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.