L'infiammazione intestinale nell'animale sperimentale come modello per lo sviluppo di nuovi farmaci: ruolo della via tachichininergica nelle malattie infiammatorie intestinali
Creators: name: Ursino, Maria Grazia <1979>
Publisher: name: Alma Mater Studiorum - Università di Bologna
Year: 2008
Subjects: BIO/14 Farmacologia

description: Background: Several lines of evidence showed that inflammation is associated with changes
in the expression of tachykinins both in human and animal models. Tachykinins, including
substance P (SP), are small peptides expressed in the extrinsic primary afferent nerve fibres
and enteric neurons of the gut: they exert their action through three distinct receptors, termed
NK1, NK2 and NK3. SP modulates intestinal motility and enteric secretion, acting
preferentially through the NK1 receptor. SP neural network and NK1 receptor expression are
increased in patients with inflammatory bowel disease, and similar changes were observed in
experimental models of inflammation. The 2,4 Dinitrobenzene Sulphonic Acid (DNBS) model
of colitis is useful to study innate immunity, non-specific inflammation and wound healing; it
has been suggested that the transmural inflammation seen in this model resembles that found
in Crohns disease and can therefore be used to study what cells and mediators are involved in
this type of inflammation.
Aim: To test the possible protective effect of the NK1 receptor antagonist SSR140333 on:
1) acute model of intestinal inflammation; 2) reactivation of DNBS-induced colitis in rats.
Methods: Acute colitis was induced in male SD rats by intrarectal administration of DNBS
(15 mg/rat in 50% ethanol). Reactivation of colitis was induced by intrarectal injections of
DNBS on day 28 (7.5 mg/rat in 35% ethanol). Animals were sacrificed on day 6 (acute colitis)
and 29 (reactivation of colitis). SSR140333 (10 mg/kg) was administered orally starting from
the day before the induction of colitis for 7 days (acute colitis) or seven days before the
reactivation of colitis. Colonic damage was assessed by means of macroscopic and
microscopic scores, myeloperoxidase activity (MPO) and TNF-α tissue levels. Enzyme
immunoassay was used to measure colonic substance P levels. Statistical analysis was
performed using analysis of variance (one-way or two-way, as appropriate) with the
Bonferronis correction for multiple comparisons.
Results: DNBS administration impaired body weight gain and markedly increased all
inflammatory parameters (p&lt;0.01). Treatment with SSR140333 10 mg/kg significantly
counteracted the impairment in body weight gain, decreased macroscopic and histological
scores and reduced colonic myeloperoxidase activity (p&lt;0.01). Drug treatment counteracted
TNF-α tissue levels and colonic SP concentrations (acute model). Similar results were
obtained administering the NK1 receptor antagonist SSR140333 (3 and 10 mg/kg) for 5 days,
starting the day after the induction of colitis. Intrarectal administration of DNBS four weeks
after the first DNBS administration resulted in reactivation of colitis, with increases in
macroscopic and histological damage scores and increase in MPO activity. Preventive
treatment with SSR140333 10 mg/kg decreased macroscopic damage score, significantly
reduced microscopic damage score but did not affect MPO activity.
Conclusions: Treatment with SSR140333 significantly reduced intestinal damage in acute
model of intestinal inflammation in rats. The NK1 receptor antagonist SSR140333 was also
able to prevent relapse in experimental colitis. These results support the hypothesis of SP
involvement in intestinal inflammation and indicate that NK receptor antagonists may have a
therapeutic potential in inflammatory bowel disease.