Therapeutic proteasome inhibition in experimental acute pancreatitis.
OBJECTIVE
To establish the therapeutic potential of proteasome inhibition, we examined the therapeutic effects of MG132 (Z-Leu-Leu-Leu-aldehyde) in an experimental model of acute pancreatitis.


METHODS
Pancreatitis was induced in rats by two hourly intraperitoneal (ip) injections of cholecystokinin octapeptide (CCK; 2 x 100 microg/kg) and the proteasome inhibitor MG132 (10 mg/kg ip) was administered 30 min after the second CCK injection. Animals were sacrificed 4 h after the first injection of CCK.


RESULTS
Administering the proteasome inhibitor MG132 (at a dose of 10 mg/kg, ip) 90 min after the onset of pancreatic inflammation induced the expression of cell-protective 72 kDa heat shock protein (HSP72) and decreased DNA-binding of nuclear factor-kappaB (NF-kappaB). Furthermore MG132 treatment resulted in milder inflammatory response and cellular damage, as revealed by improved laboratory and histological parameters of pancreatitis and associated oxidative stress.


CONCLUSIONS
Our findings suggest that proteasome inhibition might be beneficial not only for the prevention, but also for the therapy of acute pancreatitis.
Letoha
Tamás
T
Department of Medical Chemistry, University of Szeged, Dom ter 8, H-6720, Szeged, Hungary. tletoha@yahoo.com
Fehér
Liliána Z
LZ
Pecze
László
L
Somlai
Csaba
C
Varga
Ilona
I
Kaszaki
József
J
Tóth
Gábor
G
Vizler
Csaba
C
Tiszlavicz
László
L
Takács
Tamás
T
D000208:Acute Disease; D000818:Animals; D001835:Body Weight; D002766:Cholecystokinin / Q000633:toxicity; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism; D007976:Leupeptins / Q000627:therapeutic use*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009929:Organ Size; D018384:Oxidative Stress; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D061988:Proteasome Inhibitors; D051381:Rats; D017208:Rats, Wistar
D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D050884:HSP72 Heat-Shock Proteins; D007976:Leupeptins; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D002766:Cholecystokinin; D009195:Peroxidase; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde