Ramazan Yigitoglu

Pentylenetetrazol-induced kindling seizure attenuated by Ginkgo biloba extract (EGb 761) in mice

Ginkgo biloba extract (EGb 761) has been used therapeutically for centuries. It has attracted great attention as agents for improving circulation, particularly cerebral circulation, which may lead to improved mental function. Many researches hypothesized on the role of the extract in the treatment of diseases involving free radicals and oxidative damage. In the present study, anticonvulsant and antioxidant effects of EGb 761 were investigated in pentylenetetrazol (PTZ)-kindled mice. Valproic acid (VA), a major antiepileptic drug, was also tested for comparison. EGb 761-treated mice displayed a significant attenuated response to PTZ on the test day (day 26) compared with saline-treated and VA-treated animals. Valproic acid significantly increased seizure latency. Pretreatments with EGb 761 significantly protected against PTZ-induced convulsive behaviors (seizure latency, seizure score). EGb 761 and VA significantly decreased PTZ-induced oxidative injury in brain tissue. EGb 761 was found to be the most effective in preventing PTZ-induced oxidative damage among both substances studied. The data obtained support our speculation that neuroprotective action of EGb 761 may correlate with its ability to inhibit not only excessive reactive oxygen species (ROS) formation but also seizure generation. Taken together, the results of the present study show that the effect of EGb 761 on ROS production contributes to their neuroprotective action. It might be concluded that the suppression of seizure-induced ROS generation may be involved in the mechanism of action of antiepileptic drugs.

Use of melatonin to prevent selenite-induced cataract formation in rat eyes.

Purpose: To evaluate effects of melatonin on sodium selenite-induced cataract formation. Methods: Twenty-three Sprague-Dawley rat pups were randomized into three groups. Group 1(n = 9), injected with selenite (s.c.) on postpartum day 10; group 2 (n = 7), injected with selenite (s.c.) on day 10 plus melatonin (i.p.) on days 8–15; group 3 (n = 7), saline-injected controls. Development of cataract was assessed weekly under a dissection microscope. Rat lenses and serums were analyzed for antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT); oxidative stress indicators xanthine oxidase (XO) and malondialdehyde (MDA), a marker of lipid peroxidation; and protein carbonyl (PC), a marker of protein oxidation. Results: Significant differences (p < 0.05) were seen in cataract development by the three groups. All rats developed dense nuclear cataract in group 1. Dense nuclear cataract was not observed in group 2: five of seven rats developed minor cataracts, while the other two had clear lenses. In control rats (group 3), all lenses remained clear. In selenite group (group 1), lens and serum levels of MDA, PC, and XO were significantly higher and levels of SOD and CAT were significantly lower than those in control group (p < 0.001). In selenite+melatonin group (group 2), lens and serum levels of MDA, PC, and XO significantly decreased and levels of SOD and CAT significantly increased when compared with selenite group. Conclusions: Studies with the rat selenite cataract model strongly support the activity of melatonin as an endogenous antioxidant and anticataract agent.

Oxidative Stress and Protein Oxidation in Pseudoexfoliation Syndrome

Purpose: To investigate the oxidant/antioxidant status and protein oxidation in pseudoexfoliation syndrome. Methods: The activity of serum superoxide dismutase (SOD) and the levels of serum malondialdehyde (MDA) and protein carbonyl (PC) were measured in 50 patients with pseudoexfoliation (PEX) and in 55 healthy controls. Results: There was significant difference in the SOD activity in PEX group compared with the control group (p < 0.001). In addition, MDA and PC levels were significantly higher in patients than in the controls (p < 0.001). Conclusions: Decrease in SOD activity and the higher levels of MDA and PC indicate increased oxidative stress. Our results suggest a possible role of oxidative stress in pathology of PEX syndrome.

Influence of Obstructive Sleep Apnea on Fatty Liver Disease: Role of Chronic Intermittent Hypoxia

BACKGROUND: Currently the common pathogenetic mechanisms in nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA) are gaining increased attention. The aim of this study is to find out the influence of chronic intermittent hypoxemia and OSA related parameters to the severity of NAFLD. METHODS: We examined the liver functions tests and ultrasonographic data of liver as well as markers of OSA severity (apnea-hypopnea index [AHI], oxygen desaturation index, minimum oxygen saturation, percentage of time spent with SpO2 < 90%) of 106 subjects. RESULTS: Fatty liver disease was diagnosed in 71 subjects (group 1), and the remaining 35 subjects were taken as controls (group 2). The prevalence of OSA was 71.2% versus 35.7% for group 1 and 2, respectively (P < .001). As NAFLD severity increased from mild to severe form, mean AHI and oxygen desaturation index values also increased significantly. Our multivariate analysis showed that AHI, oxygen desaturation index, lowest desaturation values, and percentage of sleep duration with SpO2 < 90% were independent predictors of NAFLD after adjustment for BMI, weight, and insulin resistance. Furthermore, the most correlated parameter for the severity of NAFLD was found as the duration of hypoxia during sleep. CONCLUSIONS: The prevalence of NAFLD was higher in patients with severe OSA, suggesting a role for nocturnal hypoxemia in the pathogenesis of fatty liver disease.

Relation between Serum Thyroid Hormone and ‘Nondipper’ Circadian Blood Pressure Variability

Currently, the pathogenesis of nondipper hypertension remains largely unclear in patients without any renal or endocrine pathology. It is well known that overt hypothyroidism is strongly associated with diastolic hypertension. However, no study has addressed the pathogenic role of TSH, free T3 (FT3), and free T4 (FT4) in nondipper hypertension. The aim of the present investigation is to evaluate if higher TSH, low FT3 and FT4 would be associated with a nondipper hypertension profile, in patients with normal renal function and without any overt thyroid hormone disorder. 131 subjects were screened and those who met the following inclusion criteria were enrolled: (1) glomerular filtration rate (GFR) >60 ml/min; (2) no history of thyroid disorders; (3) no history of thyroid hormone medication. All subjects underwent 24-hour ambulatory blood pressure monitoring on a usual working day. Of the total population, 59 patients (45%) were classified as dippers and 72 (55%) were classified as nondippers. The only significant differences between dipper and nondipper patients appear to be related to FT3 levels and GFR. Nondipper patients had lower FT3 levels (4.5 ± 0.6 vs. 4.0 ± 0.9 pmol/l, p = 0.02) and low GFR (80.5 ± 12.2 vs. 86.9 ± 16.9 ml/min, p = 0.03), compared to dipper patients. The final regression model included serum TSH, FT3 levels, and GFR; the only independent predictor of nondipper hypertension was FT3 (p = 0.04). In conclusion, even if the mechanisms of our findings remain incompletely understood, we demonstrate a graded independent relation between lower level of FT3 and the risk of nondipping. Further studies are warranted to confirm this relationship and to elucidate the pathogenetic mechanisms of this relationship.

Comparison of effects of darbepoetin alfa and epoetin alfa on serum endothelin level and blood pressure.

It is well known that epoetin alfa increases serum endothelin (ET)-1 and blood pressure. No data are available, however, on the effects of darbepoetin alfa on serum ET-1 and blood pressure. This study was conducted to compare the effects of darbepoetin alfa and epoetin alfa on serum ET-1 and blood pressure in patients on hemodialysis (HD). A total of 42 patients on HD were included in the study. Serum samples for measuring levels of ET-1 were taken 30 min after administration of epoetin alfa. After blood samples had been taken from all patients, epoetin alfa was changed to darbepoetin alfa. Three months after the start of darbepoetin alfa treatment, blood samples were taken to measure the same parameters. Mean arterial blood pressure was measured before recombinant human erythropoietin (EPO) administration and 30 min after EPO administration while patients were taking epoetin alfa or darbepoetin alfa. Injection of epoetin alfa or darbepoetin alfa significantly increased serum ET-1 levels compared with levels in those patients who were not on EPO therapy (P < .05). When the effects of epoetin alfa on serum ET-1 level were compared with those of darbepoetin alfa, the 2 types of EPO were found to increase serum ET-1 levels similarly (P > .05). Administration of epoetin alfa or darbepoetin alfa increased systolic and diastolic blood pressures significantly over values in the control group (P < .05). Serum systolic and diastolic blood pressures increased similarly after injection of epoetin alfa or darbepoetin alfa. Administration of darbepoetin alfa increased blood pressure in patients on HD in a way that was positively correlated with enhanced ET-1 release; a similar correlation was noted with epoetin alfa.

Relation between Serum Calcium, Phosphate, Parathyroid Hormone and ‘Nondipper’ Circadian Blood Pressure Variability Profile in Patients with Normal Renal Function

Background and Aims: In patients with renal disease, an association between abnormal circadian blood pressure profile and abnormalities in bone and mineral metabolism, including vascular calcifications, is well known. However, such a link has not yet been reported in hypertensive patients with normal renal function. We aimed to evaluate if higher serum phosphate, calcium, parathyroid hormone (PTH) level and the calcium×phosphate (Ca×P) product would be associated with a nondipper hypertension, in patients with normal renal function and without any PTH disorder. Methods: 190 hypertensive subjects with the following inclusion criteria were enrolled: (1) normal phosphate and PTH levels; (2) glomerular filtration rate (GFR) >60 ml/min, and (3) no history of calcium, phosphate, vitamin D medication and hyperparathyroidism. Results: Of the total population, 76 patients (40%) were classified as dippers and 114 (60%) as nondippers. Nondipper patients had higher levels of phosphate (3.70 ± 0.61 vs. 3.35 ± 0.44 mg/dl, p = 0.001), Ca×P product (35.4 ± 6.5 vs. 31.5 ± 5.0, p = 0.001) and PTH (75.7 ± 28.8 vs. 46.6 ± 17.1 pg/ml, p = 0.000) compared to dipper patients. Independent predictors (multiple regression) for nondipper hypertension were PTH (β = 0.43, p = 0.001) and phosphate (β = 0.9, p = 0.03). Conclusion: We demonstrate a graded independent relation between higher levels of phosphate, PTH, Ca×P product and the risk of nondipping in hypertensive patients with an estimated GFR of >60 ml/min and normal mineral metabolism.

Prevention of Selenite-Induced Cataractogenesis by N-Acetylcysteine in Rats

Purpose: To evaluate the effect of N-acetylcysteine on selenite-induced cataract formation in a rat model. Materials and Methods: Thirty-four Sprague-Dawley rat pups were divided into three groups. Eight pups received only selenite on postpartum day 10 (group 1), 14 pups received selenite on day 10 and additional acetylcysteine on postnatal days 9 to 15 (group 2), and 12 pups received only saline (group 3, control). All pups were daily examined for the presence of cataract under the microscope, starting from the day their eyes opened. Glutathione and malondialdehyde levels were evaluated in both serum and lenticular samples while protein carbonyl level was studied only in lenticular samples. Results: In group 1, 50% of the rats developed dense nuclear opacities and 50% developed slight nuclear opacities, while in group 2 only 14.3% developed dense nuclear opacities and 21.4% developed slight nuclear opacities (p < 0.05). None of the rats in group 3 developed any lens opacity. In lenticular samples, mean glutathione level was statistically lower in group 1 compared to groups 2 and 3 (p < 0.05), while malondialdehyde and protein carbonyl levels were both statistically higher in group 1 compared to groups 2 and 3 (p < 0.05). Serum level of glutathione was statistically lower in group 1 compared to groups 2 and 3 (p < 0.05), while serum malondialdehyde level was statistically lower in group 3 compared to groups 1 and 2. Conclusions: N-acetylcysteine appears to inhibit selenite-induced cataractogenesis in the rat model, and this seems to be caused by the prevention of oxidative damage.

Dose-dependent protective effect of L-carnitine on oxidative stress in the livers of hyperthyroid rats.

OBJECTIVE The present study was designed to investigate the dose-dependent protective effect of L-carnitine (LC) on thyroid hormone-induced oxidative stress in rat liver tissue. MATERIALS AND METHODS Twenty-one male Sprague Dawley rats were divided into four groups: control, hyperthyroidism, hyperthyroidism plus L-carnitine 100, and hyperthyroidism plus L-carnitine 500. Hyperthyroidism was induced in rats by injecting 250 μg of L-thyroxine/kg body weight/day for twenty consecutive days. The activities of catalase (CAT), glutathione peroxidase (GPX) and myeloperoxidase (MPO) and the level of malondialdehyde (MDA) were measured in liver homogenates. RESULTS The liver CAT, GPX and MPO activities were significantly lower in the hyperthyroid rats than in the control group. Treating hyperthyroid rats with both low-dose (100 mg/kg) and high-dose (500 mg/kg) L-carnitine for 10 days resulted in a marked increase in the activities of the antioxidant enzymes in the liver tissue. CONCLUSION The present study indicates that the low-dose L-carnitine application was sufficient to prevent L-thyroxine-induced oxidative stress in rat livers.

NITRIC OXIDE AFFECTS SERUM FERRITIN LEVELS IN CHILDREN WITH IRON DEFICIENCY

In iron deficiency, serum levels of ferritin decrease. The lack of iron has been thought to be the main factor in this decrease, but another potential factor is nitric oxide, which has been shown to affect ferritin metabolism in vitro. The aim of this study was therefore to evaluate in children with iron deficiency the relation of serum ferritin, nitric oxide degradation products (nitrate and nitrite), and endothelin-1, a protein closely related to nitric oxide function. A total of 80 children were included in the study (39 with iron deficiency, 41 controls). Serum levels of ferritin, nitrate, nitrite, and endothelin-1 were measured in all participants. In children with iron deficiency, nitrate and nitrite levels were significantly higher (p <. 009 and. 01, respectively). Also, serum ferritin was negatively correlated with serum levels of nitrate and nitrite (p =. 034, r = −.254 for nitrate and p =. 01, r = −.593 for nitrite). No statistical relationship was found between serum ferritin and endothelin-1.