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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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Histopathological characterization of colon segments mice with DSS-induced colitis.Magnification×10. A: Distal colon sections of control mouse showing well organized crypts with goblet cells (1) and lamina propria (2). B: Colon of PBS-injected mouse with DSS-induced colitis showing crypt loss (1), mucosal erosions, sub-mucosal edema and massive infiltration of inflammatory cells (2). C: Colon of mouse treated with rivastigmine (0.5 mg/kg) that partially repaired the crypt dysplasia (1) but had little effect on cellular infiltrate and edema of the sub-mucosal layer (2). D: Colon of mouse treated with rivastigmine (1 mg/kg) that partially restored crypt damage (1), reduced sub-mucosal edema (2) and prevented cellular inflammatory infiltrate. E: Co administration of scopolamine (1 mg/kg) and rivastigmine (1 mg/kg) increased sub-mucosal edema and cellular infiltrate compared to that in colon of mice given rivastigmine (1 mg/kg) alone.
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pone-0057668-g005: Histopathological characterization of colon segments mice with DSS-induced colitis.Magnification×10. A: Distal colon sections of control mouse showing well organized crypts with goblet cells (1) and lamina propria (2). B: Colon of PBS-injected mouse with DSS-induced colitis showing crypt loss (1), mucosal erosions, sub-mucosal edema and massive infiltration of inflammatory cells (2). C: Colon of mouse treated with rivastigmine (0.5 mg/kg) that partially repaired the crypt dysplasia (1) but had little effect on cellular infiltrate and edema of the sub-mucosal layer (2). D: Colon of mouse treated with rivastigmine (1 mg/kg) that partially restored crypt damage (1), reduced sub-mucosal edema (2) and prevented cellular inflammatory infiltrate. E: Co administration of scopolamine (1 mg/kg) and rivastigmine (1 mg/kg) increased sub-mucosal edema and cellular infiltrate compared to that in colon of mice given rivastigmine (1 mg/kg) alone.

Mentions: The colon of mice drinking DDW and injected with PBS revealed well organized crypts and an intact sub-mucosal layer and lamina propria (Figure 5A). Mice with DSS-induced colitis injected with PBS showed structural damage to the colon with erosions of the crypts and sub-mucosal edema. Inflammation involved all layers of the colon with massive infiltrates discernible in the lamina propria (Figure 5B). Treatment with rivastigmine (0.5 mg/kg) caused little change in these pathological manifestations (Figure 5C), but rivastigmine (1 mg/kg) caused a partial restoration of the structure of the crypts and a reduction in sub-mucosal edema and cell infiltration (Figure 5D). Co-administration of scopolamine (1 mg/kg) with rivastigmine (1 mg/kg) increased sub-mucosal edema and cellular infiltrates compared to those given rivastigmine alone (Figure 5E).


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)

Histopathological characterization of colon segments mice with DSS-induced colitis.Magnification×10. A: Distal colon sections of control mouse showing well organized crypts with goblet cells (1) and lamina propria (2). B: Colon of PBS-injected mouse with DSS-induced colitis showing crypt loss (1), mucosal erosions, sub-mucosal edema and massive infiltration of inflammatory cells (2). C: Colon of mouse treated with rivastigmine (0.5 mg/kg) that partially repaired the crypt dysplasia (1) but had little effect on cellular infiltrate and edema of the sub-mucosal layer (2). D: Colon of mouse treated with rivastigmine (1 mg/kg) that partially restored crypt damage (1), reduced sub-mucosal edema (2) and prevented cellular inflammatory infiltrate. E: Co administration of scopolamine (1 mg/kg) and rivastigmine (1 mg/kg) increased sub-mucosal edema and cellular infiltrate compared to that in colon of mice given rivastigmine (1 mg/kg) alone.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0057668-g005: Histopathological characterization of colon segments mice with DSS-induced colitis.Magnification×10. A: Distal colon sections of control mouse showing well organized crypts with goblet cells (1) and lamina propria (2). B: Colon of PBS-injected mouse with DSS-induced colitis showing crypt loss (1), mucosal erosions, sub-mucosal edema and massive infiltration of inflammatory cells (2). C: Colon of mouse treated with rivastigmine (0.5 mg/kg) that partially repaired the crypt dysplasia (1) but had little effect on cellular infiltrate and edema of the sub-mucosal layer (2). D: Colon of mouse treated with rivastigmine (1 mg/kg) that partially restored crypt damage (1), reduced sub-mucosal edema (2) and prevented cellular inflammatory infiltrate. E: Co administration of scopolamine (1 mg/kg) and rivastigmine (1 mg/kg) increased sub-mucosal edema and cellular infiltrate compared to that in colon of mice given rivastigmine (1 mg/kg) alone.
Mentions: The colon of mice drinking DDW and injected with PBS revealed well organized crypts and an intact sub-mucosal layer and lamina propria (Figure 5A). Mice with DSS-induced colitis injected with PBS showed structural damage to the colon with erosions of the crypts and sub-mucosal edema. Inflammation involved all layers of the colon with massive infiltrates discernible in the lamina propria (Figure 5B). Treatment with rivastigmine (0.5 mg/kg) caused little change in these pathological manifestations (Figure 5C), but rivastigmine (1 mg/kg) caused a partial restoration of the structure of the crypts and a reduction in sub-mucosal edema and cell infiltration (Figure 5D). Co-administration of scopolamine (1 mg/kg) with rivastigmine (1 mg/kg) increased sub-mucosal edema and cellular infiltrates compared to those given rivastigmine alone (Figure 5E).

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