Hale Maral Kir

Effects of fluoxetine, tianeptine and olanzapine on unpredictable chronic mild stress-induced depression-like behavior in mice

AIMS Tianeptine is an atypical antidepressant drug that has a different mechanism of action than other antidepressants. Olanzapine is an atypical antipsychotic drug used for the treatment of schizophrenia. The present study was undertaken to investigate effects of chronic administration of tianeptine or olanzapine on unpredictable chronic mild stress (UCMS)-induced depression-like behavior in mice compared to a widely used SSRI antidepressant, fluoxetine. MAIN METHODS Male inbred BALB/c mice were subjected to different kinds of stressors several times a day for 7weeks and were treated intraperitoneally with tianeptine (5mg/kg), olanzapine (2.5mg/kg), fluoxetine (15mg/kg) or vehicle for 5weeks (n=7-8 per group). KEY FINDINGS All the drugs tested prevented stress-induced deficit in coat state during UCMS procedure, in grooming behavior in the splash test, decreased the attack frequency in the resident intruder test and decreased the immobility time in the tail suspension test. In the open field test olanzapine had anxiolytic-like effects in both stressed and non-stressed mice. Tianeptine, olanzapine and fluoxetine decreased the enhanced levels of plasma ACTH and IL-6. Chronic treatment with tianeptine resulted in a significant increase in both total number and density of BrdU-labeled cells in stressed animals, while fluoxetine and olanzapine had a partial effect. SIGNIFICANCE The results of this study support the hypothesis that tianeptine can be as effective as fluoxetine for the treatment of depression in spite of the differences in the mechanism of action of these drugs. Moreover, olanzapine could be used effectively in psychotic patients with depression.

Protective Effects of Increasing Vitamin E and A Doses on Cisplatin-Induced Oxidative Damage to Kidney Tissue in Rats

Objective: Cisplatin (DDP, cis-diamminedichloroplatinium II) is one of the most potent chemotherapeutic antitumor drugs, but is able to generate reactive oxygen species (ROS) and it also inhibits the activity of antioxidant enzymes in renal tissue. In the present study, we investigated the preventive effect of 100, 200 and 400 mg/kg b.w. doses of vitamin E (VE), and 25, 50, and 100 mg/kg b.w. doses of vitamin A (VA) combination on malondialdehyde (MDA), nitric oxide (NO), and glutathione (GSH) levels and superoxide dismutase (SOD) activity in cisplatin-induced toxicity in rat kidneys. Our literature survey indicated a lack of any experimental study showing the beneficial effect of VA on cisplatin-induced MDA, NO, GSH and SOD changes. For this reason, we hoped that this study would provide a unique contribution in that respect. Materials and Methods: 59 Wistar rats (11 to replace prematurely lost animals) were used. 48 evaluable rats were divided into 8 groups (n = 6 in each group): control group, DDP alone (5 mg/kg b.w.) group, 3 VE combination treatment groups of VE100+DDP, VE200+DDP, and VE400+DDP, and 3 VA combination treatment groups of VA25+DDP, VA50+DDP, and VA100+DDP. Kidney MDA, GSH, NO levels and SOD activities were determined for the assessment of oxidant-antioxidant balance. Results: While in the DDP group the tissue levels of MDA and NO were found to be significantly higher than in the control group, GSH levels and SOD activities were significantly lower. MDA and NO levels were found to be significantly lower and GSH levels and SOD activities significantly higher in the VE200+DDP and VE400+ DDP groups when compared with the DDP alone group. MDA and NO levels were found to be significantly lower in the VA50+DDP and VA100+DDP groups when compared with the DDP alone group. However, identical comparisons with the DDP alone group showed significantly higher GSH levels and SOD activities in the VA25+DDP, VA50+DDP, and VA100+DDP groups. Among the VE100+ DDP, VE200+DDP, and VE400+DDP groups, and VA25+ DDP, VA50+DDP, and VA100+DDP groups, MDA and NO levels decreased and GSH levels and SOD activities increased steadily and significantly as the doses of VE and VA increased. Conclusion: These vitamins would be effective in protecting against cisplatin-induced tissue damage in rat kidneys. It is possible that the toxic effect of cisplatin is somehow minimized by a compensatory mechanism involving VE and VA via induction of antioxidant enzyme activities following intraperitoneal injection of DDP.

Depressive Symptoms and Proinflammatory Cytokine Levels in Chronic Renal Failure Patients

Background/Aims: Cytokine secretion is known to play an important role in the pathophysiology of depression, and levels of proinflammatory cytokines are increased in chronic renal failure (CRF) patients. The objective of this study was to examine the correlation between levels of proinflammatory cytokines in CRF patients and degree of depression. Methods: 31 patients on hemodialysis, 31 patients on continuous ambulatory peritoneal dialysis, and 31 conservatively managed chronic kidney disease (CKD) patients were enrolled in this study. Depressive symptoms were measured with the Beck Depression Inventory (BDI), and ‘elevated symptoms of depression’ were defined as a BDI score ≧17. IL-6 and TNFα cytokine levels were measured by ELISA. Results: ‘Elevated symptoms of depression’ occurred in 37 of 93 patients (40%). IL-6 and TNFα levels were not significantly different among CRF patients with and without elevated depressive symptoms (p = 0.937 and p = 0.414, respectively). When analyzed by treatment subgroup, proinflammatory cytokine levels were not significantly different in patients with and without elevated symptoms of depression. Conclusion: In patients with CRF, elevated symptoms of depression were not associated with increased cytokine levels.

Effect of pentylenetetrazole and sound stimulation induced single and repeated convulsive seizures on the MDA, GSH and NO levels, and SOD activities in rat liver and kidney tissues

OBJECTIVES the aim of our study was to evaluate the activity of superoxide dismutase (SOD) and the levels of glutathione (GSH), malondialdehyde (MDA), and nitric oxide (NO) in liver and kidney tissues in a rat model of convulsive seizure induced by single and repeated doses of pentylenetetrazole (PTZ) and sound stimulation with key ringing. MATERIALS AND METHODS male Wistar adult rats (n=48), were used in the experiment. The animals were divided into six groups: (1) Single Seizure Control Group (SS-Control; n=8), (2) Repeated Seizures Control Group (RS-Control; n=8), (3) PTZ induced Single Seizure Group (SS-PTZ Group; n=8), (4) PTZ induced Repeated Seizures Group (RS- PTZ Group; n=8), (5) Key-Ringing Induced Single Seizure Group (SS-KEY Group; n=8), (6) Key-Ringing Induced Repeated Seizures Group (RS-KEY Group; n=8). Following injections rats were observed for seizure activity for 30 min. Animals were sacrificed 24h after induced seizure (single or last seizure) or saline administration. MDA, NO, GSH levels and SOD activities were determined in liver and kidney tissues. RESULTS there was no significant difference between SS-Control and RS-Control groups, SS-PTZ and SS-KEY groups, and RS-PTZ and RS-KEY groups (p>0.05) in none of the examined 4 parameters in liver and kidney tissues. The liver and kidney levels of MDA and NO in SS-PTZ group were found to be significantly higher than the SS-Control group (p<0.05). In SS-KEY group, the liver and kidney levels of MDA and NO were found to be significantly higher and GSH levels were significantly lower than the SS-Control group (p<0.05). While liver and kidney levels of MDA in RS-PTZ group and RS-KEY group were found to be significantly higher than the RS-Control group (p<0.05), liver and kidney GSH levels were significantly lower (p<0.05). The liver levels of NO in RS-PTZ group and RS-KEY group were found to be significantly higher than the RS-Control group (p<0.05). Kidney SOD activities in RS-PTZ group and RS-KEY group were found to be significantly lower than the RS-Control group (p<0.05). When RS-PTZ group is compared with the SS-PTZ group, the liver SOD activity and kidney NO level were found to be significantly lower in the RS-PTZ group (p<0.05). While the liver NO level and GSH level in RS-KEY group were significantly higher than the SS-KEY group, SOD activity was significantly lower in the RS-KEY group (p<0.05). When RS-KEY group was compared with SS-KEY group, the kidney NO level and SOD activity were found to be significantly lower in the RS-KEY group (p<0.05). CONCLUSION in conclusion, key-ringing or PTZ induced single and repeated seizures result in increased oxidative damage and lipid peroxidation, and decreased antioxidant defense mechanisms.

Adipocytokines Leptin and Adiponectin, and Measures of Malnutrition-Inflammation in Chronic Renal Failure: Is There a Relationship?

BACKGROUND Serum levels of adipocytokines such as leptin and adiponectin are significantly elevated in patients with chronic renal failure (CRF). The effect of such adipocytokines on malnutrition in the CRF population has been of substantial interest. We sought to determine the relationship between plasma leptin and adiponectin levels and malnutrition-inflammation status in end-stage renal disease patients. METHODS Thirty patients (15 women and 15 men; mean [+/-SD] age, 50 +/- 14 years) on hemodialysis, and 30 patients (12 women and 18 men; mean [+/-SD] age, 47 +/- 16) on continuous ambulatory peritoneal dialysis, were enrolled in this study. Adipocytokine levels were measured by enzyme-linked immunosorbent assay. Inflammatory markers, such as high-sensitivity serum C-reactive protein (hs-CRP), ferritin, and a nutritional inflammatory scoring system known as the malnutrition-inflammation score (MIS), were also measured in all patients. RESULTS Serum leptin had negative correlations with ferritin (r = -0.33, P = .016) and MIS (r = -0.39, P = .003). Adiponectin had a weak positive correlation with MIS (r = 0.26, P = .050), indicating that an increased level of serum adiponectin was associated with a worse nutritional status. Levels of hs-CRP, serum albumin, cholesterol, and triglycerides did not correlate with nutritional status. CONCLUSIONS Serum leptin concentration seems to be a marker of good nutritional status, rather than an appetite-suppressing uremic toxin, in patients with CRF. However, the positive correlation between serum adiponectin and worse nutritional-inflammatory status suggests that elevated adiponectin levels may contribute to the pathogenesis of malnutrition in such patients.

Serum fetuin-A concentrations are inversely related to cytokine concentrations in patients with chronic renal failure

BACKGROUND/AIMS A close relationship exists between inflammation and vascular calcification. Although fetuin-A is known to be an inhibitor of calcification, studies correlating levels of this glycoprotein to markers of inflammation are limited. To understand these relationships, we investigated the relationship between serum fetuin-A and proinflammatory cytokine levels in patients with chronic renal failure (CRF). METHODS Thirty-two patients on haemodialysis (HD), 32 conservatively managed chronic kidney disease (CKD) patients and a control group of 25 subjects with normal renal function were enrolled in this study. Serum fetuin-A, IL-1beta, IL-6 and TNF-alpha levels were measured by ELISA. Correlations between serum fetuin-A and IL-1beta, IL-6 and TNF-alpha concentrations were investigated by the Spearman correlation test. RESULTS In 64 CRF patients (on HD and with CKD), serum fetuin-A was significantly and inversely related to IL-1beta (P<0.001), IL-6 (P=0.025) and TNF-alpha levels (P=0.007), respectively. The serum fetuin-A levels of the control subjects were not significantly correlated to levels of the inflammatory markers IL-1beta, IL-6 and TNF-alpha (P=0.551, 0.985 and 0.984, respectively). CONCLUSION The negative correlation between serum fetuin-A and cytokine concentrations in CRF patients supports the hypothesis of inflammation-dependent down-regulation of fetuin-A expression.

Effects of Vitamins E, A and D on MDA, GSH, NO Levels and SOD Activities in 5/6 Nephrectomized Rats

Background: Excessive generation of reactive oxygen species (ROS) contributes to the process of progressive renal injury in a variety of clinical and experimental renal diseases. The present study was designed to test the hypothesis that treatment with vitamins decreases renal injury in chronic renal failure (CRF). Methods: Forty male Sprague-Dawley rats were divided into 5 groups: group 1, control; group 2, 5/6 nephrectomy (CRF); other groups 5/6 nephrectomy and injected vitamins (E, A, D). After 8 weeks, urea, creatinine and renal tissue malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO) levels and superoxide dismutase (SOD) activities were determined. Results: Renal tissue MDA levels were significantly lower in the control and Vit E groups compared to that of the CRF, Vit A and Vit D groups. GSH levels were significantly higher in the control group compared to that of other groups. However, GSH levels were significantly lower in the control group than those in the other groups. SOD activities of the control group were significantly higher than those in the other groups. SOD activities were significantly decreased in the Vit E group compared to the Vit A and Vit D groups. Tissue NO levels of control group were significantly increased compared to the other groups. Conclusion: According to this study, Vit E may at least in part prevent tissue injury by acting as a free radical scavenger.

The relationship between brain-derived neurotrophic factor levels, oxidative and nitrosative stress and depressive symptoms: a study on peritoneal dialysis.

Abstract Background: Depression is one of the most commonly encountered psychiatric problems in peritoneal dialysis (PD) patients. Our aim was to investigate the associations between oxidative and nitrosative stress (O&NS) and brain-derived neurotrophic factor (BDNF) in PD patients with elevated depressive symptoms (EDS). Methods: Eighty-three patients with PD and 84 healthy controls were enrolled in this study. In PD patients, two subgroups were formed: 28 with and 55 without EDS. EDS were defined as a Beck Depression Inventory (BDI) score ≥17 in patients. Serum malondialdehyde (MDA) erythrocyte, glutathione (GSH) levels measured spectrophotometrically. Serum superoxide dismutase (SOD) activity, nitric oxide (NO) and BDNF levels were determined by ELISA. Results: While MDA and NO levels were higher, levels of SOD, GSH and BDNF were lower in PD patients compared to controls (p < 0.001). The patients with EDS had higher levels of MDA and lower levels of BDNF as compared to those without EDS (p < 0.005). In linear regression analysis, the BDNF levels were dependently associated with SOD levels in PD patients (B: 0.274, p: 0.043). In addition, while a negative correlation existed between BDI scores with BDNF levels (r = –0.312, p = 0.004), a positive correlation was present between BDI scores and MDA levels (r = 0.320, p = 0.005) in PD patients. Conclusion: Our results suggest the presence of high O&NS and low antioxidant capacity accompanied with decreased levels of BDNF in PD patients, especially those with EDS were deeper. These may represent the risk factors for cellular injury and might reveal part of the mechanism causing the depressive state in PD patients.

The effects of vagal nerve stimulation in focal cerebral ischemia and reperfusion model.

AIM This study aimed to investigate the effects of VNS in transient middle cerebral artery occlusion and reperfusion (MCAO/R) rat model of ischemia based on behavioral, morphological, and molecular approaches. MATERIAL AND METHODS Wistar albino rats were divided into 3 groups: ischemia-reperfusion (I/R), I/R+VNS, and sham (for I/R). Each group was further divided into two subgroups for the assessment of neurological deficits and infarct area, or biochemical parameters related to oxidative stress. RESULTS The infarct area and neurological scores were significantly lower in I/R+VNS group compared with the I/R group. MDA levels were significantly higher in I/R group compared to control and I/R+VNS groups in the cortical and subcortical specimens. There were also betweengroup differences in terms of GSH levels. GSH levels were higher in sham group compared with and I/R and I/R+VNS groups in cortical specimens whereas these levels for lower in I/R group compared to control and I/R+VNS groups in the subcortical specimens. SOD activity was higher in control group compared to I/R and I/R+VNS groups both in the cortical and subcortical specimens. There was no difference between I/R and I/R+VNS groups in neither cortical nor subcortical specimens. CONCLUSION The neuroprotective and antioxidant properties of VNS suggest its efficacy as a potential anti-ischemic treatment.

The effect of leptin, ghrelin, and neuropeptide-Y on serum Tnf-Α, Il-1β, Il-6, Fgf-2, galanin levels and oxidative stress in an experimental generalized convulsive seizure model

The objective of this study is to examine the effects of the endogenous ligands leptin, ghrelin, and neuropeptide Y (NPY) on seizure generation, the oxidant/antioxidant balance, and cytokine levels, which are a result of immune response in a convulsive seizure model. With this goal, Wistar rats were divided into 5 groups-Group 1: Saline, Group 2: Saline+PTZ (65mg/kg), Group 3: leptin (4mg/kg)+PTZ, Group 4: ghrelin (80μg/kg)+PTZ, and Group 5: NPY (60μg/kg)+PTZ. All injections were delivered intraperitoneally, and simultaneous electroencephalography (EEG) records were obtained. Seizure activity was scored by observing seizure behavior, and the onset time, latency, and seizure duration were determined according to the EEG records. At the end of the experiments, blood samples were obtained in all groups to assess the serum TNF-α, IL-1β, IL-6, FGF-2, galanin, nitric oxide (NOֹ), malondialdehyde (MDA), and glutathione (GSH) levels. The electrophysiological and biochemical findings (p<0.05) of this study show that all three peptides have anticonvulsant effects in the pentylenetetrazol (PTZ)-induced generalized tonic-clonic convulsive seizure model. The reduction of the levels of the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 caused by leptin, ghrelin, and NPY shows that these peptides may have anti-inflammatory effects in epileptic seizures. Also, leptin significantly increases the serum levels of the endogenous anticonvulsive agent galanin. The fact that each one of these endogenous peptides reduces the levels of MDA and increases the serum levels of GSH leads to the belief that they may have protective effects against oxidative damage that is thought to play a role in the pathogenesis of epilepsy. Our study contributes to the clarification of the role of these peptides in the brain in seizure-induced oxidative stress and immune system physiology and also presents new approaches to the etiology and treatment of tendency to epileptic seizures.