Olaf Schulte-Herbrüggen

Serum neurotrophins—A study on the time course and influencing factors in a large old age sample

The neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important mediators of brain and neuronal development, the maintenance of homeostatic conditions in the adult nervous system, and the complex interplay of central and peripheral physiological and pathophysiological factors. To date there are few studies examining blood concentrations of neurotrophic factors in large samples of healthy and diseased individuals and no published study specifically addresses peripheral BDNF and NGF levels in late life. Using improved highly sensitive and specific fluorometric two-site enzyme-linked immunosorbent assays we examined BDNF (n=465) and NGF (n=175) serum levels in a large cohort of elderly individuals (age range: 70-103 years). Neither BDNF nor NGF serum levels proved to be normally distributed, indicating that previously published studies with small sample sizes using parametric testing may be misleading. A significant correlation was found between BDNF and platelet count (r=0.344, p<0.01), age and BDNF protein (r=-0.101, p=0.029) and BDNF and NGF serum levels (r=0.152, p=0.04). No other major influencing factors were found including gender, depression, and dementia.

Neurotrophins - From Pathophysiology to Treatment in Alzheimers Disease

Alzheimers disease (AD) is the most common diagnosis among dementia. As increasing longevity results in larger numbers of AD patients and thus rising economic costs, there has been intense research about the pathophysiology and treatment strategies during the last years. Since neurotrophic factors are not only responsible for neuronal development but also critical for the maintenance of neurons, they represent mediators of high interest within the research of neurodegeneration. Thereby, NGF has been identified as a dynamic pattern during the time course of neurodegeneration in AD. Post mortem studies point to a lack of NGF action in early stages of AD. In contrast NGF is found in enhanced concentrations in brains with severe AD partly due to a pathologically altered axonal transport of NGF in the neurons. Therefore, pharmacological interventions strategies focus on an neurotrophin substitution in mild to moderate cases of AD. Intensive research mostly in rodents has recently led to first promising clinical trials of intracerebral neurotrophin application pointing to a growing role of neurotrophins in the establishment of new pharmacological strategies concerning AD.

Stress-resistant mice overexpressing glucocorticoid receptors display enhanced BDNF in the amygdala and hippocampus with unchanged NGF and serotonergic function

Dysfunctional glucocorticoid receptor (GR) signaling has been shown to be involved in the pathogenesis of depressive behavior in mice and humans. In accordance with this hypothesis GR overexpressing mice are less susceptible to develop depressive-like behavior when subjected to stressful events. Here, we analyzed GR overexpressing mice for morning and evening content of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and the tissue levels of serotonin and its metabolite 5-hydroxyindoleacetic acid) in brain areas suspected to be involved in stress adaptation. BDNF concentrations in the hippocampus and amygdala/piriform cortex were significantly enhanced in GR overexpressing mice (by maximally +103%) compared to wildtype animals. Diurnal variations, as detected for NGF in the hypothalamus, for BDNF in the frontal cortex and striatum and for serotonergic function in the frontal cortex and hypothalamus, were not affected by the genotype. In conclusion, GR overexpression-dependent increases of hippocampal and amygdala BDNF content presumably represent a dynamic correlate of enhanced stress resistance.

Differential regulation of nerve growth factor and brain-derived neurotrophic factor in a mouse model of learned helplessness

Stress-induced helplessness in rodents constitutes a well-defined model to investigate neurobiological mechanisms of depression. Neurotrophins like nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have both been shown to be involved in neurobiological changes of physiological and pathological reactions to stress. In this study we investigated NGF and BDNF protein levels in the frontal cortex and hippocampus in mice treated with an established model of inducible helplessness via electric footshocks compared to untreated controls at various times (0 h up to 14 days after treatment). NGF levels were transiently decreased by one forth in the frontal cortex of shocked mice at 6 h after the stress treatment, whereas BDNF levels remained unchanged in the brain areas investigated throughout the time course. In addition, frontal cortex BDNF levels showed a significantly higher concentration in the right compared to the left hemisphere (up to 3-fold). This effect was detectable independently of treatment, namely in shocked and control mice at any time point measured. In conclusion, a transient decrease of frontal NGF constitutes the most striking correlate of neurobiological changes in this animal model of stress-induced change of behaviour. Interhemispherical differences of BDNF content in the frontal cortex are a new finding that might reflect intracerebral side dominance. Thus, subsequent studies of frontal cortex BDNF expression should carefully consider an interhemispherical variance to avoid misinterpretation.

Effects of escitalopram on the regulation of brain-derived neurotrophic factor and nerve growth factor protein levels in a rat model of chronic stress

Escitalopram (ES‐CIT) is a widely used, highly specific antidepressant. Until now there has been very little evidence on how this drug under pathological conditions affects an important feature within the pathophysiology of stress‐related disorders such as depression: the endogenous neurotrophins. By using a well‐characterized rat model in which chronic stress induces depressive‐like behavior, the levels of neurotrophins brain‐derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were determined in representative brain regions and serum using a highly sensitive improved fluorometric two‐site ELISA system. There was a significant increase of BDNF in the left and right cortices after stress treatment (twofold increase) that was reversed by application of ES‐CIT. An ES‐CIT‐dependent NGF reduction in stressed rats was detectable in the right cortex only (P = 0.027). The left hippocampus revealed significantly higher amounts of BDNF (2.5‐fold increase) protein than the right hippocampus. These interhemispheric differences were unrelated to stress or ES‐CIT treatment in all animals. BDNF and NGF of the frontal cortex, cerebellum, and serum did not change between the study groups. There was a negative correlation between body weight and serum BDNF, independent of stress or ES‐CIT treatment. In conclusion, BDNF and NGF show substantial changes in this rodent model of chronic social stress, which is susceptible to antidepressant treatment with ES‐CIT and therefore may constitute a neurobiological correlate for the disease.

Age-dependent time course of cerebral brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 in APP23 transgenic mice.

Neurotrophins, including brain‐derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin‐3 (NT‐3), have repeatedly been shown to be involved in the pathophysiology of Alzheimers disease (AD). Recent studies have claimed that these neurotrophic factors are important tools for therapeutic intervention in neurodegenerative diseases. So far, little is known about the age‐ and disease‐modulated time course of cerebral neurotrophins. Therefore, we have studied protein concentrations of BDNF, NGF, and NT‐3 in different brain areas and sciatic nerve, a neurotrophin‐transporting peripheral nerve, in a well‐characterized AD model of amyloid precursor protein‐overexpressing rodents (APP23 mice) at the ages of 5.0, 10.5, and 20.0 months. In APP23 mice, there was a significant increase of BDNF and NGF in the frontal and occipital cortices (for BDNF also in the striatum) of old 20.0‐month‐old mice (with respect to median values up to 8.2‐fold), which was highly correlated with amyloid concentrations of these brain areas. Median values of NGF and NT‐3 showed up to a 6.0‐fold age‐dependent increase in the septum that was not detectable in APP23 mice. Hippocampus, olfactory bulb, and cerebellum (except NT‐3) did not show substantial age‐ or genotype‐related regulation of neurotrophins. In the sciatic nerve, BDNF and NGF levels are increased in5‐month‐old APP23 mice and decrease with age to control levels. In conclusion, APP23 mice show a genotype‐dependent increase of cortical BDNF and NGF that is highly correlated with amyloid concentrations and may reflect an amyloid‐related glia‐derived neurotrophin secretion or an altered axonal transport of these neurotrophic factors.

Impaired Sexual Function in Patients with Borderline Personality Disorder is Determined by History of Sexual Abuse

INTRODUCTION Patients suffering from a Borderline Personality Disorder (BPD) display altered sexual behavior, such as sexual avoidance or sexual impulsivity, which has repeatedly been linked to the sexual traumatization that occurs in a high percentage of BPD patients. Until now, no empirical data exists on whether these patients concomitantly suffer from sexual dysfunction. AIM This study investigates sexual function and the impact of sexual traumatization on this issue in women with BPD as compared to healthy women. MAIN OUTCOME MEASURES Sexual function was measured using the Female Sexual Function Index. Additionally, diagnoses were made with SCID II Interviews for Axis II and with the Mini International Neuropsychiatric Interview for Axis I disorders. The Post-traumatic Stress Diagnostic Scale for trauma evaluation was used. Sexual orientation was assessed by self-evaluation. METHODS Forty-five women with BPD as diagnosed according to DSM-IV criteria and 30 healthy women completed questionnaires on sexual function and sexual abuse history, as well as interviews on axis I and II disorders and psychotropic medication. RESULTS The BPD group showed a significantly higher prevalence of sexual dysfunction. Subgroup analyses revealed that BPD with concomitant sexual traumatization, and not BPD alone, best explains impaired sexual function. Sexual inactivity was mainly related to current major depression or use of SSRI medication. In sexually active participants, medication and symptoms of depression had no significant impact on sexual function. CONCLUSIONS Not BPD alone, but concomitant sexual traumatization, predicts significantly impaired sexual function. This may have a therapeutic impact on BPD patients reporting sexual traumatization.

Differential regulation of neurotrophins and serotonergic function in mice with genetically reduced glucocorticoid receptor expression.

The neurotrophin and serotonin (5-HT) hypotheses of depression were studied in a mouse model of reduced glucocorticoid receptor (GR) function (GR(+/-) mice), which recently has been proven as a murine model of predisposition for depressive behaviour under stressful conditions. In this model we studied diurnal changes in neurotrophins and serotonergic function in candidate brain regions mediating depressive behaviour. Morning and evening levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were analyzed in representative brain regions of GR(+/-) and wildtype mice. The diurnal variation of hippocampal BDNF in wildtypes with higher levels in the morning was absent in GR(+/-) mice. Hypothalamus and parietal cortex displayed enhanced BDNF levels in GR(+/-) mice. In the frontal cortex, striatum and hypothalamus NGF increased from morning to evening in both genotypes, with an exaggeration in GR(+/-) mice. The diurnal variation of 5-HT levels and turnover did not differ significantly between genotypes. It was only in the hypothalamus that the evening level of 5-HIAA was lower in GR(+/-) mice than in wildtype mice. In conclusion, the present data indicate a contribution of altered BDNF and NGF protein levels to the predisposition for depressive behaviour in the GR(+/-) mouse model of depression, but argue against an eminent role of the serotonergic system.

Mouse Strains Differ in Their Susceptibility to Poststroke Infections

Objective: Severe infections, in particular pneumonia, have a major impact on the clinical management and outcome of stroke patients. In a mouse model we have recently demonstrated that stroke induces immunodepression which can result in life-threatening infections. Here, we investigated whether the susceptibility to infections after stroke is strain dependent. Methods and Results: Mice from 129SV, C57/B6, and Balb/C strains were subjected to experimental stroke by filament occlusion of the middle cerebral artery (MCAO) for 60 min. Infarct volumes were measured 3 days after MCAO. Microbiological assessment was based on cultures of bronchoalveolar lavage (BAL), lung tissue and blood of animals obtained 3 days after stroke. Three days after stroke 129SV mice did not only develop bacterial chest infection, but also had a strongly increased susceptibility to bacteremia. In contrast, C57BL/6 and Balb/C mice acquired bacterial lung infections only. In addition, bacterial load in BAL was significantly higher in 129SV mice than in the other mice strains. These differences in susceptibility to infection did not correlate with infarct volumes. Conclusions: Stroke-associated pneumonia developed in three commonly used mouse strains while severity of infections differed between strains. Since infections affect outcome, monitoring of infections is highly relevant for the interpretation of results in experimental stroke research.

Gender differences in a clinical sample of patients with borderline personality disorder.

The aim of the study was to investigate gender differences and similarities in patients with borderline personality disorder (BPD) with respect to Axis I comorbidity, Axis II comorbidity, general psychopathology (Symptom Checklist 90-Revised), and dimensional personality traits (NEO-Personality-Inventory Revised [NEO-PI-R] and the Dimensional Assessment of Personality Profile Basic questionnaire [DAPP-BQ]). Fifty-seven men and 114 women with BPD were included in the study. Regarding Axis I and II disorders in an exploratory analysis, men with BPD more often fulfilled the diagnostic criteria for binge eating disorder, antisocial personality disorder, narcissistic personality disorder, and conduct disorder in childhood, whereas women had higher frequencies of bulimia nervosa, posttraumatic stress disorder, and panic disorder with agoraphobia. After correcting for multiple tests, only the gender differences in narcissistic and antisocial personality disorder remained significant. In the SCL-90-R profile, no significant gender differences could be identified. In the exploratory analysis of the dimensional personality traits, women showed higher rates on the NEO-PI-R main factors (Neuroticism and Agreeableness) compared to men. In the DAPP-BQ profile, men reached higher sores on the main factor, Dissocial Behavior. When correcting for multiple tests, gender differences still existed for Neuroticism and Dissocial Behavior. Our results argue for gender differences in Axis I and II comorbidity and dimensional personality traits in BPD. However, in general, more similarities than differences were shown in this study.