The proteasome inhibitor MG132 protects against acute pancreatitis

Tamás Letoha, Csaba Somlai, Tamás Takács, Annamária Szabolcs, Zoltán Rakonczay, Katalin Jármay, Tamás Szalontai, Ilona Varga, József Kaszaki, Imre Boros, Erno Duda, László Hackler, István Kurucz, Botond Penke

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

The cell-permeant MG132 tripeptide (Z-Leu-Leu-Leu-aldehyde) is a peptide aldehyde proteasome inhibitor that also inhibits other proteases, including calpains and cathepsins. By blocking the proteasome, this tripeptide has been shown to induce the expression of cell-protective heat shock proteins (HSPs) in vitro. Effects of MG132 were studied in an in vivo model of acute pancreatitis. Pancreatitis was induced in male Wistar rats by injecting 2 × 100 μg/kg cholecystokinin octapeptide intraperitoneally (ip) at an interval of 1 h. Pretreating the animals with 10 mg/kg MG132 ip before the induction of pancreatitis significantly inhibited IκB degradation and subsequent activation of nuclear factor-κB (NF-κB). MG132 also increased HSP72 expression. Induction of HSP72 and inhibition of NF-κB improved parameters of acute pancreatitis. Thus MG132 significantly decreased serum amylase, pancreatic weight/body weight ratio, pancreatic myeloperoxidase activity, proinflammatory cytokine concentrations, and the expression of pancreatitis-associated protein. Parameters of oxidative stress (GSH, MDA, SOD, etc.) were improved in both the serum and the pancreas. Histopathological examinations revealed that pancreatic specimens of animals pretreated with the peptide demonstrated milder edema, cellular damage, and inflammatory activity. Our findings show that simultaneous inhibition of calpains, cathepsins, and the proteasome with MG132 prevents the onset of acute pancreatitis.

Original languageEnglish
Pages (from-to)1142-1151
Number of pages10
JournalFree Radical Biology and Medicine
Volume39
Issue number9
DOIs
Publication statusPublished - Nov 1 2005

    Fingerprint

Keywords

  • Acute pancreatitis
  • Calpains
  • Cathepsins
  • Free radicals
  • Heat shock proteins
  • NF-κB
  • Proteasome inhibition

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this