Halil Resmi

Diverse glial cell line-derived neurotrophic factor (GDNF) support between mania and schizophrenia: A comparative study in four major psychiatric disorders

BACKGROUND Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) have essential roles in synaptic plasticity which is involved in pathogenesis and treatment of psychiatric disorders. However, it is not clear whether they act simultaneously during illness states in major psychiatric disorders. METHODS BDNF and GDNF serum levels were measured concomitantly by enzyme-linked immunosorbent assay (ELISA) method in 171 patients diagnosed with schizophrenia (n=33), bipolar disorder-manic episode (n=39), bipolar/unipolar depression (n=64, 24/40) and obsessive-compulsive disorder (n=35) according to DSM-IV, and 78 healthy volunteers. SCID-I and SCID non-patient version were used for clinical evaluation of the patients and healthy volunteers, respectively. Correlations between the two trophic factor levels, and illness severity scores, duration of illness and medication dosages were studied across different illnesses. RESULTS While patients had equally lower BDNF levels in all diagnoses, GDNF levels were significantly higher in mania and lower in schizophrenia compared to healthy controls. BDNF levels were negatively correlated to illness severity scores in affective episodes (mania and depression). Longer duration of illness (>5 years) had an impact on lower GDNF levels in schizophrenia. BDNF levels and antipsychotic drug dosages in schizophrenia, and GDNF levels and antidepressant drug dosages in obsessive-compulsive disorder were positively correlated. CONCLUSION Our data confirmed the evidence of equally deficient neuronal support by BDNF in all major psychiatric illnesses, but suggested a diverse glial functioning between schizophrenia and mania.

Alterations in BDNF (brain derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) serum levels in bipolar disorder: The role of lithium

OBJECTIVE Brain-derived neurotrophic factor (BDNF) has been consistently reported to be decreased in mania or depression in bipolar disorders. Evidence suggests that Glial cell line-derived neurotrophic factor (GDNF) has a role in the pathogenesis of mood disorders. Whether GDNF and BDNF act in the same way across different episodes in bipolar disorders is unclear. METHOD BDNF and GDNF serum levels were measured simultaneously by enzyme-linked immunosorbent assay (ELISA) method in 96 patients diagnosed with bipolar disorder according to DSM-IV (37 euthymic, 33 manic, 26 depressed) in comparison to 61 healthy volunteers. SCID- I and SCID-non patient version were used for clinical evaluation of the patients and healthy volunteers respectively. Correlations between the two trophic factor levels, and medication dose, duration and serum levels of lithium or valproate were studied across different episodes of illness. RESULTS Patients had significantly lower BDNF levels during mania and depression compared to euthymic patients and healthy controls. GDNF levels were not distinctive. However GDNF/BDNF ratio was higher in manic state compared to euthymia and healthy controls. Significant negative correlation was observed between BDNF and GDNF levels in euthymic patients. While BDNF levels correlated positively, GDNF levels correlated negatively with lithium levels. Regression analysis confirmed that lithium levels predicted only GDNF levels positively in mania, and negatively in euthymia. LIMITATIONS Small sample size in different episodes and drug-free patients was the limitation of thestudy. CONCLUSION Current data suggests that lithium exerts its therapeutic action by an inverse effect on BDNF and GDNF levels, possibly by up-regulating BDNF and down-regulating GDNF to achieve euthymia.

Effects of repeated administered ghrelin on chronic constriction injury of the sciatic nerve in rats.

Chronic constriction injury (CCI) is a peripheral mononeuropathic pain model that is caused by an injury to the peripheral nervous system and refractory to available conventional treatment. Mechanisms involved in neuropathic pain are still unclear. Previous studies reveal that proinflammatory cytokines contribute to CCI-induced peripheral nerve pathology. Ghrelin, a novel identified gastric peptide, has been shown to have antinociceptive activity and also anti-inflammatory properties by decreasing proinflammatory cytokines. Therefore, the aim of the present study was to investigate the effects of ghrelin on the CCI and its relationship with proinflammatory cytokines in rats. Wistar rats underwent sciatic nerve ligation to induce CCI fallowed by repeated ghrelin administrations (50 and 100microg/kg i.p., once daily) for a period of 14 days. Mechanical hyperalgesia was assessed before surgery and at day 14 after CCI. TNF-alpha, IL-1beta and IL-6 were measured in blood and spinal cord. The changes of sciatic nerve was assessed histologically by both light and electron microscopy. Ghrelin attenuated mechanical hyperalgesia, reduced spinal TNF-alpha and IL-1beta levels and enhanced sciatic nerve injury with correlated morphometric recovery. These results indicate that the protective effect by ghrelin in the spinal cord is mediated through the suppression of TNF-alpha and IL-1beta. Thus ghrelin may be a promising peptide in the management of neuropathic pain.

Toxicity Induced by he Chemical Carcinogen 7,12-Dimethylbenz[a]anthracene and the Protective Effects of Selenium in Wistar Rats

7,12-Dimethylbenz[a]anthracene (DMBA), a polycyclic aromatic hydrocarbon (PAH), has been used extensively as a tool to initiate mammary carcinogenesis and subsequent chemoprevention. On the other hand, selenium (Se) is potentially useful in oncology because this element possesses anticarcinogenic and chemopreventive properties. Se-containing enzymes such as glutathione peroxidase (GPx) play an important role in PAH metabolism and detoxification. In this study, rats were administered a single, oral dose of DMBA (12 mg). In the Se group, rats received 20 µg Se daily via gavage, starting 2 wk before the DMBA administration and continued for 1 wk. One hundred twenty days after DMBA administration the rats were sacrificed and toxicity was evaluated using histopathological and biochemical criteria. Five rats (30%) died in the DMBA group within the study period, whereas no death occurred in the DMBA–Se-treated group. Malignant tumor frequency was 33% in the DMBA group, while no malignant tumors occurred in the DMBA–Se-treated group. Some inflammatory changes rather than epithelial changes were found upon histopathological examination. GPx activity and blood urea nitrogen levels were higher and kidney GST activity was lower in the DMBA–Se-treated group compared to DMBA alone. In conclusion, Se appears to be effective in preventing some of the adverse effects associated with DMBA. This research has been partially carried out at Dokuz Eylul University School of Medicine, Learning Resources Center Research Laboratory (ARLAB). The authors thank Dr. Ali Riza Sisman for his kind contributions and Prof. Dr. Gul Guner and Dr. Sam Kacew for their helpful advice.

Decreased Right Hippocampal Volumes and Neuroprogression Markers in Adolescents with Bipolar Disorder

Objectives: The aim of the present study was to assess differences and correlations between the hippocampal volumes (HCVs), serum nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) levels in adolescents with bipolar disorder (BP) compared to healthy controls. Methods: Using structural magnetic resonance imaging, we compared HCVs of 30 patients with euthymic BP who were already enrolled in a naturalistic clinical follow-up. For comparison, we enrolled 23 healthy controls between the ages of 13 and 19. The boundaries of the hippocampus were outlined manually. The BDNF and NGF serum levels were measured with the sandwich ELISA. Results: The groups did not differ in the right or left HCVs or in the NGF or BDNF serum levels. However, negative correlations were found between the right HCVs and the duration of the disorder and medication and positive correlations were found between the duration of the medications and the NGF and BDNF levels in the patient group. Additionally, positive correlations were found between the follow-up period and left normalized HCVs in both the BP and lithium-treated groups. Conclusions: The right HCVs may vary with illness duration and the medication used to treat BP; NGF and BDNF levels may be affected by long-term usage. Further research is needed to determine whether these variables and their structural correlates are associated with clinical or functional differences between adolescents with BP and healthy controls.

Erythrocyte Deformability and Oxidative Stress in Inflammatory Bowel Disease

BackgroundOxidative stress and reduced microvascular flow are important factors in the pathogenesis of inflammatory bowel disease (IBD). The increased oxidative stress reduces the eriytrocyte deformability. However, in IBD, there are no studies in the literature which evaluate erythrocyte deformability.AimsIn our study, we investigated the effect of oxidative stress and erythrocyte deformability in IBD.MethodsForty-three patients with active IBD, 48 patients with inactive IBD and 45 healthy controls were included. The erytrocyte deformability, malonyldialdehyde levels, glutation peroxidase and sulfhydryl levels were measured in peripheral venous blood samples.ResultsErytrocyte malonyldialdehyde levels in both active and inactive IBD were significantly increased compared with control groups. Plasma glutation peroxidase levels did not show statistically significant difference between all groups. The decreased plasma sulfhydryl levels in active IBD were statistically significant compared with both the inactive IBD and the control group, but plasma sulfhydryl levels in inactive IBD group did not show statistically significant differences when compared with the control group. Elongation index values in both active and inactive IBD increased significantly compared with the control group. Statistically significant correlations were not found between the elongation index and glutation peroxidase, malonyldialdehyde, sulfhydryl levels in all groups.ConclusionsOur study is the first to evaluate the erythrocyte deformability in IBD. In our study, increased erytrocyte malonyldialdehyde levels and decreased plasma sulfhydryl levels manifested the role of oxidative stress in the pathogenesis of the disease. It is thought that the increased erythrocyte malonyldialdehyde values cause the reduction in erythrocyte deformability.

Erythrocyte membrane and cytoskeletal protein glycation and oxidation in short-term diabetic rabbits

Abstract The objective of this study was to elucidate the glycation and oxidation processes in plasma and erythrocyte membrane proteins as well as the major erythrocyte cytoskeletal protein, spectrin, using a short-term experimental rabbit diabetes model. Diabetes was induced with a single-dose alloxan injection. Spectrin was purified from erythrocyte ghosts with selective solubilization followed by gel filtration chromatography techniques, and tested for purity using sodium dodecyl sulfate-poly-acrylamide gel electrophoresis. Glycation in plasma proteins was measured as fructosamin3 using the nitroblue tetrazolium method, and in erythrocyte membrane and purified spectrin, as ketoamine equivalents, by the hydrazine/phenylhydrazine method. Protein oxidation in plasma, erythrocyte membrane proteins, and purified spectrin was evaluated in terms of sulfhydryl oxidation, based on cis-dichlorodiammine platinum (II) binding. Carbonyl formation was also measured in plasma and membrane proteins. Sulfhydryl oxidation, carbonyl groups and glycated protein levels showed statistically significant differences between the diabetic and control groups for both the plasma and the erythrocyte membrane proteins. The cis-dichlorodiammine platinum (II) binding was significantly different in diabetic rabbit erythrocyte spectrin, while glycation was not significantly different for this protein. Our data clearly demonstrate that both protein glycation and oxidation are biochemical alterations occurring in diabetes, even of short duration.

A Preliminary Observation of Increased Glial Cell Line-Derived Neurotrophic Factor in Manic Switch due to Electroconvulsive Treatment in Depressive Patients.

Objective Neurotrophic factors are known to be involved in the pathogenesis of mood disorders. However, the precise neurobiology underlying relapse into depression or switch to mania under antidepressant treatment is not fully understood. Evidence suggests the role of neuroplasticity in these processes. Method Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor (GDNF) serum levels were measured concomitantly during electroconvulsive treatment (ECT) in 30 depressive patients (25 patients with unipolar, 5 with bipolar depression), including those who relapsed into depression (n = 6) or switched to mania (n = 3) within 1 to 4 weeks after the end of the ECT, and in 33 healthy volunteers. Results Despite significant decrease in depression scores, the levels of brain-derived neurotrophic factor did not significantly change during the ECT, also in the patients who relapsed into depression or switched to mania. However, GDNF levels were lower in the ECT responders compared with pre-ECT levels (z = −2.203; P = 0.01) and increased in manic switch compared with the ECT responders (z = −2.761; P = 0.001) (Cohen d = −1.75; effect size r = −0.66) and healthy controls as well (P = 0.044). Conclusions Our data suggest the role of GDNF in manic switch and the involvement of glial system in the pathogenesis of mood disorders.

Correlations between amygdala volumes and serum levels of BDNF and NGF as a neurobiological markerin adolescents with bipolar disorder.

BACKGROUND The amygdala is repeatedly implicated as a critical component of the neurocircuitry regulating emotional valence. Studies have frequently reported reduced amygdala volumes in children and adolescents with bipolar disorder (BD). Brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) play critical roles in growth, differentiation, maintenance, and synaptic plasticity of neuronal systems in adolescent brain development. The aim of the present study was to assess amygdala volumesand its correlation with serum levels of NGF and BDNF in euthymic adolescents with BD and healthy controls. METHODS Using structural MRI, we compared the amygdala volumes of 30 euthymic subjects with BD with 23 healthy control subjects aged between 13 and 19 years during a naturalistic clinical follow-up. The boundaries of the amygdala were outlined manually. Serum BDNF and NGF levels were measured using sandwich-ELISA and compared between the study groups. RESULTS The right or left amygdala volume did not differ between the study groups.The right and left amygdala volumes were highly correlated with levels of BDNF in the combined BD group and the valproate-treated group.Both R and L amygdala volumes were correlated with BDNF levels in healthy controls. The left amygdala volumes were correlated with BDNF levels in the lithium-treated group. LIMITATIONS This cross-sectional study cannot inform longitudinal changes in brain structure. Further studies with larger sample sizes are needed to improve reliability. CONCLUSIONS The correlations between amygdala volumes and BDNF levels might be an early neuromarker for diagnosis and/or treatment response in adolescents with BD.

The combination of bortezomib and resveratrol may prevent muscle wasting in diabetes

Hypercatabolic syndrome is a biochemical state characterized by a imbalance between catabolism and anabolism in favor of catabolism. Diabetes is an example of hypercatabolic syndrome with presence of decreased insulin level or impaired insulin signaling besides increased inflammatory cytokines. One of the significant outcomes of this state is accelerated protein degradation and muscle wasting. Increased ubiquitin-proteasomal system activity is the major responsible for the muscle wasting. Increase in expression and activities of proteasomal proteins in diabetes had been determined. NF-κB transcription factor mediated inflammation and oxidative stress accompanies proteasomal activity increase. Oxidative stress continuously produces substrate for proteasomes by causing protein oxidation. An intervention that inhibits proteasomal activity, suppressing inflammation and oxidative stress may form a solution in order to prevent muscle wasting. Therefore, I am considering that the combined use of bortezomib, a proteasome inhibitor and an anti-inflammatory with resveratrol, an antioxidant and anti-inflammatory, could prevent diabetes induced muscle wasting. This combination may be a novel therapeutic approach for muscle wasting.