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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, MPO, TBARS and ChE activity in rats with DNBS-induced colitis.ChE = ChE activity. Data are mean ± SEM from 13 animals per group. Percent of reduction compared to values in group treated with distilled water and DNBS. Significantly different from the rats treated by rectal administration of rivastigmine (1 mg/kg) *p<0.05, ** p<0.01.
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pone-0057668-g008: Effect of rivastigmine on TNF-α, MPO, TBARS and ChE activity in rats with DNBS-induced colitis.ChE = ChE activity. Data are mean ± SEM from 13 animals per group. Percent of reduction compared to values in group treated with distilled water and DNBS. Significantly different from the rats treated by rectal administration of rivastigmine (1 mg/kg) *p<0.05, ** p<0.01.

Mentions: There were no significant differences in the activity of ChE in the colon of rats drinking water (41±10.3) or those given DNBS (32.9±6.0 µmoles acetylthiocholine hydrolysed/min/gm protein) or in plasma (5.92±0.42 and 5.88±0.48 µmoles acetylthiocholine hydrolysed/min/gm protein), respectively. MPO activity in the colon of rats treated with DNBS increased almost 10-fold to 54±10 from 5.7 U/mg protein in controls drinking water, while TBARS increased from 0.78±0.07 µM/mg protein in control rats to 2.01±0.26 µM/mg protein in rats treated with DNBS. TNF-α in the colon increased from 0.035±0.01 ng/mg protein in control rats to 0.168±0.02 ng/mg protein in those treated with DNBS. The effect of rivastigmine on ChE activity in the colon and plasma and on colonic TNF-α, MPO activity, and TBARS was calculated as per cent change of that in rats treated with DNBS and is shown in Figure 8. Rivastigmine (1 mg/kg) decreased MPO activity, TBARS and TNF-α in the colon by more than 60%, colonic and plasma ChE by 40–45%. Rivastigmine (2 mg/kg) caused a significantly greater reduction in MPO and ChE activity in colon and plasma than a dose of 1 mg/kg.


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, MPO, TBARS and ChE activity in rats with DNBS-induced colitis.ChE = ChE activity. Data are mean ± SEM from 13 animals per group. Percent of reduction compared to values in group treated with distilled water and DNBS. Significantly different from the rats treated by rectal administration of rivastigmine (1 mg/kg) *p<0.05, ** p<0.01.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0057668-g008: Effect of rivastigmine on TNF-α, MPO, TBARS and ChE activity in rats with DNBS-induced colitis.ChE = ChE activity. Data are mean ± SEM from 13 animals per group. Percent of reduction compared to values in group treated with distilled water and DNBS. Significantly different from the rats treated by rectal administration of rivastigmine (1 mg/kg) *p<0.05, ** p<0.01.
Mentions: There were no significant differences in the activity of ChE in the colon of rats drinking water (41±10.3) or those given DNBS (32.9±6.0 µmoles acetylthiocholine hydrolysed/min/gm protein) or in plasma (5.92±0.42 and 5.88±0.48 µmoles acetylthiocholine hydrolysed/min/gm protein), respectively. MPO activity in the colon of rats treated with DNBS increased almost 10-fold to 54±10 from 5.7 U/mg protein in controls drinking water, while TBARS increased from 0.78±0.07 µM/mg protein in control rats to 2.01±0.26 µM/mg protein in rats treated with DNBS. TNF-α in the colon increased from 0.035±0.01 ng/mg protein in control rats to 0.168±0.02 ng/mg protein in those treated with DNBS. The effect of rivastigmine on ChE activity in the colon and plasma and on colonic TNF-α, MPO activity, and TBARS was calculated as per cent change of that in rats treated with DNBS and is shown in Figure 8. Rivastigmine (1 mg/kg) decreased MPO activity, TBARS and TNF-α in the colon by more than 60%, colonic and plasma ChE by 40–45%. Rivastigmine (2 mg/kg) caused a significantly greater reduction in MPO and ChE activity in colon and plasma than a dose of 1 mg/kg.

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