Volume 4 • Issue 2 • 1000167 Research Article Open Access Baraka and Guemei, Biochem Pharmacol (Los Angel) 2015, 4:2 DOI: 10.4172/2167-0501.1000167 Biochemistry & Pharmacology: Open Access B i o c h e m i s t r y & P h a r m a c o l o g y : O p e n A c c e s s ISSN: 2167-0501 Biochem Pharmacol (Los Angel), an open access journal ISSN:2167-0501 Abstract Aim: The aim of the current study was to assess the possible protective effects of advanced glycation end product (AGE) inhibitors against liver fbrosis 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 fbrosis group in which liver fbrosis was induced by thioacetamide. Groups V and VI included treated liver fbrosis 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 fbrosis evidenced histologically and by a signifcant increase in hepatic hydroxyproline level. TAA also resulted in a signifcant increase in serum AST, ALT activities as well as hepatic AGEs, TGF-β1, MDA and TIMP concentrations, together with a signifcant decrease in hepatic GSH. Administration of either aminoguanidine or lisinopril resulted in signifcant amelioration of above mentioned parameters. Conclusion: Targeting AGEs could represent a therapeutic option for patients at risk for developing liver fbrosis. Can Pharmacological Targeting of Advanced Glycation End Products Provide Protection Against Experimentally Induced Liver Fibrosis? Baraka AM* and Guemei A Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Egypt *Corresponding author: Baraka AM, Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Egypt, Tel: 00201224568012; E-mail: azza.baraka@alexmed.edu.eg Received: January 26, 2015; Accepted: February 28, 2015; Published March 07, 2015 Citation: Baraka AM, Guemei A (2015) Can Pharmacological Targeting of Advanced Glycation End Products Provide Protection Against Experimentally Induced Liver Fibrosis? Biochem Pharmacol (Los Angel) 4: 167. doi:10.4172/2167- 0501.1000167 Copyright: © 2015 Baraka AM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Keywords: Advanced glycation end products; Lisinopril; Aminoguanidine; Tioacetamide; Fibrosis Introduction Liver cirrhosis is a serious irreversible disease and is the tenth leading cause of death in developed countries. If treated properly at fbrosis stage, cirrhosis could be prevented. Several experimental ameliorative strategies have been tested. However, there is still a remarkable lack of defnitive evidence supporting specifc therapies in these settings that can either cure or at least halt the progress of liver injury to liver fbrosis. Terefore, better strategies and /or drugs are desperately needed that would reduce the risk of liver fbrosis. Although the pathophysiology of liver cirrhosis is not completely understood, some key events leading to tissue injury and thereby to liver fbrosis have been identifed [1]. Much attention has been paid in the recent years to the nonenzymatic glycation and advanced glycation end products (AGEs) hypothesis. Tis 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 non- alcoholic steatohepatitis, which could cause hepatic fbrosis. Indeed, Elevated levels of serum AGEs were observed in patients with non- alcoholic steatohepatitis [2]. Non-enzymatic glycation involves the reaction of the carbonyl group of sugar aldehydes with the N-terminus of free amino groups of proteins, resulting in the formation of Schif’s base that is subsequently rearranged to amadori products in a reaction called Maillard reaction. Tese amadori products or glycated proteins may then react with other proteins, lipids or DNA resulting in irreversible crosslinking and the formation of AGEs (post-amadori or glycotoxins) [3]. Although AGEs formation happens as a result of normal aging, it occurs at an accelerated rate in diseases as diabetes mellitus [4], renal failure [5], diabetic nephropathy [6], infammatory conditions [7] and liver cirrhosis [8]. Recently, AGEs have been reported to signifcantly increase in hepatic fbrosis and to play a critical role in stimulating extracellular matrix (ECM) synthesis [9]. Several possible mechanisms could account for the ability of AGEs to stimulate liver fbrosis. AGEs can increase oxidative stress; induce production of pro-infammatory cytokines as tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β) [3]. Efects of AGEs are mediated by their receptor system, which could be generally divided into two categories. Receptor for AGEs (RAGE) facilitates oxidative stress (OS), cell growth and infammation [10] and AGE receptors (AGE-Rs), eg. AGE-R1 (also called OST-48), is responsible for detoxifcation and clearance of AGEs [11]. Inhibition of AGEs formation, blockade of AGEs-RAGE interaction, suppression of RAGE expression, interruption of its signaling and induction of AGE-R1 expression are, thus, novel therapeutic strategies for targeting AGE-mediated diseases [12,13]. AGE inhibitors, as aminoguanidine, carnosine, acarbose and pyridoxamine, vary widely in structure, but they have common mechanism of action, which is the trapping of reactive carbonyl groups