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Candesartan, rather than losartan, improves motor dysfunction in thioacetamide-induced chronic liver failure in rats
H A Murad1,2, Z J Gazzaz3, S S Ali4
1Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia.
Abstract:
Minimal hepatic encephalopathy is more common than the acute syndrome. Losartan, the first angiotensin-II receptor blocker (ARB), and candesartan, another widely-used ARB, have protected against developing fibrogenesis, but there is no clear data about their curative antifibrotic effects. The current study was designed to examine their effects in an already-established model of hepatic fibrosis and also their effects on the associated motor dysfunction. Low-grade chronic liver failure (CLF) was induced in 3-month old Sprague-Dawley male rats using thioacetamide (TAA, 50 mg·kg-1·day-1) intraperitoneally for 2 weeks. The TAA-CLF rats were randomly divided into five groups (n=8) treated orally for 14 days (mg·kg-1·day-1) as follows: TAA (distilled water), losartan (5 and 10 mg/kg), and candesartan (0.1 and 0.3 mg/kg). Rats were tested for rotarod and open-field tests. Serum and hepatic biochemical markers, and hepatic histopathological changes were evaluated by H&E and Masson's staining. The TAA-CLF rats showed significant increases of hepatic malondialdehyde, hepatic expression of tumor necrosis factor-α (TNF-α), and serum ammonia, alanine aminotransferase, γ-glutamyl transferase, TNF-α, and malondialdehyde levels as well as significant decreases of hepatic and serum glutathione levels. All treatments significantly reversed these changes. The histopathological changes were moderate in losartan-5 and candesartan-0.1 groups and mild in losartan-10 and candesartan-0.3 groups. Only candesartan significantly improved TAA-induced motor dysfunction. In conclusion, therapeutic antifibrotic effects of losartan and candesartan in thioacetamide-induced hepatic fibrosis in rats are possibly through angiotensin-II receptor blocking, antioxidant, and anti-inflammatory activities. Improved motor dysfunction by candesartan could be attributed to better brain penetration and slower "off-rate" from angiotensin-II receptors. Clinical trials are recommended.
Insights
Losartan and candesartan show therapeutic antifibrotic effects in thioacetamide-induced liver fibrosis in rats. Candesartan uniquely improved motor dysfunction, suggesting potential benefits for hepatic encephalopathy.
Area of Science:
- Pharmacology
- Hepatology
- Toxicology
Background:
- Minimal hepatic encephalopathy is common, and while angiotensin-II receptor blockers (ARBs) like losartan and candesartan may prevent liver fibrosis, their curative effects are unclear.
- Established hepatic fibrosis models are crucial for evaluating antifibrotic therapies and their impact on associated motor dysfunction.
Purpose of the Study:
- To investigate the curative antifibrotic effects of losartan and candesartan in an established thioacetamide-induced chronic liver failure (CLF) rat model.
- To assess the impact of these ARBs on motor dysfunction associated with thioacetamide-induced CLF.
Main Methods:
- Chronic liver failure was induced in rats using thioacetamide.
- Rats with established liver fibrosis were treated with varying doses of losartan or candesartan.
- Motor function was evaluated using rotarod and open-field tests; biochemical and histopathological analyses were performed.
Main Results:
- Both losartan and candesartan reversed thioacetamide-induced increases in oxidative stress and inflammation markers, and improved liver function tests.
- Histopathological examination revealed dose-dependent reduction in fibrosis severity with both drugs.
- Candesartan, but not losartan, significantly improved motor dysfunction in the thioacetamide-induced CLF model.
Conclusions:
- Losartan and candesartan demonstrate therapeutic antifibrotic effects in thioacetamide-induced hepatic fibrosis, likely via angiotensin-II receptor blockade, antioxidant, and anti-inflammatory mechanisms.
- Candesartan's superior efficacy in improving motor dysfunction may be linked to enhanced brain penetration and receptor binding kinetics.
- Further clinical trials are recommended to explore the potential of these ARBs in managing hepatic fibrosis and encephalopathy.
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