Received for publication June 18, 2008.
Revised September 29, 2008.
Accepted for publication September 30, 2008.

Risperidone attenuates local as well as systemic inflammatory responses to ameliorate diet-induced severe necrotic pancreatitis in mice: it may provide a new therapy for acute pancreatitis

Abstract

In a previous paper, we showed that a selective 5-HT2A antagonist, risperidone, ameliorated cerulein-induced edematous pancreatitis in mice. In the present paper, young female mice were fed a choline-deficient ethionine-supplemented diet. All the mice developed severe necrotic pancreatitis, and approximately 50% of them died within 4 days. Serum levels of proinflammatory IL-6 significantly increased on day 3, and returned towards the control on day 4 of CDE 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-HIAA increased on feeding a CDE diet to reach a peak on day 3, and returned towards 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. We thus speculate that acinar cell injury triggers local inflammatory reactions, and, if coincided with enhanced IL-6 release, leads to a systemic inflammatory response syndrome (SIRS) which is responsible for the mortality. In addition, it is suggested that diet-induced 5-HT release and 5-HT2A receptor activation are involved in the whole process of pancreatitis development. Risperidone may provide a new therapy for the disease.

Key words: 5-HT (serotonin, 5-hydroxytryptamine), 5-HT2A antagonist, IL-6 (interleukin-6), Local inflammation, Pancreatitis, SIRS (systemic inflammatory response syndrome)