Lipid peroxidation inhibition reduces NF-kappaB activation and attenuates cerulein-induced pancreatitis.
Increased lipid peroxidation, enhanced nuclear factor kappa-B (NF-kappaB) activation and augmented tumor necrosis factor-alpha (TNF-alpha) production have been implicated in cerulein-induced pancreatitis. We investigated whether lipid peroxidation inhibition might reduce NF-kappaB activation and the inflammatory response in cerulein-induced pancreatitis. Male Sprague-Dawley rats of 230-250g body weight received administration of cerulein (80 microg/kg s.c. for each of four injections at hourly intervals). A control group received four s.c. injections of 0.9% saline at hourly intervals. Animals were randomized to receive either raxofelast, an inhibitor of lipid peroxidation (20 mg/kg i.p. administered with the first cerulein injection) or its vehicle (1 ml/kg of a 10% DMSO/NaCl solution). All these rats were sacrificed 2 h after the last injection of either cerulein or its vehicle. Raxofelast administration (20 mg/kg i.p. with the first cerulein) significantly reduced malondialdehyde (MDA) levels, an index of lipid peroxidation (CER + DMSO = 3.075 +/- 0.54 micromol/g; CER + raxofelast = 0.693 +/- 0.18 micromol/g; p < 0.001), decreased myeloperoxidase (MPO) activity (CER + DMSO = 22.2 +/- 3.54 mU/g; CER + raxofelast = 9.07 +/- 2.05 mU/g, p < 0.01), increased glutathione levels (GSH) (CER + DMSO = 5.21 +/- 1.79 micromol/g; CER + raxofelast = 15.71 +/- 2.14 micronol/g; p < 0.001), and reduced acinar cell damage evaluated by means of histology and serum levels of both amylase (CER + DMSO = 4063 +/- 707.9 U/l; CER + raxofelast = 1198 +/- 214.4 U/l; p < 0.001), and lipase (CER + DMSO = 1654 +/- 330 U/l; CER + raxofelast = 386 +/- 118.2 U/l; p < 0.001), Furthermore, raxofelast reduced pancreatic NF-kappaB activation and the TNF-alpha mRNA levels and tissue content of mature protein in the pancreas. Indeed, lipid peroxidation inhibition might be considered a potential therapeutic approach to prevent the severe damage in acute pancreatitis.
Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina (Azienda Ospedaliera Universitario G. Martino), Tore Biologica 5th Floor, Via Consolare Valeria, Gazzi, 98100 Messina, Italy.
Domenica
D
Altavilla
Ciro
C
Famulari
Maria
M
Passaniti
Giuseppe M
GM
Campo
Antonio
A
Macrì
Paolo
P
Seminara
Herbert
H
Marini
Margherita
M
Calò
Letterio B
LB
Santamaria
Daniela
D
Bono
Francesco S
FS
Venuti
Chiara
C
Mioni
Sheila
S
Leone
Salvatore
S
Guarini
Francesco
F
Squadrito
D000681:Amylases / Q000097:blood; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002108:Ceruletide / Q000494:pharmacology*; D003593:Cytoplasm / Q000378:metabolism; D019281:Dimerization; D005978:Glutathione / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D008049:Lipase / Q000097:blood; D015227:Lipid Peroxidation; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism; D010195:Pancreatitis / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
D001572:Benzofurans; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D014810:Vitamin E; D002108:Ceruletide; D009195:Peroxidase; D008049:Lipase; D000681:Amylases; D005978:Glutathione; C071049:Raxofelast