reduces microglial activation, encephalitogenic T cells proliferation, and TNF-α and IFN-γ production (82). | Used in improving functional and clinical symptoms of AD and Parkinson’s (83, 84) |
| Hup A | A highly selective, centrally-acting AChE inhibitor also antagonizes NMDA receptors. | HupA administration showed a reduction of proinflammatory cytokines TNF-α and IL-1β in sepsis-associated encephalopathy. Increased expressions of ChAT and CHRM1 attributed to reduced neuronal apoptosis and septic symptoms relief (85, 86). HupA reduces proinflammatory cytokines (IFN-γ and IL-17) and chemokines in the EAE while increases anti-inflammatory cytokines (IL-4 and IL-10 (4). | Hup A is administered for the treatment of AD and schizophrenia (86, 87) |
| Neostigmine | Blocks the active site of AChE and has limited ability to pass the blood-brain barrier. | Neostigmine increases HLA-DR expression and stimulates TNF-α production in resting DCs. It significantly reduced TNF-α and IL-12p70 production and prevented up-regulation of HLA-DR expression triggered by LPS (26). | It is administered for neurophysiological modifications in MG. It is also used to treat acute colonic pseudo-obstruction, Ogilvie syndrome, and GI disorders (88, 89). |
| Pyridostigmine (PY) | A potent carbamate peripheral inhibitor of AChE increases the transmission of impulses from cholinergic neurons across the synaptic cleft. | PY enhances anti-inflammatory response in HIV-1-infected patients by reducing T cell proliferation and IFN-γ production and increases IL-4 and IL-10 expression (90). It has a pro-eosinophilic effect through downregulation of IL-5, IL-13, and eotaxin in DSS-induced colitis. It also attenuates DSS-induced microbiota dysbiosis and improves epithelial integrity (91). Cholinergic modulation with PY induces greater recruitment of M2 macrophages and circulatory Treg cells soon after myocardial infarction in rats (92). | PY is used for the management of MG (93). Oral PY to be helpful in different GI dysmotility (94). |
| Physostigmine | Interfere with acetylcholine signaling such as atropine, scopolamine. | Physostigmine significantly decreases the expression of IL-1β, TNF-α, and IL-10 in the spleen and plasma in mice models, along with reduced neurodegeneration in the hippocampus (95). | ChEI was first investigated for the treatment of AD however discontinued for multiple adverse effects (96). |
| Ambenonium chloride | AChE inhibitor and down-regulates α6β2 -nAChR mediated dopamine release. | Reduce the aggregation of the β-amyloid peptide (Aβ) and a prion-peptide in AD (97) | |
| Acotiamide hydrochloride | A selective, reversible AChE inhibitor improved clonidine-induced hypomotility. | Used for treatment of functional dyspepsia (98). | |
| Corydaline | Inhibits AChE in a dose-dependent manner. | Inhibits pro-inflammatory cytokines expression (TNF-α, IL-6) in LPS-challenged macrophages. | |
| Donepezil | Centrally acting reversible AChEI and also upregulates nAChR in neurons (99, 100). | It shows anti-inflammatory effects and prevents BBB degradation by modulating MMP-2/9, NGF/proNGF, IFN-γ/IL-4, and p-Akt in EAE (101). Pre-treatment with donepezil suppressed TNF-α−induced sustained intracellular Ca2+ elevation via the PI3K pathway in rodent microglial cells. It also suppresses NO production and increases the phagocytic activity of mouse primary microglial cells (102). In macrophages, donepezil reduces inflammatory cytokines (IL-1β, IL-2, IL-6, IL-18, and TNF-α) and attenuates LPS-induced nuclear translocation of NF-κB (103). It inhibits RANK-induced bone degradation by inhibiting osteoclast differentiation (104). | It is mainly used to treat AD, PD, Schizophrenia, and depression (105–106). |
| Choline alfoscerate (α-GPC) | Parasympathomimetic acetylcholine precursor, acting as acetylcholine release promoter (107). | – | – |
| Cisapride | Stimulate serotonin receptors mediated increases of acetylcholine release in the enteric nervous system (108). | – | – |
| Curcumin | Stimulates vagus nerve and enhance ACh biosynthesis by upregulating enhanced ChAT activity and expression of VAChT in murine RA model. (109) Upregulates gene expression of M1 and M3 mAChR, choline acetyltransferase, and GLUT3 in the cerebral cortex of diabetic rats (110). |
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