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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 on TNF-α and IL-6 released from peritoneal macrophages of DSS treated mice.Legend as in Figure 3. Data are mean ± SEM and represent pooled data from 6 animals per group. Significantly different from mice with DSS-induced colitis treated with PBS, ** p<0.01.
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pone-0057668-g007: Effect of rivastigmine on TNF-α and IL-6 released from peritoneal macrophages of DSS treated mice.Legend as in Figure 3. Data are mean ± SEM and represent pooled data from 6 animals per group. Significantly different from mice with DSS-induced colitis treated with PBS, ** p<0.01.

Mentions: Levels of TNF-α and IL-6 proteins were very low or undetectable in un-stimulated peritoneal macrophages extracted from PBS treated and rivastigmine-treated mice. However, when stimulated by LPS (10 µg/ml) for 6 h (TNF-α) and 20 h (IL-6) the release of these cytokines increased about 10-fold. In contrast to our findings in the colon, rivastigmine (0.5 or 1 mg/kg) caused a significant reduction in TNF-α but not of IL-6 in peritoneal macrophages compared to those injected with PBS (Figure 7).


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 on TNF-α and IL-6 released from peritoneal macrophages of DSS treated mice.Legend as in Figure 3. Data are mean ± SEM and represent pooled data from 6 animals per group. Significantly different from mice with DSS-induced colitis treated with PBS, ** p<0.01.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0057668-g007: Effect of rivastigmine on TNF-α and IL-6 released from peritoneal macrophages of DSS treated mice.Legend as in Figure 3. Data are mean ± SEM and represent pooled data from 6 animals per group. Significantly different from mice with DSS-induced colitis treated with PBS, ** p<0.01.
Mentions: Levels of TNF-α and IL-6 proteins were very low or undetectable in un-stimulated peritoneal macrophages extracted from PBS treated and rivastigmine-treated mice. However, when stimulated by LPS (10 µg/ml) for 6 h (TNF-α) and 20 h (IL-6) the release of these cytokines increased about 10-fold. In contrast to our findings in the colon, rivastigmine (0.5 or 1 mg/kg) caused a significant reduction in TNF-α but not of IL-6 in peritoneal macrophages compared to those injected with PBS (Figure 7).

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