Peripheral site acetylcholinesterase inhibitors targeting both inflammation and cholinergic dysfunction

Department of Chemistry, Lehigh University, Bethlehem, PA 18015, USA.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 03/2010; 20(9):2987-90. DOI: 10.1016/j.bmcl.2010.02.102
Source: PubMed


The design and study of two classes of noncompetitive acetylcholinesterase inhibitors (AChEIs) which also function as NSAID prodrugs are reported. The most potent AChEIs disclosed contain an aromatic alkyl-aryl linker between an NSAID and a lipophilic choline mimic and they inhibit acetylcholinesterase (AChE) in the submicromolar range. These agents have the therapeutic potential to dually target inflammation by releasing an NSAID in vivo and activating the cholinergic anti-inflammatory pathway via cholinergic up-regulation.

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Available from: Christophe D Guillon, Oct 06, 2015
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    • "The result of this study demonstrates that the raise of IL-1beta in the hippocampus and cortex was significantly reduced by intraperitoneal administration of physostigmine and neostigmine, before surgery following LPS-treatment. It has been shown earlier that the administration of CNS-active acetylcholinesterase inhibitors depletes systemic pro-inflammatory cytokines and ameliorates both central and peripheral inflammation [50], [51]. "
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    ABSTRACT: Exogenous stress like tissue damage and pathogen invasion during surgical trauma could lead to a peripheral inflammatory response and induce neuroinflammation, which can result in postoperative cognitive dysfunction (POCD). The cholinergic anti-inflammatory pathway is a neurohumoral mechanism that plays a prominent role by suppressing the inflammatory response. Treatments with acetylcholinesterase inhibitors enhance cholinergic transmission and may therefore act as a potential approach to prevent neuroinflammation. In the presence or absence of acetylcholinesterase inhibitors, adult Wistar rats underwent surgery alone or were additionally treated with lipopolysaccharide (LPS). Physostigmine, which can overcome the blood-brain barrier or neostigmine acting only peripheral, served as acetylcholinesterase inhibitors. The expression of pro- and anti-inflammatory cytokines in the cortex, hippocampus, spleen and plasma was measured after 1 h, 24 h, 3 d and 7 d using Real-Time PCR, western blot analysis or cytometric bead array (CBA). Fluoro-Jade B staining of brain slices was employed to elucidate neurodegeneration. The activity of acetylcholinesterase was estimated using a spectrofluorometric method. Surgery accompanied by LPS-treatment led to increased IL-1beta gene and protein upregulation in the cortex and hippocampus but was significantly reduced by physostigmine and neostigmine. Furthermore, surgery in combination with LPS-treatment caused increased protein expression of IL-1, TNF-alpha and IL-10 in the spleen and plasma. Physostigmine and neostigmine significantly decreased the protein expression of IL-1 and TNF-alpha. Neuronal degeneration and the activity of acetylcholinesterase were elevated after surgery with LPS-treatment and reduced by physostigmine and neostigmine. Along with LPS-treatment, acetylcholinesterase inhibitors reduce the pro-inflammatory response as well as neurodegeneration after surgery in the cortex and hippocampus. This combination may represent a tool to break the pathogenesis of POCD.
    PLoS ONE 11/2013; 8(5):e62679. DOI:10.1371/journal.pone.0062679 · 3.23 Impact Factor
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    • "Activities of class 1 and 2 compounds against AChE have been presented previously and will be discussed only briefly (Young et al., 2010). The IC 50 values of compounds 1–8 range from 0.51 to 2.29 μM, with 7 showing the highest degree of inhibition. "
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    ABSTRACT: As part of a continuous effort to develop efficient counter measures against sulfur mustard injuries, several unique NSAID prodrugs have been developed and screened for anti-inflammatory properties. Presented herein are three classes of prodrugs which dually target inflammation and cholinergic dysfunction. Compounds 1-28 contain common NSAIDs linked either to choline bioisosteres or to structural analogs of acetylcholinesterase (AChE) inhibitors. These agents have shown utility as anti-vesicants and anti-inflammatory agents when screened in a mouse ear vesicant model (MEVM) against both 2-chloroethyl ethyl sulfide (CEES), a blistering agent, and 12-O-tetradecanoylphorbol-13-acetate (TPA), a common topical irritant. Many of the prodrugs have activity against CEES, with 5, 18, 22 and 27 reducing inflammation by more than 75% compared with a control. Compounds 12, 13, 15 and 22 show comparable activity against TPA. Promising activity in the MEVM is related to half-lives of NSAID release in plasma, moderate to high lipophilicity, and some degree of inhibition of AChE, a potential contributor to sulfur mustard-mediated tissue damage.
    Journal of Applied Toxicology 02/2012; 32(2):135-41. DOI:10.1002/jat.1645 · 2.98 Impact Factor
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    • "Activities of class 1 and 2 compounds against AChE have been presented previously and will be discussed only briefly (Young et al., 2010). The IC 50 values of compounds 1–8 range from 0.51 to 2.29 μM, with 7 showing the highest degree of inhibition. "
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