Investigation of the protective effect of erdosteine against cyclosporine-inducedinjury in rat liver with histological and biochemical methods

Abstract

IntroductionCyclosporine A (CsA), an immunosuppressive agent, has been used in organ transplantation cases and the treatment of autoimmune diseases for a long time (1,2). It is a cyclic polypeptide with 11 amino acids, which is produced by fermentation of Trichoderma polysporum and Cylindrocarpon (3). Cyclosporine G, formed by replacement of alpha-aminobutyric acid by norvaline, has an identical effect to that observed with CsA (4,5).From the 1980s onwards, side effects began to occur with the wide prescription of CsA. These include nephrotoxicity, cardiotoxicity, hypertension, infections, and hepatotoxicity (6-8).The mechanism of tissue damage caused by CsA has not been fully understood. Several authors have suggested that reactive oxygen species production, oxidative stress, and depletion of the hepatic antioxidant system are possible mechanisms of CsA hepatotoxicity (9,10).Although the mechanism of CsA side effects is not fully understood, several studies showed that the use of antioxidant agents can reduce the toxicity (10,11).Erdosteine [N-(carboxymethylthioacetyl)-homocysteine thiolactone] is a mucolytic agent that was developed for the treatment of chronic pulmonary disease. Erdosteine includes two blocked sulfhydryl groups that are unlocked with hepatic metabolization. The reducing potential of these sulfhydryl groups provides antioxidant activity and free radical scavenging of erdosteine (12,13).Erdosteine is known to have antioxidant properties and has been used in many studies on account of its Background/aim: In the present study, the protective effect of erdosteine against cyclosporine-induced injury in rat liver was investigated with histological and biochemical methods.Materials and methods: Thirty-two Wistar albino male rats were randomly divided into 4 groups: control (n = 8), cyclosporine (n = 8, 20 mg kg -1 day -1 i.p.), cyclosporine + erdosteine (n = 8, erdosteine 12 mg kg -1 day -1 orally), and erdosteine (n = 8). At the end of day 12, liver tissues were removed for histological and biochemical analysis. After liver tissues were fixed in 10% buffered neutral formalin, routine histological processes were applied and tissue sections were stained with hematoxylin and eosin, periodic acid-Schiff, and elastic fiber stain methods. One hundred lobules of liver were examined for each group and evaluated statistically. The levels of malondialdehyde and glutathione peroxidase, as well as the activities of superoxide dismutase, were determined. Results:The cyclosporine group showed significant histopathological changes compared to the control. In the cyclosporine + erdosteine group, histopathological changes of hepatic damage were markedly reduced. Histological findings were supported by biochemical results. Conclusion:Erdosteine could attenuate cyclosporine-induced liver injury.

Effect on Endoplasmic Reticulum Stress of the Combined Oral Contraceptives in the Liver

“…33 In rats in which liver damage has caused by cyclosporine, no damage was observed in the central vein endothelium in the elastin fiber staining and no difference was found in the glycogen distribution in the preparations stained with PAS compared to the control group. 34 In our study, as a result of our histological staining with Orcein, it was determined that the elastic fiber density around the vena centralis increased in the EE+DRSP, EE, and DRSP groups compared to the control group. In addition, as a result of our PAS histochemical staining; it was observed that glycogen storage of liver epithelial cells was weak in the EE+DRSP group, while it was normal in all other groups.…”

Hepatoprotective effect of the tyrosine kinase inhibitor nilotinib against cyclosporine‐A induced liver injury in rats through blocking the Bax/Cytochrome C/caspase‐3 apoptotic signaling pathway

“…Several previous findings propose that reactive oxygen species (ROS) production, increase in malondialdehyde (MDA), oxidative stress, and exhaustion of the hepatic antioxidant system are considered mechanisms of CsA hepatotoxicity. [11] In vitro and in vivo reports showed that CsA, which has a lipophilic structure, is readily linked to cell membranes and stimulates lipid peroxidation that leads to the formation of free radicals. [11,12] Apoptosis is a substantial process in tissue homeostasis and the development of most multicellular organisms.…”

“…[11] In vitro and in vivo reports showed that CsA, which has a lipophilic structure, is readily linked to cell membranes and stimulates lipid peroxidation that leads to the formation of free radicals. [11,12] Apoptosis is a substantial process in tissue homeostasis and the development of most multicellular organisms. [13] It is initiated through the activation of the intrinsic pathway that works via the mitochondria, which participate in the arrangement of numerous apoptotic processes.…”

“…[ 11 ] In vitro and in vivo reports showed that CsA, which has a lipophilic structure, is readily linked to cell membranes and stimulates lipid peroxidation that leads to the formation of free radicals. [ 11,12 ]…”