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Rivastigmine alleviates experimentally induced colitis in mice and rats by acting at central and peripheral sites to modulate immune responses.

Shifrin H, Nadler-Milbauer M, Shoham S, Weinstock M - PLoS ONE (2013)

Bottom Line: These effects were accompanied by significantly greater ChE inhibition in cortex, brain stem, plasma and colon than that after 0.5 mg/kg.Co-administration of rivastigmine (1 mg/kg) with the muscarinic antagonist scopolamine significantly increased the number of CD11b expressing cells in the colon but did not change DAI compared to those treated with rivastigmine alone.The study revealed that the ChE inhibitor rivastigmine is able to reduce gastro-intestinal inflammation by actions at various sites at which it preserves ACh.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Institute of Drug Research, Hebrew University Medical Center, Jerusalem, Israel.

ABSTRACT
The cholinergic anti-inflammatory system and α7 nicotinic receptors in macrophages have been proposed to play a role in neuroimmunomodulation and in the etiology of ulcerative colitis. We investigated the ability of a cholinesterase (ChE) inhibitor rivastigmine, to improve the pathology of ulcerative colitis by increasing the concentration of extracellular acetylcholine in the brain and periphery. In combination with carbachol (10 µM), rivastigmine (1 µM) significantly decreased the release of nitric oxide, TNF-α, IL-1β and IL-6 from lipopolysaccharide-activated RAW 264.7 macrophages and this effect was abolished by α7 nicotinic receptor blockade by bungarotoxin. Rivastigmine (1 mg/kg) but not (0.5 mg/kg), injected subcutaneously once daily in BALB/c mice with colitis induced by 4% dextran sodium sulphate (DSS), reduced the disease activity index (DAI) by 60% and damage to colon structure. Rivastigmine (1 mg/kg) also reduced myeloperoxidase activity and IL-6 by >60%, and the infiltration of CD11b expressing cells by 80%. These effects were accompanied by significantly greater ChE inhibition in cortex, brain stem, plasma and colon than that after 0.5 mg/kg. Co-administration of rivastigmine (1 mg/kg) with the muscarinic antagonist scopolamine significantly increased the number of CD11b expressing cells in the colon but did not change DAI compared to those treated with rivastigmine alone. Rivastigmine 1 and 2 mg given rectally to rats with colitis induced by rectal administration of 30 mg dintrobezene sulfonic acid (DNBS) also caused a dose related reduction in ChE activity in blood and colon, the number of ulcers and area of ulceration, levels of TNF-α and in MPO activity. The study revealed that the ChE inhibitor rivastigmine is able to reduce gastro-intestinal inflammation by actions at various sites at which it preserves ACh. These include ACh released from vagal nerve endings that activates alpha7 nicotinic receptors on circulating macrophages and in brainstem neurons.

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Effect of rivastigmine with and without scopolamine on CD11b+ cell infiltration in DSS-induced colitis.A: Immunofluorescence stained mouse tissue sections showing CD11b (red) cells. White arrows show cells which express with CD11b+ in colitis tissue (pink). B: Quantification of the pink CD11b+ expressing cells (ImageJ) in the samples of mice colon sections. Data represent the mean ± SEM from three slides per animal, 6 animals per group; scale bar 20 µm. Significantly different from mice with DSS-induced colitis treated with PBS, **p<0.01; significantly different from mice treated with rivastigmine (0.5 mg/kg), # p<0.05; significantly different from mice treated with rivastigmine (1 mg/kg), §p<0.05.
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pone-0057668-g006: Effect of rivastigmine with and without scopolamine on CD11b+ cell infiltration in DSS-induced colitis.A: Immunofluorescence stained mouse tissue sections showing CD11b (red) cells. White arrows show cells which express with CD11b+ in colitis tissue (pink). B: Quantification of the pink CD11b+ expressing cells (ImageJ) in the samples of mice colon sections. Data represent the mean ± SEM from three slides per animal, 6 animals per group; scale bar 20 µm. Significantly different from mice with DSS-induced colitis treated with PBS, **p<0.01; significantly different from mice treated with rivastigmine (0.5 mg/kg), # p<0.05; significantly different from mice treated with rivastigmine (1 mg/kg), §p<0.05.

Mentions: In mice treated with PBS and 4% DSS there was a significant infiltration of CD11b expressing cells (Figure 6A). Treatment with rivastigmine (1 mg/kg) but not (0.5 mg/kg) reduced the number of CD11b expressing cells by more than 80% (Figure 6B). Scopolamine given together with rivastigmine (1 mg/kg) significantly increased the number of CD11b expressing cells in the colon compared to those given rivastigmine alone (p<0.05).


Rivastigmine alleviates experimentally induced colitis in mice and rats by acting at central and peripheral sites to modulate immune responses.

Shifrin H, Nadler-Milbauer M, Shoham S, Weinstock M - PLoS ONE (2013)

Effect of rivastigmine with and without scopolamine on CD11b+ cell infiltration in DSS-induced colitis.A: Immunofluorescence stained mouse tissue sections showing CD11b (red) cells. White arrows show cells which express with CD11b+ in colitis tissue (pink). B: Quantification of the pink CD11b+ expressing cells (ImageJ) in the samples of mice colon sections. Data represent the mean ± SEM from three slides per animal, 6 animals per group; scale bar 20 µm. Significantly different from mice with DSS-induced colitis treated with PBS, **p<0.01; significantly different from mice treated with rivastigmine (0.5 mg/kg), # p<0.05; significantly different from mice treated with rivastigmine (1 mg/kg), §p<0.05.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585220&req=5

pone-0057668-g006: Effect of rivastigmine with and without scopolamine on CD11b+ cell infiltration in DSS-induced colitis.A: Immunofluorescence stained mouse tissue sections showing CD11b (red) cells. White arrows show cells which express with CD11b+ in colitis tissue (pink). B: Quantification of the pink CD11b+ expressing cells (ImageJ) in the samples of mice colon sections. Data represent the mean ± SEM from three slides per animal, 6 animals per group; scale bar 20 µm. Significantly different from mice with DSS-induced colitis treated with PBS, **p<0.01; significantly different from mice treated with rivastigmine (0.5 mg/kg), # p<0.05; significantly different from mice treated with rivastigmine (1 mg/kg), §p<0.05.
Mentions: In mice treated with PBS and 4% DSS there was a significant infiltration of CD11b expressing cells (Figure 6A). Treatment with rivastigmine (1 mg/kg) but not (0.5 mg/kg) reduced the number of CD11b expressing cells by more than 80% (Figure 6B). Scopolamine given together with rivastigmine (1 mg/kg) significantly increased the number of CD11b expressing cells in the colon compared to those given rivastigmine alone (p<0.05).

Bottom Line: These effects were accompanied by significantly greater ChE inhibition in cortex, brain stem, plasma and colon than that after 0.5 mg/kg.Co-administration of rivastigmine (1 mg/kg) with the muscarinic antagonist scopolamine significantly increased the number of CD11b expressing cells in the colon but did not change DAI compared to those treated with rivastigmine alone.The study revealed that the ChE inhibitor rivastigmine is able to reduce gastro-intestinal inflammation by actions at various sites at which it preserves ACh.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Institute of Drug Research, Hebrew University Medical Center, Jerusalem, Israel.

ABSTRACT
The cholinergic anti-inflammatory system and α7 nicotinic receptors in macrophages have been proposed to play a role in neuroimmunomodulation and in the etiology of ulcerative colitis. We investigated the ability of a cholinesterase (ChE) inhibitor rivastigmine, to improve the pathology of ulcerative colitis by increasing the concentration of extracellular acetylcholine in the brain and periphery. In combination with carbachol (10 µM), rivastigmine (1 µM) significantly decreased the release of nitric oxide, TNF-α, IL-1β and IL-6 from lipopolysaccharide-activated RAW 264.7 macrophages and this effect was abolished by α7 nicotinic receptor blockade by bungarotoxin. Rivastigmine (1 mg/kg) but not (0.5 mg/kg), injected subcutaneously once daily in BALB/c mice with colitis induced by 4% dextran sodium sulphate (DSS), reduced the disease activity index (DAI) by 60% and damage to colon structure. Rivastigmine (1 mg/kg) also reduced myeloperoxidase activity and IL-6 by >60%, and the infiltration of CD11b expressing cells by 80%. These effects were accompanied by significantly greater ChE inhibition in cortex, brain stem, plasma and colon than that after 0.5 mg/kg. Co-administration of rivastigmine (1 mg/kg) with the muscarinic antagonist scopolamine significantly increased the number of CD11b expressing cells in the colon but did not change DAI compared to those treated with rivastigmine alone. Rivastigmine 1 and 2 mg given rectally to rats with colitis induced by rectal administration of 30 mg dintrobezene sulfonic acid (DNBS) also caused a dose related reduction in ChE activity in blood and colon, the number of ulcers and area of ulceration, levels of TNF-α and in MPO activity. The study revealed that the ChE inhibitor rivastigmine is able to reduce gastro-intestinal inflammation by actions at various sites at which it preserves ACh. These include ACh released from vagal nerve endings that activates alpha7 nicotinic receptors on circulating macrophages and in brainstem neurons.

Show MeSH
Related in: MedlinePlus