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Current Clinical Pharmacology


ISSN (Print): 1574-8847
ISSN (Online): 2212-3938

Research Article

Role of Nrf2/HO-1 and PI3K/Akt Genes in the Hepatoprotective Effect of Cilostazol

Author(s): Marwa Hassan*, Mohamad A. Ibrahim, Heba M. Hafez, Mervat Z. Mohamed, Nagwa M. Zenhom and Hend M. Abd Elghany

Volume 14 , Issue 1 , 2019

Page: [61 - 67] Pages: 7

DOI: 10.2174/1574884713666180903163558


Background: Cilostazol, a phosphodiesterase 3 inhibitor (PDE3I), is a platelet aggregation inhibitor and vasodilator that is useful for treating intermittent claudication. Experimental studies have shown that cilostazol has potent anti-inflammatory, anti-oxidant effects effects.

Objectives: Although the hepatoprotective effect cilostazol has been studied, the molecular mechanisms of such protection, including: the nuclear factor-erythroid 2-related factor 2 (Nrf2) / hemoxygenase (HO-1) and the phosphoinositide 3-kinase (PI3K) /serine/threonine kinase (Akt) pathways are not fully explored, which is the aim of this study.

Methods: To achieve the aim of this study, 35 rats were grouped into: control groups, liver injury group (model- non treated: injected with thioacetamide (TAA), 150 mg/kg, i.p.), and two cilostazoltreated groups (treated with cilostazol 10 and 50 mg/kg, p.o.). The rats were treated for 8 days and injected with TAA on the 7th day of the experiment and sacrificed 48 hours after TAA injection.

Results: The model group showed evidence of liver injury as indicated by the elevation of liver enzymes and confirmed by histopathological findings. TAA-induced liver injury was accompanied by down-regulation of the cytoprotective pathways: PI3K/Akt and Nrf2/HO-1 mRNAs. Cilostazol administration ameliorated TAA-induced liver injury, where it caused a significant improvement in the activity of liver enzymes as well as in the histopathological changes. Such an effect was associated with a significant increase in the expression of PI3K/Akt and Nrf2/HO-1 mRNAs as detected by Real-time reverse transcription polymerase chain reaction (RT-PCR).

Conclusion: Cilostazol protected rats against TAA hepatotoxicity through up-regulation of PI3K/Akt and Nrf2/HO-1 gene expression.

Keywords: PI3K/Akt, Nrf2/HO-1, thioacetamide, hepatotoxicity, cilostazol, angiogenesis.

Graphical Abstract
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