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Inhibition of inflammation using alpha 7 receptor-binding cholinergic agonists

A cholinergic and agonist technology, applied in the field of cholinergic agonists to reduce inflammation, can solve problems such as minor side effects

Inactive Publication Date: 2012-09-12
THE FEINSTEIN INST FOR MEDICAL RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This agonist may have fewer side effects than currently identified relatively non-specific agonists

Method used

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  • Inhibition of inflammation using alpha 7 receptor-binding cholinergic agonists
  • Inhibition of inflammation using alpha 7 receptor-binding cholinergic agonists
  • Inhibition of inflammation using alpha 7 receptor-binding cholinergic agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0348] Example 1. The α7 nicotinic receptor as a molecular substrate at the neuroimmune synapse

[0349] Example overview

[0350] Here we show that inhibition of TNF release from macrophages by acetylcholine requires the α7 subunit of the nicotinic receptor. α-Bungarotoxin binds to a discrete cluster of receptors expressed on the surface of primary human macrophages. Immunoblotization with an α7-specific antibody demonstrated the identity of the α7 subunit in proteins isolated by adhesion of α-bungarotoxin-bound beads. Exposure of macrophages to α7 antisense oligonucleotides reduced α-bungarotoxin binding and restored TNF release in the presence of nicotine. Mice lacking the α7 subunit of the nicotinic receptor produced significantly more TNF, IL-1β, and IL-6 during endotoxemia than wild-type mice. Macrophages isolated from α7 knockout mice do not respond to cholinergic agonists and continue to produce TNF. As a result, electrical stimulation of the vagus nerve in a man...

Embodiment 2

[0372] Example 2: Compounds (V) and (VI) are protective in sepsis in cecal ligation and perforation mouse model

[0373] Compounds of formula (V) and (VI) are particularly effective in the treatment of sepsis in cecal ligation and perforation murine models.

[0374]

[0375] 3-(2,4-Dimethoxybenzylidene)anabaseine (V)

[0376]

[0377] 3-(4-Hydroxy-2-methoxy-benzylidene)anabaseine (VI)

[0378] Such as Fink and Heard, J.of Surg.Res.49:186-196 (1990), Wichman et al., Crit.Care Med.26:2078-2086 (1998) and Remick et al., Shock 4:89- 95 (1995) performed cecal ligation and perforation (CLP). Briefly, anesthesia was administered intramuscularly with 75 mg / kg ketamine (Fort Dodge, Fort Dodge, Iowa) and 20 mg / kg xylazine (Bohringer Ingelheim, St. Joseph, MO). A midline incision was made and the cecum was isolated. A 6-0 polypropylene textile fiber suture ligation was performed 5.0 mm from the end of the cecum distal to the ileocecal valve.

[0379]Make a single puncture of...

Embodiment 3

[0382] Example 3: Compound (V) and Nicotine Inhibit LPS-Induced TNF-α Release in Rat RAW 264.7 Macrophage-Like Cells

[0383] Murine RAW 264.7 macrophage-like cells (American Type Tissue Culture Collection, Rockville, Md., USA) were cultured in DMEM supplemented with 10% fetal bovine serum, penicillin and streptomycin. Cells were seeded at 90% confluence in Opti-MEM 1 medium in 24-well tissue culture plates. Cells were treated with 0.001, 0.01, 0.1, 1, 10 or 100 [mu]M of compound (V) or nicotine (Sigma). Five minutes after compound (V) or nicotine addition, cells were treated with LPS (500 ng / ml). After 4 hours, the supernatant was collected and TNF-α was detected by ELISA (mouse ELISA kit from R & D Systems Inc., Minneapolis, MN).

[0384] The result is as Figure 7 As shown, it was proved that compound (V) inhibited the TNF-α release of RAW 264.7 cells in a dose-dependent manner like nicotine.

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Abstract

Methods of inhibiting release of a proinflammatory cytokine from a macrophage are provided. The methods comprise treating the macrophage with a cholinergic agonist that is selective for an alpha7 nicotinic receptor. Methods for inhibiting an inflammatory cytokine cascade are also provided. The methods comprise treating the patient with a cholinergic agonist. Methods for determining whether a compound is a cholinergic agonist reactive with an alpha7 nicotinic receptor are also provided. The methods comprise determining whether the compound inhibits release of a proinflammatory cytokine from a mammalian cell, or determining whether the compound reduces the ability of a cholinergic agonist to inhibit the release of a proinflammatory cytokine from a mammalian cell. Oligonucleotides or mimetics capable of inhibiting attenuation of lipopolysaccharide-induced TNF release from a mammalian macrophage upon exposure of the macrophage to a cholinergic agonist are also provided. The oligonucleotides or mimetics consist essentially of a sequence greater than 5 nucleotides long that is complementary to an mRNA of an alpha7 receptor. Additionally, methods of inhibiting attenuation of TNF release from a mammalian macrophage upon exposure of the macrophage to a cholinergic agonist are provided. These methods comprise treating the macrophage with the above-described oligonucleotide or mimetic.

Description

[0001] This application is a branch of an application whose application date is December 05, 2003, application number is 200380108261.5 (international application number is PCT / US2003 / 038708), and the title of the invention is "inhibiting inflammation with α7 receptor binding cholinergic agonists". case application. [0002] related application [0003] This application claims the benefit of US Provisional Application Serial No. 60 / 431,650, filed December 6,2002. The entirety of the aforementioned application is hereby incorporated by reference. [0004] Government funding [0005] This invention was made in whole or in part with support from the National Institutes of Health, Grant No. GM57226. The government has certain rights in this invention. Background of the invention [0006] The present invention relates to methods of reducing inflammation. In particular, the invention relates to methods of reducing inflammation using alpha7 receptor binding cholinergic agonists...

Claims

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Application Information

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IPC IPC(8): A61K31/46A61K31/444A61K31/439A61P29/00A61K31/00A61P1/00A61P9/00A61P11/00A61P15/00A61P31/00A61P33/00A61P37/00A61P43/00G01N33/68G01N33/94
CPCA61K31/00A61K31/439A61K31/444A61K31/46G01N33/6863G01N33/9406G01N2333/525G01N2333/54A61P1/00A61P1/02A61P1/04A61P1/16A61P1/18A61P11/00A61P11/02A61P11/04A61P11/06A61P13/02A61P15/00A61P15/06A61P17/00A61P17/02A61P19/00A61P19/02A61P19/06A61P19/08A61P21/04A61P25/00A61P25/02A61P25/28A61P27/02A61P29/00A61P29/02A61P3/00A61P31/00A61P31/04A61P31/10A61P31/14A61P31/16A61P31/18A61P31/22A61P33/00A61P33/04A61P33/06A61P35/00A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P5/14A61P7/00A61P9/00A61P9/04A61P9/10A61P3/10Y02A50/30
Inventor 凯文·J·翠西王红
Owner THE FEINSTEIN INST FOR MEDICAL RES
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