Can Pharmacological Targeting of Advanced Glycation End Products Provide Protection Against Experimentally Induced Liver Fibrosis?

Baraka Am Guemei A

doi:10.4172/2167-0501.1000167

Abstract

Aim: The aim of the current study was to assess the possible protective effects of advanced glycation end product (AGE) inhibitors against liver fibrosis and the possible underlying mechanisms. Material and Methods: The present study was conducted on 48 male Wistar albino rats that were grouped into six groups of 8 rats each. Groups I-III; normal groups that were injected intraperitoneally (I.P.) with normal physiological saline, and either received no treatment (Group I), or received aminoguanidine (group II) or lisinopril (group III) daily for 4 weeks by I.P. injection. Group IV included untreated liver fibrosis group in which liver fibrosis was induced by thioacetamide. Groups V and VI included treated liver fibrosis group in which aminoguandine and lisinopril were injected I.P., daily for 4 weeks, concomitantly with thioacetamide. At the end of the treatment period (4 weeks), serum was collected to measure aminotransferases (AST and ALT) activities. Hepatic levels of AGEs, transforming growth factor-B1 (TGF-β1), tissue inhibitor of matrix metalloproteinase (TIMP), malondialdehyde (MDA), reduced glutathione (GSH) and hydroxyproline levels were assessed. Histopathological examination of liver was also carried out. Results: TAA administration resulted in hepatic fibrosis evidenced histologically and by a significant increase in hepatic hydroxyproline level. TAA also resulted in a significant increase in serum AST, ALT activities as well as hepatic AGEs, TGF-β1, MDA and TIMP concentrations, together with a significant decrease in hepatic GSH. Administration of either aminoguanidine or lisinopril resulted in significant amelioration of above mentioned parameters. Conclusion: Targeting AGEs could represent a therapeutic option for patients at risk for developing liver fibrosis.

Highlights

Liver cirrhosis is a serious irreversible disease and is the tenth leading cause of death in developed countries
Targeting advanced glycation end product (AGE) could represent a therapeutic option for patients at risk for developing liver fibrosis
Treatment with either aminoguanidine or lisinopril resulted in a significant decrease in serum AST, ALT activities and in hepatic AGEs, MDA, TGF-β1, tissue inhibitor of matrix metalloproteinase (TIMP) and HPO concentrations as well as a significant increase in GSH concentration as compared to non-treated TAA group

Summary

Introduction

Liver cirrhosis is a serious irreversible disease and is the tenth leading cause of death in developed countries. Better strategies and /or drugs are desperately needed that would reduce the risk of liver fibrosis. The pathophysiology of liver cirrhosis is not completely understood, some key events leading to tissue injury and thereby to liver fibrosis have been identified [1]. Much attention has been paid in the recent years to the nonenzymatic glycation and advanced glycation end products (AGEs) hypothesis. This hypothesis has been issued based on the fact that diabetes is featured by hyperglycemia, which facilitates the formation of AGEs and diabetes is commonly accompanied by nonalcoholic steatohepatitis, which could cause hepatic fibrosis. Elevated levels of serum AGEs were observed in patients with nonalcoholic steatohepatitis [2]

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