In a previous article, we showed that a potent
serotonin-, 5-hydroxytryptamine-2A (5-HT(2A)) antagonist,
risperidone, ameliorated
cerulein-induced edematous
pancreatitis in mice. In the present article, young female mice were fed a
choline-deficient,
ethionine-supplemented diet. All of the mice developed severe necrotic
pancreatitis, and approximately 50% of them died within 4 days. Serum levels of proinflammatory
interleukin (IL)-6 significantly increased on day 3 and returned toward the control on day 4 of
choline-deficient
ethionine-supplemented (CDE) diet treatment. The time course of
IL-6 levels paralleled those of plasma
amylase and
lipase activities. On the other hand, platelet counts significantly decreased on day 3, and the change became more marked on day 4, coinciding with mortality and histological alterations of the pancreas (
edema, inflammatory cell infiltration,
necrosis). Preceding these changes, plasma levels of 5-hydroxyindoleacetic
acid (5-HIAA) increased on feeding a CDE diet to reach a peak on day 3 and returned toward the control on day 4.
Risperidone (0.1-3.2 mg/kg twice a day) hardly affected the
5-HIAA levels but dose-dependently attenuated the serum
IL-6 levels, plasma
amylase/
lipase levels, platelet counts, histological alterations, and mortality of diet-induced
pancreatitis mice. These results are discussed in relation to the pathogenesis of
acute pancreatitis. Thus, we speculate that acinar cell injury triggers local inflammatory reactions and, if coincided with enhanced
IL-6 release, leads to a
systemic inflammatory response syndrome, which is responsible for the mortality. In addition, it is suggested that diet-induced
5-HT release and
5-HT(2A) receptor activation are involved in this whole process of
pancreatitis development.
Risperidone may provide a new
therapy for the disease.