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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 cytokines and MPO activity in colon of mice with DSS-induced colitis.PBS = phosphate buffered saline. DSS = dextran sodium sulphate. Data are mean ± SEM, Significantly different from mice treated with PBS and drinking DSS *p<0.05, **p<0.01.
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pone-0057668-g003: Effect of rivastigmine on cytokines and MPO activity in colon of mice with DSS-induced colitis.PBS = phosphate buffered saline. DSS = dextran sodium sulphate. Data are mean ± SEM, Significantly different from mice treated with PBS and drinking DSS *p<0.05, **p<0.01.

Mentions: DSS solution causes an abnormal response to luminal flora resulting in the release of a burst of pro-inflammatory cytokines. This was also seen in the current study in which levels of TNF-α, IL-6 and IL-1β protein increased 3-fold, 7-fold and 1.7-fold respectively on the 8th day of drinking DSS solution. Rivastigmine (0.5 mg/kg and 1 mg/kg) reduced by about 50% and 60% respectively, the concentration of IL-6 but not those of TNF-α and IL-1β (Figures 3 A–C). Co-treatment with scopolamine did not affect the reduction in IL-6 induced by rivastigmine (1 mg/kg). There was a 7-fold increase in MPO activity in the colon in mice with DSS-induced colitis on the 8th day of the experiment. Treatment with rivastigmine (0.5 and 1 mg/kg) reduced MPO by 40% and 70%, respectively (Figure 3D). The activity of MPO increased in proportion to the DAI score for all groups (Table 2 and Figure 3D).


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 cytokines and MPO activity in colon of mice with DSS-induced colitis.PBS = phosphate buffered saline. DSS = dextran sodium sulphate. Data are mean ± SEM, Significantly different from mice treated with PBS and drinking DSS *p<0.05, **p<0.01.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0057668-g003: Effect of rivastigmine on cytokines and MPO activity in colon of mice with DSS-induced colitis.PBS = phosphate buffered saline. DSS = dextran sodium sulphate. Data are mean ± SEM, Significantly different from mice treated with PBS and drinking DSS *p<0.05, **p<0.01.
Mentions: DSS solution causes an abnormal response to luminal flora resulting in the release of a burst of pro-inflammatory cytokines. This was also seen in the current study in which levels of TNF-α, IL-6 and IL-1β protein increased 3-fold, 7-fold and 1.7-fold respectively on the 8th day of drinking DSS solution. Rivastigmine (0.5 mg/kg and 1 mg/kg) reduced by about 50% and 60% respectively, the concentration of IL-6 but not those of TNF-α and IL-1β (Figures 3 A–C). Co-treatment with scopolamine did not affect the reduction in IL-6 induced by rivastigmine (1 mg/kg). There was a 7-fold increase in MPO activity in the colon in mice with DSS-induced colitis on the 8th day of the experiment. Treatment with rivastigmine (0.5 and 1 mg/kg) reduced MPO by 40% and 70%, respectively (Figure 3D). The activity of MPO increased in proportion to the DAI score for all groups (Table 2 and Figure 3D).

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