Selective cyclooxygenase inhibition improves hepatic encephalopathy in fulminant hepatic failure of rat.

Ching-Chih Chang, Sun-Sang Wang, Hui-Chun Huang, Cho-Yu Chan, Fa-Yauh Lee, Han-Chieh Lin, Jing-Yi Nong, Chiao-Lin Chuang, Shou-Dong Lee

Index: Eur. J. Pharmacol. 666(1-3) , 226-32, (2011)

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Abstract

Prostaglandin plays an important role in the pathogenesis of hepatic encephalopathy. This study investigated the therapeutic effects of selective cyclooxygenase (COX) inhibitor on hepatic encephalopathy in thioacetamide-induced fulminant hepatic failure (FHF) rats. The selective COX-1 inhibitor (SC-560), COX-2 inhibitor (NS-398) or distilled water (control) was administered in the normal and FHF rats. The mortality rates were calculated and severity of hepatic encephalopathy was evaluated using Opto-Varimex activity sensors. Besides, the levels of blood ammonia, 6-keto-prostaglandin-F(1α) (PGF(1α), active metabolite of prostacyclin), tumor necrosis factor α (TNF-α) and liver biochemistry tests were measured. The hepatic mRNA expressions of nitric oxide synthase and COX were determined, and the liver histopathological changes were examined. The liver biochemistries and motor activities were similar among COX-1, COX-2 treated and control groups. SC-560 treatment improved the survival of FHF rats (mortality rates: SC-560 group 0%, control 33%; P=0.037). Besides, SC-560 treatment improved hepatic encephalopathy and decrease plasma levels of PGF(1α), but did not change TNF-α levels. There were no significant differences in liver biochemistry and ammonia levels except that the aspartate aminotransferase levels were lower in the NS-398 treated group. Both hepatic COX-1 and COX-2 mRNA expressions were attenuated after SC-560 treatment. The decreased COX-2 and increased constitutive nitric oxide synthase mRNA expressions were found after NS-398 treatment. Besides, the histopathology of liver got improved after selective COX inhibition. In conclusion, COX-1 inhibition by SC-560 decreases the mortalities and improves motor activities, suggesting COX-1, rather than COX-2, plays a major role in hepatic encephalopathy of FHF rats.Copyright © 2011 Elsevier B.V. All rights reserved.