Ersin Fadillioglu

Erdosteine prevents doxorubicin-induced cardiotoxicity in rats.

The clinical use of doxorubicin (Dxr) is limited by its cardiotoxic effects which are mediated by oxygen radicals. The purpose of this study was to investigate in vivo protective effects of erdosteine, an antioxidant agent because of its secondary active metabolites in vivo, against the cardiotoxicity induced by Dxr in rats. Three groups of male Sprague-Dawley rats (60 days old) were used. Group 1 was untreated group used as control; the other groups were treated with Dxr (single i.p. dosage of 20 mg kg(-1) b.wt.) or Dxr plus erdosteine (10 mg kg(-1) day(-1), orally), respectively. Erdosteine or oral saline treatment was done starting 2 days before Dxr for 12 days. The analyses were done at the 10th day of Dxr treatment. The protein carbonyl content, the activities of myeloperoxidase, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine kinase (CK) as well as heart rate and blood pressures were significantly increased in Dxr group in comparison with the other groups. However, pulse pressure was decreased in Dxr group. The body and heart weights were decreased in both Dxr administered groups in comparison with control group. Disorganization of myocardial histology, picnotic nuclei, edema, and increase in collagen content around vessels were seen in the slides of Dxr group, whereas normal myocardial microscopy was preserved in Dxr plus erdosteine group. Collectively, these in vivo hemodynamic, enzymatic and morphologic studies provide an evidence for a possible prevention of cardiac toxicity in Dxr-treated patients.

Effects of erdosteine treatment against doxorubicin-induced toxicity through erythrocyte and plasma oxidant/antioxidant status in rats.

The clinical use of doxorubicin (Dxr), an antineoplastic agent, is limited by its extensive toxicity which is mostly mediated by oxidant injury. We have studied the effect of erdosteine, a mucolytic drug showing antioxidant properties, in preventing Dxr-toxicity to improve future Dxr therapy. Male Sprague-Dawley rats were divided into four groups. The first group that underwent no medication was accepted as control group; the second group was treated with a single i.p. injection of Dxr (20 mg kg(-1) b.wt.); the third group was treated with oral erdosteine alone (10 mg kg(-1) b.wt. day(-1) for 12 days); and in the last group erdosteine was administered starting before Dxr injection for 12 days. The thiobarbituric acid reactive substances (TBARS) level of Dxr group was higher in both plasma and erythrocyte than the other groups. In plasma and erythrocyte, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were increased in Dxr plus erdosteine group in comparison with control group, and the activities of GSH-Px were increased in Dxr plus erdosteine group in comparison with Dxr group. The erythrocyte catalase (CAT) activity of Dxr plus erdosteine group was higher than control and Dxr groups. Plasma xanthine oxidase activities and nitric oxide (NO) levels were not significantly different between groups, however erythrocyte NO level of Dxr group was higher than control. In conclusion, Dxr administration resulted in increased lipid peroxidation in plasma as well as erythrocyte and erdosteine treatment helped to prevent oxidative injury by increasing antioxidant enzymes, especially SOD, GSH-Px and CAT, in rats.

Serum nitric oxide, catalase, superoxide dismutase, and malondialdehyde status in patients with ankylosing spondylitis

In this study, serum antioxidant and oxygen derived free radical status of patients with ankylosing spondylitis (AS) was investigated and compared with that of age- and sex-matched healthy controls. The relationship of these parameters to disease activity indices was also examined. Thirty patients with AS not currently under disease-modifying antirheumatic drug (DMARD) treatment (e.g., sulfasalazine or methotrexate) (15 active and 15 inactive) and 16 age- and sex-matched healthy controls were included in the study. Catalase (EC 1.11.1.6), total (Cu-Zn and Mn) superoxide dismutase (SOD) (EC 1.15.1.1) activities, and malondialdehyde (MDA), nitrite (NO2-), and nitrate (NO3-) levels as indices of nitric oxide (NO) production were evaluated using appropriate methods. There was no statistically significant difference found in SOD activity or NO and MDA levels between active and inactive patients. Inactive patients showed no significant difference in all the measured oxidant/antioxidant parameters when compared to healthy controls. Active patients had significantly higher levels of MDA and catalase enzyme activity (P=0.002 and P=0.007, respectively). There was no significant correlation between oxidant/antioxidant parameters and disease activity, C-reactive protein, erythrocyte sedimentation rate, or Bath Ankylosing Spondylitis Disease Activity Index (CRP, ESR, or BASDAI) in either group, except catalase enzyme activity, which had a significant correlation with CRP and ESR levels in active patients (r=0.69 and P=0.004, r=0.52 and P=0.04, respectively). Our results indicate that oxidative stress and lipid peroxidation are accelerated in untreated patients with active AS. Serum catalase activity may be closely related to disease activity. In this regard, we underscore the likely benefit of some therapeutic interventions including high-potential antioxidants that will potentiate the antioxidant defense mechanism and reduce peroxidation in the management of AS.

The activities of tissue xanthine oxidase and adenosine deaminase and the levels of hydroxyproline and nitric oxide in rat hearts subjected to doxorubicin: protective effect of erdosteine

The aim of this experimental study was to investigate the effects of erdosteine, an antioxidant agent, on doxorubicin (DXR)-induced cardio-toxicity through nitric oxide (NO) levels, collagen synthesis, xanthine oxidase (XO) and adenosine deaminase (ADA) activities in rats. Rats were treated with erdosteine (10 mg/kg b.wt. per day, orally) or saline starting 2 days before administrating a single dose of DXR (20 mg/kg i.p.) or saline. At the 10th day of the DXR administration, hearts were removed under anesthesia for biochemical measurements. Enzyme activities as well as OH-proline and NO levels were found to be significantly increased in DXR group compared with the control group. All of the parameters studied except ADA activity were decreased significantly approximating to the control levels upon erdosteine administration. In conclusion, erdosteine seems to be an alternative agent for protection of cardiac tissue against DXR-induced cardio-toxicity through its regulatory effect on XO activity and NO level.

Preventive effect of melatonin on bleomycin-induced lung fibrosis in rats

Abstract:  Oxidative stress has an important role in the pathogenesis of idiopathic pulmonary fibrosis. Melatonin has direct and indirect free radical‐detoxifying activity. The present study investigated whether melatonin treatment attenuates bleomycin‐induced lung fibrosis in rats. A group of rats was given one dose of bleomycin while the control animals were given saline. The first dose of melatonin (4 mg/kg/day) was given 2 days before the bleomycin injection. At day 14, fibrotic changes were evaluated using Aschofts criteria and lung hydroxyproline content. Bleomycin produced a 2.7‐fold rise in the fibrosis score that was decreased 65% by melatonin (P < 0.05) and a 1.4‐fold increase in hydroxyproline content which was completely prevented by melatonin. Protein carbonyl and thiobarbituric acid reactive substances levels, which were significantly elevated in the bleomycin treated rats, were significantly attenuated by melatonin. Bleomycin administration significantly reduced the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH‐Px) in lung tissue. The reduction in CAT activity was prevented by melatonin but SOD and GSH‐Px were not influenced. These results revealed that melatonin may prevent the development of bleomycin‐induced lung fibrosis via the repression of protein and lipid peroxidation.

Effects of electromagnetic radiation from a cellular telephone on epidermal Merkel cells

The number of reports on the effects induced by electromagnetic radiation (EMR) from cellular telephones in various cellular systems is still increasing. Until now, no satisfactory mechanism has been proposed to explain the biological effects of this radiation except a role suggested for mast cells. Merkel cells may also play a role in the mechanisms of biological effects of EMR. This study was undertaken to investigate the influence of EMR from a cellular telephone (900 MHz) on Merkel cells in rats. A group of rats was exposed to a cellular telephone in speech position for 30 min. Another group of rats was sham‐exposed under the same environmental conditions for 30 min. Exposure led to significantly higher exocytotic activity in Merkel cells compared with the sham exposure group. This finding may indicate the possible role of Merkel cells in the pathophysiology of the effects of EMR.

Prevention of renal ischemia/reperfusion-induced injury in rats by leflunomide

Objective: There is increasing evidence to suggest that toxic oxygen radicals play an essential role in the pathogenesis of ischemia/reperfusion (I/R) injury in the kidney. This study was designed to investigate the effects of leflunomide, an isoxazole derivative and a unique immunomodulatory agent, in I/R‐induced renal injury in rats.

Melatonin treatment against remote organ injury induced by renal ischemia reperfusion injury in diabetes mellitus

Oxidative stress may have a role in liver damage after acute renal injury due to various reasons such as ischemia reperfusion (IR). Diabetes mellitus (DM) is an important disease for kidneys and may cause nephropathy as a long term complication. The aim of this study was to investigate protective effect of melatonin, a potent antioxidant, against distant organ injury on liver induced by renal IR in rats with or without DM. The rats were divided into six groups: control (n=7), DM (n=5), IR (n=7), DM+IR (n=7), melatonin+IR (Mel+IR) (melatonin, 4 mg/ kg during 15 days) (n=7), and Mel+DM+IR groups (n=7). Diabetes developed 3 days after single i.p. dose of 45 mg/kg streptozotocin. After 15 day, the left renal artery was occluded for 30 min followed 24 h of reperfusion in IR performed groups. DM did not alter oxidative parameters alone in liver tissue. The levels of malondialdehyde, protein carbonyl and nitric oxide with activities of xanthine oxidase and myeloperoxidase were increased in liver tissues of diabetic and non-diabetic IR groups. Nitric oxide level in DM was higher than control. The activities of catalase and superoxide dismutase were increased in IR groups in comparison with control and DM. ALT and AST levels were higher in IR and DM+IR groups than control and DM. Melatonin treatment reversed all these oxidant and antioxidant parameters to control values as well as serum liver enzymes. We concluded that renal IR may affect distant organs such as liver and oxidative stress may play role on this injury, but DM has not an effect on kidney induced distant organ injury via oxidant stress. Also, it was concluded that melatonin treatment may prevent liver oxidant stress induced by distant injury of kidney IR.

Melatonin improves methanol intoxication‐induced oxidative liver injury in rats

Abstract:  This study was performed to evaluate the effect of melatonin on methanol‐induced liver injury. We evaluated the levels of malondialdehyde (MDA), protein carbonylation (PC), myeloperoxidase (MPO) activities and to assess lipid peroxidation, protein oxidation, neutrophil accumulation and nitrite which is a stable end product of nitric oxide respectively. We also studied superoxide dismutase, catalase, and glutathione peroxidase activities of liver tissue to evaluate the changes in the antioxidant status. Histopathological alterations were also determined. The experiment was performed on Wistar rats, which received intragastric 3 g/kg methanol as a 50% solution in isotonic saline once. After 6 and 24 hr all the drug received and intoxicated rats were killed under anesthesia. Pretreatment with melatonin (10 mg/kg) decreased the MDA levels significantly, restored the PC levels to the control, prevented the increase of nitrite level and MPO activity significantly and reversed to the control levels, prevented the reduction in all of the antioxidant enzyme activities. Additionally in melatonin treated group piecemeal necrosis, lobular lytic necrosis, and portal inflammation returned to normal histologic appearances when compared with methanol administration. In conclusion, melatonin has protective effects against methanol‐induced hepatic injury.

Protective effects of erdosteine on rotenone-induced oxidant injury in liver tissue

Rotenone, an insecticide of botanical origin, causes toxicity through inhibition of complex I of the respiratory chain in mitochondria. This study was undertaken to determine whether rotenone-induced liver oxidant injury is prevented by erdosteine, a mucolytic agent showing antioxidant properties. There were four groups of Male Wistar Albino rats: group one was untreated as control; the other groups were treated with erdosteine (50 mg/kg per day, orally), rotenone (2.5 mg/mL once and 1 mL/kg per day for 60 days, i.p.) or rotenone plus erdosteine, respectively. Rotenone treatment without erdosteine increased xanthine oxidase (XO) enzyme activity and also increased lipid peroxidation in liver tissue P < 0.05). The rats treated with rotenone plus erdosteine produced a significant decrease in lipid peroxidation and XO activities in comparison with rotenone group PB / 0.05). Erdosteine treatment with rotenone led to an increase in catalase (CAT) and superoxide dismutase (SOD) activities in comparison with the rotenone group PB / 0.05). There was no significant difference in nitric oxide (NO) level between groups. There were negative correlations between CAT activity and malondialdehyde (MDA) level (r= -0.934, P <0.05) with between CAT and SOD activities (r= -0.714, P <0.05), and a positive correlation between SOD activity and MDA level (r= 0.828, P <0.05) in rotenone group. In the rotenone plus erdosteine group, there was a negative correlation between XO activity and NO level in liver tissue (r= -0.833, P -0.05). In the light of these findings, erdosteine may be a protective agent for rotenone-induced liver oxidative injury in rats.