title: Risperidone attenuates local and 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 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.
authors.affiliation: UMN Pharma Inc., Akita, Japan. i-yamaguchi@umnpharma.com
authors.forename: Isamu
authors.initials: I
authors.lastname: Yamaguchi
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hamada
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoshida
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Isayama
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kanazashi
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
mesh_terms: D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002796:Choline Deficiency; D005001:Ethionine / Q000009:adverse effects; D005260:Female; D007249:Inflammation / Q000503:physiopathology / Q000517:prevention & control; D015850:Interleukin-6 / Q000097:blood; D008049:Lipase / Q000097:blood; D051379:Mice; D008813:Mice, Inbred ICR; D010195:Pancreatitis / Q000175:diagnosis*; D019283:Pancreatitis, Acute Necrotizing / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy* / Q000401:mortality; D018967:Risperidone / Q000627:therapeutic use*; D016019:Survival Analysis
chemical_list: D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D008049:Lipase; D000681:Amylases; D018967:Risperidone; D005001:Ethionine