Matthias L. Schroeter

Serum markers support disease-specific glial pathology in major depression

BACKGROUND Recently, it was shown by histopathological studies that mood disorders are characterized by disease-specific glial pathology. METHODS To validate this hypothesis in vivo we measured weekly and simultaneously serum levels of the neuronal marker neuron-specific enolase and S100B, a protein expressed in astro- and oligodendroglia in the human brain, in 10 patients with major depressive disorder and 10 age- and gender-matched control subjects. Furthermore, we conducted a systematic, quantitative meta-analysis of all published studies on S100B involving 193 patients suffering from mood disorders and 132 healthy control subjects by calculating effect sizes. RESULTS S100B was elevated at admission and discharge in our patients with major depression compared with control subjects, whereas there were no significant differences for neuron-specific enolase. During treatment S100B decreased slightly, although this effect was not significant. It had no significant impact on neuron-specific enolase. The meta-analysis revealed that serum levels of S100B are consistently elevated in mood disorders during acute major depressive or manic episodes. Additionally, it demonstrated that serum S100B decreases during antidepressive treatment reliably if clinical improvement is sufficient. LIMITATIONS As the study measured only serum S100B, future (cell culture) studies have to elucidate molecular mechanisms of this protein in mood disorders. Moreover, results have to be replicated in a larger patient group. CONCLUSIONS S100B may represent a biomarker for mood disorders, particularly major depression, and their treatment. Together with unaltered levels of neuron-specific enolase, our results support in vivo the histopathologically generated hypothesis of disease-specific glial pathology in mood disorders.

S100B is increased in mood disorders and may be reduced by antidepressive treatment

Previous studies have reported alterations of glial cells and particularly astrocytes in mood disorders. Therefore, serum concentration of the astrocytic marker S100B was ascertained with an immunoluminometric assay in 20 patients with mood disorder and 12 healthy age-matched controls. Serum S100B was elevated in major depression (median after admission 410 ng/l, at discharge < 100 ng/l) and mania (130, 160 ng/l), when compared with controls (< 100 ng/l; p < 0.01). Antidepressive treatment reduced S100B in conjunction with severity of depressive symptoms (p < 0.01). The severity of depression (Hamilton Depression Rating Scale) was positively correlated with S100B (rs = 0.51, p < 0.005). Elevated serum S100B during depressive and manic episodes of mood disorders may indicate alterations of astrocytes, which are reversed by antidepressive treatment.

Astrocytes enhance radical defence in capillary endothelial cells constituting the blood-brain barrier.

Astrocytes (AC) induce blood‐brain barrier (BBB) properties in brain endothelial cells (EC). As antioxidative activity (AOA) is assumed to be a BBB characteristic, we tested whether AC improve AOA of EC. Monocultivated AC showed higher AOA [manganese superoxide dismutase (SOD), catalase (Cat), glutathione peroxidase (GPx)] than EC. Cocultivation elevated AOA in EC (MnSOD, CuZnSOD, Cat, GPx), and AC (MnSOD, CuZnSOD, GPx). Hypoxia increased radical‐induced membrane lipid peroxidation in monocultivated, but not in cocultivated EC. Thus, EC/AC cocultivation intensifies AOA in both cell types, protects the EC, and therefore, the BBB against oxidative stress. The high AOA is regarded as an essential property of the BBB, which is induced by AC.

Effects of oxidative stress on the expression of antioxidative defense enzymes in spontaneously hypertensive rat hearts

Little is known concerning the effect of oxidative stress on the expression of antioxidative enzymes in the decompensated cardiac hypertrophy of spontaneously hypertensive rats (SHR), considered as a model of dilative cardiomyopathy in man. Superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) were characterized in isolated perfused hearts of 18 month old SHR and the age-matched normotensive control Wistar-Kyoto (WKY) rats, before and after 30 min infusion of 25 microM H(2)O(2). After infusion of H(2)O(2), aortic flow decreased in WKY from 26.2 +/- 2.2 to 16.0 +/- 0.8 ml/min (p <.05) but not in SHR (18.2 +/- 1.9 vs. 20.7 +/- 2.2 ml/min). This protection was related to the higher myocardial activities of GPx, MnSOD and CuZnSOD in SHR, compared with those of the WKY group. Although total SOD activity in the SHR fell after H(2)O(2) exposure (to 1.81 +/- 0.13 from 3.56 +/- 0.49 U/mg of protein), catalase activity increased (to 2.46 +/- 0.34 from 1.56 +/- 0.29 k min(-1)mg(-1)protein), compared with the pre-infusion period (p <.05 in each case). In additional studies, hearts were subjected to 30 min of global ischemia followed by 30 min of reperfusion. The results obtained in ischemic/reperfused hearts show the same changes in enzyme activities measured as it was observed in H(2)O(2) perfused hearts, indicating that oxidative stress is independent of the way it was induced. The higher catalase activity derived from elevated mRNA synthesis. The antioxidative system in dilative cardiomyopathic hearts of SHR is induced, probably due to episodes of oxidative stress, during the process of decompensation. This conditioning of the antioxidative potential may help overcome acute stress situations caused by reactive oxygen species in the failing myocardium.

S100B serum levels are closely correlated with body mass index: an important caveat in neuropsychiatric research.

Elevated blood levels of S100B in neuropsychiatric disorders have so far been mainly attributed to glial pathologies. However, increases or dysfunction of adipose tissue may be alternatively responsible. Our study assessed S100B serum levels in 60 adult subjects without a prior history of neuropsychiatric disorders. S100B concentrations were closely correlated with the body mass index (BMI, range 18-45 kg/m(2)) as well as levels of leptin and adipocyte-type fatty acid-binding protein (A-FABP/FABP4) that are well-known adipose-related factors. Effect sizes as measured by Cohens d indicated medium (0.8 > d > 0.5) to strong effects (d > 0.9) of BMI on S100B blood levels. In conclusion, physiological S100B levels in humans appear to closely reflect adipose tissue mass, which should therefore be considered as an important confounding factor in clinical studies examining the role of S100B.

Elevated serum levels of the glial marker protein S100B are not specific for schizophrenia or mood disorders

Elevated serum levels of the glial marker protein S100B are not specific for schizophrenia or mood disorders

Elevated S100B levels in schizophrenia are associated with insulin resistance.

Several studies have shown that circulating S100B protein levels are elevated in schizophrenia. This finding has been specifically attributed to glial pathology, as S100B is produced by astroand oligodendroglial cells and is thought to act as a neurotrophic factor with effects on synaptogenesis, dopaminergic and glutamatergic neutrotransmission. However, this study suggests that overweight and insulin resistance may be alternatively responsible. Adipose tissue has already been highlighted by others as an important extracerebral source of S100B, as it contains considerable amounts of S100B. S100B secretion from adipocytes is reduced by insulin and is activated by physiological factors such as stress and fasting. Therefore, weight gain or adipocyte dysfunction, including insulin insensitivity, could offer important alternative explanations for elevated S100B levels, given the increased prevalence of metabolic syndrome in schizophrenic patients and their firstdegree relatives. The assumption of such extracerebral origins of altered S100B levels in schizophrenia is challenged by findings of elevated S100B in cerebrospinal fluid and postmortem brain tissue. However, glial abnormalities in S100B release may also be caused by disrupted energy supply, as suggested by earlier cell culture studies. Accordingly, impaired insulin signaling has been observed in the dorsolateral prefrontal cortex of schizophrenic patients. Consequently, altered peripheral and cerebral glucose usage is an important factor to be studied to clarify its relation to S100B in schizophrenia. Our study thus assessed S100B in both medicated and drug-free schizophrenic patients, along with body mass index (BMI), measures of glucose usage and adipokine levels. After obtaining written informed consent, serum samples were taken from 26 patients with acute paranoid schizophrenia (according to DSM-IV, 17 men/9 women, age 34.7±11.3 years, BMI 27.7±5.7, 16 smokers/10 nonsmokers) and from 32 matched controls (20 men/12 women, age 34.4±10.8, BMI 24.3±3.8, 14 smokers/18 nonsmokers). Eleven patients were unmedicated for X6 weeks; 15 were treated with atypical antipsychotics for 26±21 days. Psychopathology was monitored using the positive and negative syndrome scale. Exclusion criteria consisted of an earlier history of immune diseases, immunomodulating treatment, cancer, chronic terminal disease, cardiovascular disorders, diabetes, substance abuse and severe trauma. Only control cases without a past or family history of neuropsychiatric disorders were included. Blood was collected between 9:00 and 11:00 AM. S100B was measured immunoluminometrically (LIAISON S100, DiaSorin, Dietzenbach, Germany). LINCOplex human adipokine panels A and B (Millipore Corporation, Billerica, MA, USA) were used for the determination of leptin, monocyte chemotactic protein 1, hepatocyte growth factor (HGF), resistin and active plasminogen activator inhibitor 1. Glucose and triglycerides were measured by commercial enzymatic methods. Levels of cotinine, an estimate of tobacco exposure, were quantified by enzymelinked immunosorbent assay (Calbiotech, Spring Valley, CA, USA). Parametric two-tailed tests were applied because of normal distribution of data (Pearson’s correlation, ANCOVA with covariates ‘BMI’ and ‘cotinine level’, unpaired t-test). Schizophrenic patients showed elevated S100B levels (F(1,55) = 6.675, P = 0.012) and impaired insulin sensitivity, as indicated by increased glucose (F(1,55) = 13.785, P < 0.001), C-peptide (F(1,55) = 10.578, P = 0.002) and C-peptide/glucose ratios (F(1,55) = 8.238, P = 0.006). In medicated schizophrenic patients, S100B and BMI were elevated (P = 0.041/P < 0.001), but controls with a BMIX25 were also found to show increased S100B levels (T(1,30) = 2.366, P = 0.025). Moreover, in healthy controls, BMI (r = 0.540, P = 0.001), adipokines (leptin: r = 0.545, P = 0.001, HGF: r = 0.441, P = 0.012, resistin: r = 0.377, P = 0.033) and C-peptide/glucose ratios (r = 0.432, P = 0.014) predicted S100B levels. However, in schizophrenic patients, S100B was elevated in both unmedicated (P = 0.049, closely BMI-matched subgroup: P = 0.028) and medicated patients (P = 0.041). Similarly, the finding of insulin resistance, as assessed by C-peptide/glucose ratios, persisted in unmedicated (P = 0.016, closely BMImatched subgroup: P = 0.015) and medicated patients (P = 0.038). Figure 1 illustrates the results. Our results are suggestive of primary insulin resistance in schizophrenia, resulting in an increased release of S100B from brain and adipose tissue, independent of BMI. The commonly observed weight gain on neuroleptic treatment, however, occurs on the basis of an increased metabolic vulnerability in patients because of medication-independent primary insulin resistance. Future studies in larger samples may focus on drug-naive schizophrenic subjects and the comparison of different standardized treatment regimens to further elucidate the suggested link between S100B and abnormal energy metabolism. Molecular Psychiatry (2010) 15, 3–11 & 2010 Nature Publishing Group All rights reserved 1359-4184/10

Astrocytes induce manganese superoxide dismutase in brain capillary endothelial cells.

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*NO and oxyradical metabolism in new cell lines of rat brain capillary endothelial cells forming the blood-brain barrier.

Astrocytes induce blood–brain barrier (BBB) properties in brain endothelial cells (EC). .O2., generated in blood and EC, opens the BBB. Hence, high activity of superoxide dismutase (SOD) is a prerequisite for normal BBB function. Therefore, the influence of rat astrocytes on the expression of manganese (Mn)SOD in rat EC was investigated in two coculture models of the BBB, allowing either exchange of soluble factors or additionally cellular contacts. Activity, protein content and mRNA expression of endothelial MnSOD were significantly increased in both coculture models in comparison to monoculture by soluble astrocytic factors, such as cytokines. High activity of endothelial MnSOD may be considered as a further essential property of the BBB, which is induced and maintained by astrocytes.