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. 2010 Nov;161(5):1002-11.
doi: 10.1111/j.1476-5381.2010.00933.x.

Flavocoxid, a dual inhibitor of cyclooxygenase-2 and 5-lipoxygenase, reduces pancreatic damage in an experimental model of acute pancreatitis

F Polito  1 , A Bitto, N Irrera, F Squadrito, C Fazzari, L Minutoli, D Altavilla
Affiliations

Flavocoxid, a dual inhibitor of cyclooxygenase-2 and 5-lipoxygenase, reduces pancreatic damage in an experimental model of acute pancreatitis

F Polito et al. Br J Pharmacol. 2010 Nov.

Abstract

Background and purpose: 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.

Experimental approach: 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.

Key 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 and implications: 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.

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Figures

Figure 1
Figure 1
(A) Western blot analysis of COX-2 in the pancreas obtained from the experimental groups, 2 h after the last caerulein injection (CER; 80 µg·kg−1 i.p. for each of four injections at hourly intervals) or with four i.p. injections 0.9% saline at hourly intervals (Sham-CER). Animals were treated with flavocoxid (CER + flavocoxid; 20 mg·kg−1 i.p., administered 30 min after the first injection of caerulein) or its vehicle (CER + vehicle; 1 mL·kg−1 of 0.9% NaCl solution). Bars represent the mean ± SD of seven animals. #P < 0.01 versus CER + vehicle. *P < 0.05 versus Sham-CER. (B) Western blot analysis of 5-LOX in the pancreas obtained from the experimental groups, 2 h after the last injection of caerulein (CER) or saline (Sham-CER). Animals were treated with flavocoxid (CER + flavocoxid) or its vehicle (CER + vehicle). Bars represent the mean ± SD of seven animals. #P < 0.01 versus CER + vehicle. *P < 0.05 versus Sham-CER. COX, cyclooxygenase.
Figure 2
Figure 2
(A) Prostaglandin E2 (PGE2) levels in serum samples obtained from the experimental groups, 2 h after the last injection of caerulein (CER; 80 µg·kg−1 i.p.) or saline (Sham-CER). Animals were treated with flavocoxid (CER + flavocoxid) or its vehicle (CER + vehicle). Bars represent the mean ± SD of seven animals. #P < 0.01 versus CER + vehicle. *P < 0.05 versus Sham-CER. (B) LTB4 levels in serum samples obtained from the experimental groups, 2 h after the last injection of caerulein (CER; 80 µg·kg−1 i.p.) or saline (Sham-CER). Animals were treated with flavocoxid (CER + flavocoxid) or its vehicle (CER + vehicle). Bars represent the mean ± SD of seven animals. #P < 0.01 versus CER + vehicle. *P < 0.05 versus Sham-CER. LTB4, leukotriene B4.
Figure 3
Figure 3
mRNA for TNF-α in pancreatic samples obtained from the experimental groups, 2 h after the last injection of caerulein (CER; 80 µg·kg−1 i.p.) or saline (Sham-CER). Animals were treated with flavocoxid (CER + flavocoxid) or its vehicle (CER + vehicle). Bars represent the mean ± SD of seven animals. #P < 0.01 versus CER + vehicle. *P < 0.05 versus Sham-CER. TNF-α, tumour necrosis factor-α.
Figure 4
Figure 4
(A) Serum amylase activity in rats injected with caerulein (CER; 80 µg·kg−1 i.p.) or with saline (Sham-CER). Animals were treated with flavocoxid (CER + flavocoxid) or its vehicle (CER + vehicle). Bars represent the mean ± SD of seven animals. #P < 0.01 versus CER + vehicle. *P < 0.05 versus Sham-CER. (B) Serum lipase activity in in rats injected with caerulein (CER; 80 µg·kg−1 i.p) or with saline (Sham-CER). Animals were treated with flavocoxid (CER + flavocoxid) or its vehicle (CER + vehicle). Bars represent the mean ± SD of seven animals. #P < 0.01 versus CER + vehicle. *P < 0.05 versus Sham-CER. (C) Degree of pancreatic oedema in rats injected with caerulein (CER; 80 µg·kg−1 i.p) or with saline (Sham-CER). Animals were treated with flavocoxid (CER + flavocoxid) or its vehicle (CER + vehicle). Bars represent the mean ± SD of seven animals. #P < 0.01 versus CER + vehicle. *P < 0.05 versus Sham-CER.
Figure 5
Figure 5
(A) Normal histology of a sample of pancreas obtained from a Sham-CER rat, i.e. saline only injections. Original magnification × 20. (B) Normal histology of a sample of pancreas obtained from a Sham + flavocoxid rat, i.e. flavocoxid after saline. Pancreas lobules and acini are intact, uniform size of acinar cells and peripheral localization of acinar nuclei. Original magnification × 20. (C) Representative sample of pancreas from a rat treated with CER. The pancreas shows a massive oedema, infiltration of inflammatory cells and cytoplasmatic vacuolization. Original magnification × 20. (D) Representative sample of pancreas from a rat treated with flavocoxid after CER. There was a significant reduction in oedema and inflammatory cell infiltrate. Original magnification × 20. CER, caerulein.
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