Molecular and cellular pharmacologyCilostazol attenuates indices of liver damage induced by thioacetamide in albino rats through regulating inflammatory cytokines and apoptotic biomarkers
Introduction
The liver is a highly vital organ, playing an important role in the metabolic functions. From the last years, the morbidity and mortality of many forms of liver diseases have increased all over the world (Trivedi and Hirschfield, 2013, Suk et al., 2014).
Cilostazol is a type III phosphodiesterase enzyme (PDE3) inhibitor with partial type V phosphodiesterase (PDE5) activity, which has been related to the elevation of the intracellular cyclic adenosine monophosphate (cAMP) level by preventing its hydrolysis (Kimura et al., 1985). Moreover, cilostazol reduces recurrent cerebral infarction (Gotoh et al., 2000) and mitigates ischemic brain injury post-transient focal cerebral ischemia by cyclic adenosine monophosphate response element binding protein (CREB) activator of progenitor cells and enhance hepatic blood flow and sinusoidal perfusion besides regulating pro-inflammatory cytokines (Akcan et al., 2006, Uchiyama, 2010).
Ursodeoxycholic acid is a secondary bile acid, which is a metabolic derivative of intestinal bacteria and it has anti-oxidative properties (Chun and Low, 2012). The positive effects of ursodeoxycholic acid in non-cholestatic liver injury is through preventing the damage of the liver mitochondrial functions and maintaining its structure in chronic alcohol toxicity (Lukivskaya et al., 2007). The mechanism of the ursodeoxycholic acid action could be related to the transposition of toxic bile acids from the bile acid pool as well as immunomodulatory and cytoprotective effects, and we used it in this study as a reference drug in evaluating cilostazol effects (Dilger et al., 2012, Kotb, 2012).
In this experiment, we decided to investigate the ability of cilostazol in combination with ursodeoxycholic acid in mitigating or restoring liver damage accompanied by inflammatory disorders, and complications.
Section snippets
Drugs and chemicals
Thioacetamide was purchased from [Sigma-Aldrich Co., USA], while cilostazol (Pletal) from Otsuka Pharmaceuticals (UK) and ursodeoxycholic acid (Ursofalk) from MINAPHARM-Egypt. Cilostazol and ursodeoxycholic acid were administered orally, which they suspended in distilled water.
Animals
Mature male Wistar albino rats weighing 120–130 g were obtained from the National Research Centre Animal House (Dokki, Giza, Egypt) and were kept in a standard polypropylene cages under standard environmental conditions
Serum liver function parameters (AST & ALT)
The control positive group showed a significantly marked elevation in serum AST and ALT levels compared with the normal control group as shown in Table 1. Protected groups treated with either cilostazol 5 or 10 mg/kg exhibited a significant decrease in these 2 parameters level in comparison with the control positive group, but the effect of cilostazol (10 mg/kg) was more predominate and significant than cilostazol (5 mg/kg) in serum AST level. Meanwhile, the protected group treated with only
Discussion
The present study presents new insight into the possible mechanism of cilostazol, a PDE3 inhibitor with partial PDE5 activity, toward the attenuation of thioacetamide-induced hepatic injury in rats. Thioacetamide was used in a single dose as a hepatotoxicant and inducer of liver injury.
Thioacetamide has been shown to be useful as in vivo tool in studying liver injuries as the lesions elicited by it resembles those seen in most cases shown in human liver diseases.
Thioacetamide is a thiono
Conclusion
In conclusion, the present study demonstrates that administration of cilostazol can reduce liver injury in rats induced by thioacetamide. The protective effect of cilostazol may be via the amelioration of oxidative stress, the reversal in the expression of pro-inflammatory cytokines, elevation in the cAMP level that results in the suppression of expression of TNF-α and NF-Kβ and thereby alleviates hepatic injury.
Conflict of interest
The authors have declared that no competing interests exist.
Funding
The authors have no support or funding to report.
Author contributions
All authors of the current manuscript contributed equally to accomplish different parts of this work.
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