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Effect of OKY-046 and ONO-3708 on liver injury in mice
1Department of Pharmacology, Gifu Pharmaceutical University, Japan.
Abstract:
The effects of OKY-046, a selective thromboxane A2 (TXA2) synthetase inhibitor, and ONO-3708, a novel TXA2 receptor antagonist, on liver disease were investigated in mice. The liver injury was induced by either an injection of antibasic liver protein (BLP) antibody into DBA/2 mice that had been previously immunized with rabbit IgG or by an injection of bacterial lipopolysaccharide (LPS) into Corynebacterium parvum (C. parvum) pretreated DDY mice. 1) In both injury models, clear elevation of glutamate transaminase (GOT and GPT) activity due to extensive liver parenchymal cell damage was observed; this was confirmed by significant histopathological changes in the liver. 2) Typical histopathological changes in the liver were submassive hepatocellular necrosis in the anti-BLP antibody-induced injury model and focal necrosis in the LPS-induced model. Inflammation and increased cell infiltration in portal connective tissue were observed in both cases. 3) Administration of OKY-046 (50 mg/kg) and ONO-3708 (0.5, 1.0 and 2.0 mg/kg) suppressed the elevation of serum GOT and GPT levels and histopathological changes in both experimental liver injury models. 4) Indomethacin inhibited the development of liver disease caused by anti-BLP antibody but not by bacterial LPS. Prostaglandin I2 inhibited the elevation of serum GOT and GPT levels and histopathological changes of the liver in the mice treated with anti-BLP antibody and showed the tendency to inhibit the development of liver injury caused by bacterial LPS.
Insights
This study investigated thromboxane A2 (TXA2) inhibitors and antagonists in mouse liver injury models. Both OKY-046 and ONO-3708 demonstrated protective effects, reducing liver damage and inflammation.
Area of Science:
- Pharmacology
- Hepatology
- Immunology
Background:
- Thromboxane A2 (TXA2) plays a role in liver injury.
- Understanding TXA2's role can lead to new therapeutic strategies for liver disease.
Purpose of the Study:
- To investigate the effects of a TXA2 synthetase inhibitor (OKY-046) and a TXA2 receptor antagonist (ONO-3708) on experimental liver injury in mice.
- To compare the efficacy of these agents in different liver injury models.
Main Methods:
- Liver injury was induced using anti-basic liver protein (BLP) antibody or bacterial lipopolysaccharide (LPS) in mice.
- Mice were treated with OKY-046 or ONO-3708.
- Liver damage was assessed by measuring serum glutamate transaminase (GOT and GPT) levels and examining liver histopathology.
Main Results:
- Both OKY-046 and ONO-3708 significantly suppressed the elevation of serum GOT and GPT levels in both liver injury models.
- Histopathological examination confirmed reduced liver parenchymal cell damage, submassive hepatocellular necrosis, focal necrosis, and inflammation in treated mice.
- Indomethacin and Prostaglandin I2 showed varying degrees of protective effects depending on the injury model.
Conclusions:
- Selective TXA2 synthetase inhibition (OKY-046) and TXA2 receptor antagonism (ONO-3708) are effective in ameliorating experimental liver injury.
- Targeting the TXA2 pathway offers a potential therapeutic approach for liver diseases.