Flavocoxid, a dual inhibitor of cyclooxygenase-2 and 5-lipoxygenase, reduces pancreatic damage in an experimental model of acute pancreatitis.
OBJECTIVE
Acute pancreatitis is an autodigestive process resulting in acute inflammation of the pancreas. Accumulating evidence indicates the essential contribution of cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LOX) to acute pancreatitis. We studied the effects of flavocoxid, a plant-derived dual inhibitor of COX-2 and 5-LOX, in a model of caerulein (CER)-induced acute pancreatitis.


METHODS
Rats were given CER (80 µg·kg⁻¹ for each of four injections at hourly intervals) or vehicle (Sham-CER). Animals were then randomized to receive flavocoxid (20 mg·kg⁻¹ i.p.) or vehicle, 30 min after the first CER injection. Two hours after the last CER injection, we evaluated damage to the pancreas by histological methods; serum levels of amylase, lipase, leukotriene (LT)B₄ and prostaglandin (PG)E₂ ; pancreatic expression of COX-2 and 5-LOX and tumour necrosis factor-α (TNF-α) gene expression by real-time polymerase chain reaction.


RESULTS
Caerulein induced inflammatory changes in the pancreas and raised values of the other variables measured. In CER-treated animals, but not in those given saline, flavocoxid inhibited COX-2 and 5-LOX expression, reduced serum levels of lipase and amylase and the degree of pancreatic oedema. Treatment with flavocoxid blunted the increased pancreatic TNF-α mRNA expression, serum leukotriene B₄ and prostaglandin E₂ levels, and protected against histological damage in terms of vacuolization and leukocyte infiltration.


CONCLUSIONS
Our results confirm the key role of both COX-2 and 5-LOX in the inflammatory response to acute pancreatitis. Flavocoxid may provide a potential therapeutic approach to the treatment of patients at high risk of developing this life-threatening condition.
Polito
F
F
Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Messina, Italy.
Bitto
A
A
Irrera
N
N
Squadrito
F
F
Fazzari
C
C
Minutoli
L
L
Altavilla
D
D
D000208:Acute Disease; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000187:drug effects / Q000378:metabolism; D002392:Catechin / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D004338:Drug Combinations; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D010195:Pancreatitis / Q000188:drug therapy* / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley
D052246:Cyclooxygenase 2 Inhibitors; D004338:Drug Combinations; D016859:Lipoxygenase Inhibitors; C544478:flavocoxid; D002392:Catechin; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2