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Amikacin-induced acute renal injury in rats: protective role of melatonin
(Wiley, 2003) Parlakpinar, H; Ozer, MK; Sahna, E; Vardi, N; Cigremis, Y; Acet, A
It is well established that some agents such as aminoglycosides generate free oxygen radicals, leading to an increased oxireductase production, which in turn increases tissue toxicity. The aim of this study is to test whether melatonin, the chief secretory product of the pineal gland and a highly effective antioxidant and free radical scavenger, reduces the nephrotoxicity caused by amikacin (AK). Herein, we investigated the physiologic and pharmacological role of melatonin in influencing AK-induced nephrotoxicity. For this, pinealectomized (Px) and sham operated (non-Px) rats were used. Both AK and melatonin were administered to all groups. We investigated the effects of melatonin on AK-induced changes in levels of malondialdehyde (MDA), a lipid peroxidation product, glutathione (GSH), an antioxidant whose levels are influenced by oxidative stress, and blood urea nitrogen (BUN) and serum creatine (Cr) levels. Morphologic changes in the kidney were also examined by using light microscopy. MDA levels were found to be higher in Px than in non-Px AK-treated animals. Melatonin administration to Px rats reduced MDA levels. In relative to non-Px rats, Px animals treated with AK had significantly lower GSH concentrations while melatonin administration elevated GSH levels in the kidney; however, this stimulatory effect of melatonin was not observed in non-Px AK-treated rats. Treatment with AK alone resulted in significantly higher plasma Cr and BUN levels. Repeated administration of melatonin prevented the AK-induced elevation of plasma Cr and BUN levels. Morphologic damage to renal tubules as a result of AK was more severe in the renal cortex than in the medulla. The damage to the kidney induced by AK was reversed by melatonin in the Px rats. In conclusion, these results show that physiologic melatonin concentrations are important in reducing AK-induced renal damage, while pharmacologic concentrations of melatonin did not add to the beneficial effect.
Caffeic acid phenethyl ester (CAPE) attenuates cerebral vasospasm after experimental subarachnoidal haemorrhage by increasing brain nitric oxide levels
(Pergamon-Elsevier Science Ltd, 2006) Aladag, MA; Turkoz, Y; Ozcan, C; Sahna, E; Parlakpinar, H; Akpolat, N; Cigremis, Y
Background: Cerebral vasospasm, a medical complication of aneurysmal subarachnoid hemorrhage (SAH), is associated with high morbidity and mortality rates, even after the aneurysm has been secured surgically or endovascularly. Evidence accumulated during the last decade suggest that scavenging a vasodilator, nitric oxide (NO), by superoxide anions (O-2(-)), and activating a strong vasoconstructor, protein kinase C (PKC), are the two most important mechanisms in the pathogenesis of vasospasm. Our aim in this study was to determine whether caffeic acid phenethyl ester (CAPE), a non-toxic oxygen free radical scavenger, prevents vasospasm in an experimental rat model of SAH. Methods: Twenty eight rats (225-250 g) were divided into four groups equally: group 1, control group group 2, SAH group; group 3, SAH plus placebo group; and group 4, SAH plus CAPE group. We used double haemorrhage method for SAH groups. Starting 6 h after SAH, 10 mu mol/kg CAPE or an equal volume of 0.9% saline were administered by intraperitoneal injection twice daily for 5 days to SAH plus CAPE and SAH plus placebo groups, respectively. CAPE or 0.9% saline injections were continued up to 5th day after SAH. Rats were sacrificed on the 5th day. Brain sections at the level of the pons were examined by light microscopy. Measurements were made for the cross-sectional areas of the lumen and the vessel wall (intimae plus media) of basilar artery by a micrometer. The levels of malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO) were measured in rat brain tissue. Results: Administration of CAPE significantly attenuated the vasoconstriction of the basilar artery. There were marked narrowing in the lumens of and thickening in the walls of basilar arteries in the SAH, and the SAH plus placebo compared with CAPE group (p < 0.001). We also observed that CAPE administration significantly decreased the tissue level of MDA, while significantly increased the tissue levels of GSH, NO in the SAH plus CAPE group compared to only SAH group, p < 0.05. Conclusions: Our results indicate that CAPE is effective in attenuating delayed cerebral vasoconstriction following experimental SAH. Our findings also suggest that the elevation of lipid peroxidation and reduction of NO bioavailability, resulting from the generation and the interaction of free radicals, have a significant role in the pathogenesis of vasospasm after SAH. (c) 2005 ISDN. Published by Elsevier Ltd. All rights reserved.
The effect of resveratrol in experimental cataract model formed by sodium selenite
(Taylor & Francis Inc, 2006) Doganay, S; Borazan, M; Iraz, M; Cigremis, Y
Purpose : To investigate if resveratrol can prevent sodium selenite-induced experimental cataract model in rats. Methods : Forty-eight Spraque-Dawley rat pups were divided into 3 treatment groups: (1) normal saline-% 5 ethanol injected i.p. on postpatum day 10; (2) Na selenite (30 nmol/g body wt) injected s.c on day 10; (3) Na selenite s.c on day 10 + resveratrol (40 mg/kg) i.p on days 10-13. On day 21, cataract development was graded by slit-lamp examination and photography. Encapsulated lenses and erythrocytes were analyzed for reduced glutathione (GSH) and malondialdehyde (MDA), a marker of lipid peroxidation. Lenses were also analyzed for total nitrite (TN). Results : All control lenses in group 1 were clear. In group 2, all rats developed cataracts (grade 3-grade 6), whereas in group 3, only 9 of 16 rats developed cataracts (grade 2-grade 3). The difference of cataract frequency between groups 2 and 3 was statistically significant (p p < 0.05). Group 3 lenses and erythrocytes had higher mean GSH and lower mean MDA levels than those in group 2 (p < 0.05). TN was highest in group 3 and lowest in group 1 (p < 0.05). Conclusions: Resveratrol suppressed selenite-induced oxidative stress and cataract formation in rats. This protective effect was supported by higher GSH and lower MDA in lens and erythrocytes. The presence of oxidative stress in selenite cataract development and its prevention by resveratrol support the possibility that high natural consumption of resveratrol in food can help prevent human senile cataract.
The effects of chronic exposure to ethanol and cigarette smoke on the level of reduced glutathione and malondialdehyde in rat kidney
(Springer, 2004) Cigremis, Y; Turkoz, Y; Akgoz, M; Sozmen, M
The aim of this study was to investigate the effects of chronic ethanol intake and cigarette smoke exposure on rat kidney. The animals were divided into four experimental groups: (1) the control group (C), (2) the ethanol group (E), (3) the cigarette smoke group (CS), and (4) the cigarette smoke plus ethanol group (CS+E). Apart from the control group, these were treated with ethanol and/or cigarette smoke for 6 months. The animals were killed and the kidneys removed to determine the levels of reduced glutathione (GSH) and malondialdehyde (MDA) and for histopathological analysis. The levels of GSH/g wet tissue were 1.58+/-0.09 mumol, 0.91+/-0.05 mumol, 1.14+/-0.06 mumol, and 0.82+/-0.04 mumol for C, E, CS, and CS+E, respectively. In groups of E, CS, and CS+E, the GSH values were significantly lower than that of group C animals (P<0.05). Although, we detected lower GSH levels in the CS+E than the CS group (P<0.05), a significant difference in GSH levels between CS+E and E was not observed. The levels of MDA/g wet tissue were 40.1+/-3.4 nmol, 71.4+/-2.8 nmol, 64.0+/-3.6 nmol, and 76.5+/-4.3 nmol, for C, E, CS and CS+E, respectively. In E, CS, and CS+E, the MDA values were significantly higher than in group C (P<0.05). The increase in MDA levels in CS+E were not significantly different from groups E or CS. Histopathological analysis of the kidney slices showed severe degeneration of the tissues. Advanced hydropic degeneration of kidney tubules was clearly observed in the CS group. In group E, advanced tubular and interstitial damage, mononuclear cell infiltration and tubular thyroidization were clearly visible. In group CS+E, an intense inflammatory cell infiltration was detected under the transitional epithelium. We conclude that chronic exposure to ethanol and cigarette smoke may cause an oxidative burst in rat kidney by increasing the formation of reactive oxygen species.
Efficacy of melatonin as protectant against oxidative stress and structural changes in liver tissue in pinealectomized rats
(Urban & Fischer Verlag, 2004) Sahna, E; Parlakpinar, H; Vardi, N; Cigremis, Y; Acet, A
Previous observations demonstrated that physiological levels of metatonin, the pineal secretory product, are important in protecting against oxidative stress-induced tissue damage. We investigated the effects of pinealectomy and administration of exogenous melatonin on liver tissue in rats. Pinealectomized (Px) and sham-operated (non-Px) rats were used. We evaluated structural changes, reduced glutathione (GSH) levels and matondialdehyde (MDA) levels. Rats were divided into three groups (10 rats in each group): control. (non-Px), Px+vehicle and Px+metatonin (4 mg/kg given daily intraperitoneally for 10 days). Liver GSH levels were significantly tower in Px rats than in the control group. Melatonin administration significantly increased GSH levels (p<0.05). Px caused a significant increase in MDA levels as compared with the control group and metatonin administration to Px rats significantly reduced MDA levels in the liver (p<0.05). Sinusoidal dilatation to a varying degree developed in all Px rats. Severity of mononuclear cell. infiltration and sinusoidal congestion were tower in Px+melatonin group than in the Px group. These findings suggest that a significant increase in oxidative and structural changes occur in rat livers after pinealectomy, which can be diminished by melatonin treatment. (C) 2004 Published by Elsevier GmbH.
Ischemia-reperfusion leads to depletion of glutathione content and augmentation of malondialdehyde production in the rat heart from overproduction of oxidants: Can caffeic acid phenethyl ester (CAPE) protect the heart?
(Springer, 2005) Ozer, MK; Parlakpinar, H; Cigremis, Y; Ucar, M; Vardi, N; Acet, A
During restoration of blood flow of the ischemic heart induced by coronary occlusion, free radicals cause lipid peroxidation with myocardial injury. Lipid peroxidation end-products, such as malondialdehyde (MDA), have been used to assess oxygen free radical-mediated injury of the ischemic-reperfused (I/R) myocardium in rats. This experimental study assessed the preventive effect of caffeic acid phenthyl ester (CAPE), antioxidant, on I/R-induced lipid peroxidation in the rat heart. We are also interested in the role of CAPE on glutathione (GSH) levels, an antioxidant whose levels are influenced by oxidative stress. I/R leads to the depletion of GSH which is the major intracellular nonprotein sulphydryl and plays an important role in the maintenance of cellular proteins and lipid in their functional state and acts primarily to protect these important structures against the threat of oxidation. In addition, we also examined morphologic changes in the heart by using light microscopy. The left coronary artery was occluded for 30 min and then reperfused for 120 min more before the experiment was terminated. CAPE (50 mu M kg(-1)) was administered 10 min prior to ischemia and during occlusion by infusion. At the end of the reperfusion period, rats were sacrificed, and the heart was quickly removed for biochemical determination and histopathological analysis. I/R was accompanied by a significant increase in MDA production and decrease in GSH content in the rat heart. Administration of CAPE reduced MDA production and prevented depletion of GSH content. These beneficial changes in these biochemical parameters were also associated with parallel changes in histopathological appearance. These findings imply that I/R plays a causal role in heart injury due to overproduction of oxygen radicals or insufficient antioxidant and CAPE exert cardioprotective effects probably by the radical scavenging and antioxidant activities.
Melatonin reduces torsion-detorsion injury in rat ovary: biochemical and histopathologic evaluation
(Wiley, 2004) Turkoz, Y; Celik, O; Hascalik, S; Cigremis, Y; Hascalik, M; Mizrak, B; Yologlu, S
This experimental study was designed to determine the effects of melatonin on the levels of malondialdehyde (MDA), reduced glutathione (GSH), xanthine oxidase (XO) after adnexial torsion/detorsion (ischemia/reperfusion, I/R) of the ovaries of in rats. Forty adult albino rats were divided into five groups: sham operation, torsion, I/R plus saline, I/R plus melatonin and torsion plus melatonin. Rats in the sham-operated group underwent a surgical procedure similar to the other groups but the adnexa was not occluded. Rats in the torsion group were killed after adnexal torsion for 3 hr. Melatonin and saline were injected intraperitoneally (10 mg/kg) 30 min before detorsion to the I/R plus melatonin group and I/R plus saline group respectively. After 3 hr of ovarian detorsion, the rats were killed and ovaries were removed. Melatonin was injected intraperitoneally (10 mg/kg) 30 min before torsion to the torsion plus melatonin group. After 3 hr of ovarian torsion, the rats were killed and ovaries were harvested. The tissue levels of MDA, GSH and XO were measured. MDA and XO levels in the I/R plus saline group increased significantly when compared with torsion and sham-operated groups (P < 0.001). MDA and XO levels in the I/R plus melatonin group were lower than I/R plus saline and differences between the two groups were statistically significant (P < 0.001). GSH levels in the I/R plus saline group decreased significantly when compared with ischemia and sham-operated groups (P < 0.001). GSH levels in the I/R plus melatonin treated rats were significantly higher than I/R plus saline and ischemia groups (P < 0.001). The tissue levels of XO, MDA and GSH were similar between ischemia and ischemia plus melatonin groups. Morphologically, polymorphonuclear neutrophil infiltration and vascular dilatation were obvious in the I/R-damaged ovaries, and the changes also partially reversed by melatonin. This study demonstrates that melatonin protects the ovaries against oxidative damage associated with reperfusion following an ischemic insult.
Myocardial ischemia/reperfusion-induced oxidative renal damage in rats: Protection by caffeic acid phenethyl ester (cape)
(Lippincott Williams & Wilkins, 2005) Ozer, MK; Parlakpinar, H; Vardi, N; Cigremis, Y; Ucar, M; Acet, A
Myocardial ischemia-reperfusion (MI/R) may induce renal damage. A rat model of M/IR injury was established. The left coronary artery was clamped for 30 min, constituting the ischemic period, and was then released for 120 min, thus constituting the reperfusion period. The purpose of this study was to evaluate the effects of caffeic acid phenethyl ester (CAPE), an antioxidant, on renal dysfunction in rats undergoing MI/R. CAPE (50 mu mol/kg) was administered by infusion 10 min before ischemia and during occlusion. Hemodynamic changes were recorded during the different periods. At the end of the reperfusion period, rats were sacrificed, and the kidneys were quickly removed for biochemical determination and histopathological analysis. MI/R was accompanied by a significant increase in malondialdehyde (MDA) production and decrease in glutathione (GSH) content in the rat kidney. Administration of CAPE reduced MDA production and prevented depletion of GSH content. These beneficial changes in these biochemical parameters were also associated with parallel changes in histopathological appearance. These findings imply that MI/R plays a causal role in kidney injury through overproduction of oxygen radicals or insufficient antioxidant, and CAPE exerts renal-protective effects probably by its radical scavenging and antioxidant activities.
The protective effect of caffeic acid phenethyl ester on ischemia-reperfusion injury in rat ovary
(Elsevier Science Bv, 2004) Celik, O; Turkoz, Y; Hascalik, S; Hascalik, M; Cigremis, Y; Mizrak, B; Yologlu, S
Objective: This experimental study was designed to determine the changes in tissue levels of malondialdehyde, end-product of lipid peroxidation (MDA), reduced glutathione (GSH) and xanthine oxidase (XO) and the effect of caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE) on these metabolite levels after adnexal torsion-detorsion model in rats. Method: Forty adult female albino rats were divided into five groups: basal control (n = 8), sham operation (n = 8), torsion-detorsion plus saline (n = 8), torsion-detorsion plus CAPE (n = 8). and only torsion (n = 8). Rats in the sham operation group underwent a surgical procedure similar to the other groups but the adnexa was not torsioned. Rats in the torsion group were killed after 360degrees clockwise adnexal torsion for 3 It and ovaries were harvested. CAPE was injected intraperitoneally 30 min before detorsion in the CAPE/cletorsion group and saline was administered in the saline/detorsion group. After 3 h of adnexal detorsion, the rats in both groups were killed and adnexa were surgically removed. Results: MDA levels and XO activities in torsion-detorsion plus saline group increased significantly when compared to basal control, torsion and sham operation groups (P < 0.001). In the CAPE group, MDA levels and XO activities were lower than those of torsion-detorsion plus saline group, and differences between the two groups were statistically significant (P < 0.001). GSH levels in torsion-detorsion plus saline group were decreased significantly when compared to basal control and sham operation groups (P < 0.001). GSH levels in the CAPE group were higher than those of torsion-detorsion plus saline group, and differences between the two groups were statistically significant (P < 0.004). Morphologically, polymorphonuclear leukocytic infiltration and vascular dilatation were obvious in the ischernia-reperfusion damaged ovary, a change partially reversed by CAPE. Conclusions: These results suggest that administration of CAPE has beneficial effects in the prevention of ischemia-reperfusion injury of the ovaries. (C) 2004 Elsevier Ireland Ltd. All rights reserved.
The protective effects of physiological and pharmacological concentrations of melatonin on renal ischemia-reperfusion injury in rats
(Springer, 2003) Sahna, E; Parlakpinar, H; Ozturk, F; Cigremis, Y; Acet, A
Reactive oxygen species have been implicated in the pathophysiology of renal ischemia reperfusion (I/R) injury. The pineal secretory product melatonin is known to be a potent free radical scavenger and antioxidant. This study was designed to investigate the effects of physiological and pharmacological concentrations of melatonin on I/R injury. Rats were pinealectomized (Px) or sham-operated (control) 2 months before the I/R studies. There were eight groups of eight rats each. After a right nephrectomy to produce damage, left renal vessels were occluded for 60 min, followed by 24 h reperfusion, in rats. Malondialdehyde (MDA) levels resulting from I/R were significantly higher in the pinealectomized rats than in the control group. Melatonin administration (4 mg kg(-1) i.p. either before ischemia or reperfusion) to Px and sham-operated rats significantly reduced the MDA values and returned them to the control values. Morphological changes in the groups were similar to the MDA levels. Serum levels of blood urea nitrogen and creatine were unchanged. These results suggest that physiological and pharmacological melatonin concentrations are important for the reduction of I/R-induced damage. We also demonstrated that melatonin, even when administrated just before reperfusion, had a protective effect on I/R injury. It would seem valuable to test melatonin in clinical trials for the prevention of possible I/R injury.
Resveratrol, a red wine constituent polyphenol, protects from ischemia-reperfusion damage of the ovaries
(Karger, 2004) Hascalik, S; Celik, O; Turkoz, Y; Hascalik, M; Cigremis, Y; Mizrak, B; Yologlu, S
Objective: The aim of this study is to investigate the effects of resveratrol on histopathological changes, antioxidant status and lipid peroxidation, in torsion-detorsion injury in rat ovaries. Method: To determine whether ischemia followed by reperfusion can induce ovarian oxidative damage, we created a model of adnexal ischemia-reperfusion by using rats. Ischemia was induced by unilateral occlusion of the tubo-ovarian vessels for 3 h. Reperfusion was achieved by releasing the occlusion and restoring the circulation for 3 h. Thirty-two adult female albino rats were divided equally into 4 groups: sham operation, torsion, saline/detorsion and resveratrol/detorsion. Rats in the torsion group were killed after 360degrees clockwise adnexal torsion for 3 h. Resveratrol was injected intraperitoneally 30 min before detorsion in the resveratrol/detorsion group, and saline was administered in the saline/detorsion group. After 3 h of adnexal detorsion in both of these groups, the rats were killed and adnexa were removed. The tissue levels of malondialdehyde, reduced glutathione and xanthine oxidase activity were measured. Results: Malondialdehyde and xanthine oxidase levels in the saline/detorsion group were increased significantly when compared to the torsion and sham operation groups (p<0.001). Malondialdehyde levels in the resveratrol group were lower than in the saline/detorsion group, and differences between the two groups were statistically significant (p<0.001). Xanthine oxidase levels in the resveratrol group were lower than in the saline/detorsion and torsion groups, and differences between these groups were statistically significant (p<0.001). Reduced glutathione levels in the saline/ detorsion group were decreased significantly when compared to the torsion and sham operation groups. Reduced glutathione levels in the resveratrol group were significantly higher than in the saline/detorsion group (p<0.006). Histological examination showed a significant improvement in ovarian morphology in the resveratrol-treated rats compared with the ischemia and ischemia-reperfusion groups. Conclusion: Our results demonstrated that intraperitoneal resveratrol administration reduced the lipid peroxidation products of ischemic rats and ovarian damage was reduced as indicated by histological examination. Copyright (C) 2004 S. Karger AG, Basel.
Use of caffeic acid phenethyl ester and cortisone may prevent proliferative vitreoretinopathy
(Hindawi Ltd, 2004) Turkoz, Y; Er, H; Borazan, M; Yilmaz, H; Mizrak, B; Parlakpinar, H; Cigremis, Y
PURPOSE: To investigate whether caffeic acid phenethyl ester ( CAPE) and cortisone prevent proliferative vitreoretinopathy (PVR). Methods: Twenty pigmented rabbits were used in this study. All rabbits except controls received an intravitreal injection of 0.15 ml (75,000 U) of platelet-rich plasma into their left eye. The animals were divided into four groups: group I was treated with intraperitoneal injection of 0.5 ml (15 mumol/kg) of CAPE for 3 days, group II received 0.15 ml (4 mg/kg) of intravitreal cortisone, group III received nothing ( blank group), and group IV ( control group) received only 1 ml of 1% ethanol intraperitoneally daily for 3 days. Proliferative changes were graded in a masked fashion by indirect ophthalmoscopy for a 15-day follow-up period. The malondialdehyde (MDA), reduced glutathione (GSH) and total nitrite ( NO) levels were measured in the vitreous humor. Results: The grades of PVR were B - C in group I, and C - D in group II. The PVR grade in the control group was C - D. The mean MDA level in group I (4.0 +/- 0.8 mumol/l) was significantly lower than in the blank group (6.0 mumol/l) (p< 0.05). The mean GSH level in group I (71.0 +/- 11.2 mu mol/l) was significantly different than in the blank group (p< 0.05). The MDA and GSH levels in group II were 4.7 +/- 0.6 mumol/l and 53.8 +/- 7.8 mumol/l, respectively. Both these levels were not significantly different from the blank group (p > 0.05). The NO levels in both treatment groups were significantly lower than in the blank group ( p< 0.001). Conclusion: These findings suggest an inhibitory effect of CAPE on PVR. The inhibitory effect was supported by lower MDA and NO with higher GSH levels in treatment groups than in the blank group. There was no detected significant effect of cortisone for preventing PVR experimentally.

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