Effects of H3 inverse agonists and acetylcholinesterase inhibitors on the peristaltic reflex induced on the guinea-pig isolated perfused ileum

Vincent Simoen, Yves Lamberty, Michel Guyaux, Bernard Christophe

UCB Pharma, Braine l’Alleud, Belgium

Histamine H3 receptor inverse agonists are known to enhance the release of histamine and various neuromediators including acetylcholine, suggesting a possible therapeutic interest in cognition-related disorders such as Alzheimer disease (Esbenshade et al., 2008 for review) and a viable alternative to current symptomatic treatments, which are mainly acetylcholinesterase inhibitors (Giacobini, 2004). This class of compounds has however limited efficacy and is associated with some adverse effects, in particular on the gastrointestinal tract. Acetylcholinesterase inhibitors were shown to induce salivation, increase gastric, pancreatic and intestinal secretions, increase tone and motility of the gut resulting in abdominal cramps, vomiting, diarrhoea and defecation. The perfused guinea-pig ileum has been identified as a useful assay in order to study the intestinal motility and in particular the peristaltic reflex (Shiina et al., 2005). The present experiments were designed to compare effects of histamine H3 inverse agonists (ciproxifan, GSK189254 and JNJ5207852) and acetylcholinesterase inhibitors (donepezil, galanthamine, tacrine) on the peristaltic reflex of the guinea-pig perfused ileum.

A small part of the terminal ileum (3 cm) was removed from the male Dunkin Hartley guinea-pig (400 – 680 g, sacrificed by stunning and exsanguination under guidelines approved by the UCB Pharma ethical committee) and flushed of luminal contents. The ileum was secured horizontally into the Mayflower organ bath containing 25 ml of Krebs’ solution (37 °C, 95% O2-5% CO2). After a 60-min period of stabilisation under an intraluminal oral to aboral flow rate of 0.5 ml/min, the peristaltic reflex was induced by increasing the intraluminal pressure up to the threshold point. After equilibration of the peristaltic waves by adjustment of the pump flow rate and the ileum tension, a cumulative concentration-response curve to test compound (10-9 to maximum 10-5 M) was constructed. Compound potency was calculated as pD2 values according to the method described by Van Rossum et al. (1963). Results are presented as mean ± SD. Control tissues were treated with the solvent only.

H3 inverse agonists (ciproxifan, GSK189254 and JNJ5207852) did not have any effect on the induced peristalsis. Conversely, acetylcholinesterase inhibitors induced a concentration-dependent decrease of the threshold pressure producing the peristaltic reflex. Based on their potency (pD2 values, n=4), the compounds are ranked as follow: donepezil (7.20 ± 0.25) > tacrine (6.32 ± 0.24) ≥ galanthamine (6.12 ± 0.53). For each compound, this decrease was complete, the threshold pressure becoming equal to the basal line pressure. In the same time, these compounds induced an irregular increase of the peristaltic wave’s amplitude and an increase in the rate of contractions. This overall picture suggested a facilitator effect of the peristalsis associated to an increase of the propulsive effect intensity.

In conclusion, contrary to acetylcholinesterase inhibitors, H3 inverse agonists have no effect on the peristaltic reflex of the guinea pig isolated perfused ileum

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