Vitamin A bei Neuropsychiatrischen Erkrankungen

In der vorliegenden Arbeit konnten mehrere Aspekte der zerebralen Retinoidhomöostase im adulten ZNS aufgezeigt werden. Zunächst konnte experimentell nachgewiesen werden, dass humane neuronale Zellkulturen sowie murine Mikroglia in funktionell relevantem Ausmaß CYP450-Isozyme exprimieren, welche sowohl hemm- als auch induzierbar sind und einen relevanten Beitrag zum Abbau endogener Retinsäuren leisten. Während die zentrale Funktion von CYP450 Isozymen in neuronalen Zellen nicht abschließend geklärt ist, konnte hier am Beispiel der Retinoidhomöostase exemplarisch aufgezeigt werden, dass sich Änderungen der CYP-Aktivität in Neuronen als auch Mikroglia über differenziellen Abbau endogener Liganden wie der Retinsäure auf neuronale Funktionen auswirken können (Hellmann-Regen et al. 2012). Auch ein direkter, funktionell relevanter Einfluss von Licht unterschiedlicher Wellenlängen auf die chemischen und biologischen Eigenschaften von Retinoiden konnte dargestellt werden (HellmannRegen et al. 2013a). Ferner konnte gezeigt werden, dass eine Modulation des CYP450-vermittelten Abbaus von Retinsäure sich signifikant auf die Retinoidhomöostase auswirkt und somit das CYP450-System als therapeutisches Target im ZNS in Frage kommt (Hellmann-Regen et al. 2013b). Abschließend konnte zunächst am Beispiel des pleiotropen, antientzündlichen Minocyclins sowie am Beispiel des ebenfalls antientzündlichen Fluoxetins aufgezeigt werden, dass beide Substanzen über eine signifikante Hemmung spezifischen und unspezifischen Retinsäurekatabolismus zu einer Steigerung lokaler Retinsäurespiegel führen (Regen et al. 2014, Hellmann-Regen et al. 2015, Regen et al. 2015, Regen et al. 2016). Es liegt somit nahe, dass über eine lokale pharmakokinetische Interaktion am CYP450-System eine relevante Beeinflussung des Katabolismus endogener Substrate wie beispielsweise der Retinoide stattfindet und der lokale Abbau endogener Retinoide ein vielversprechendes therapeutisches Target darstellen könnte

Psychosocial stress increases testosterone in patients with borderline personality disorder, post-traumatic stress disorder and healthy participants

Background: The gonadal hormone testosterone not only regulates sexual behavior but is also involved in social behavior and cognition in both sexes. Changes in testosterone secretion in response to stress have been reported. In addition, stress associated mental disorders such as borderline personality disorder (BPD) and posttraumatic stress disorder (PTSD) are characterized by alterations in basal testosterone metabolism. However, testosterone changes to stress have not been investigated in mental disorders such as BPD and PTSD so far. Methods: In the study described, we investigated testosterone reactivity to an acute psychosocial stressor, the Trier Social Stress Test (TSST). Our sample consisted of young adult women with BPD (n = 28), PTSD (n = 22) or both disorders (n = 22), and healthy control (n = 51). Based on previous studies on basal testosterone secretion in these disorders, we expected the stress-associated testosterone reactivity to be higher in the BPD group and lower in the PTSD group, when compared to the healthy control group. Results: The study could demonstrate an increase in testosterone after acute stress exposure across all groups and independent of BPD or PTSD status. Different possible explanations for the absence of a group effect are discussed. Conclusions: From the results of this study, we conclude that stress-related changes in testosterone release are not affected by BPD or PTSD status in a female patient population. This study expands the knowledge about changes in gonadal hormones and stress reactivity in these disorders

Clozapine modulates retinoid homeostasis in human brain and normalizes serum retinoic acid deficit in patients with schizophrenia

The atypical antipsychotic clozapine is one of the most potent drugs of its class, yet its precise mechanisms of action remain insufficiently understood. Recent evidence points toward the involvement of endogenous retinoic acid (RA) signaling in the pathophysiology of schizophrenia. Here we investigated whether clozapine may modulate RA-signaling. Effects of clozapine on the catabolism of all-trans RA (at-RA), the biologically most active metabolite of Vitamin A, were assessed in murine and human brain tissue and peripheral blood-derived mononuclear cells (PBMC). In patients with schizophrenia with and without clozapine treatment and matched healthy controls, at-RA serum levels and blood mRNA expression of retinoid-related genes in PBMCs were quantified. Clozapine and its metabolites potently inhibited RA catabolism at clinically relevant concentrations. In PBMC-derived microsomes, we found a large interindividual variability of the sensitivity toward the effects of clozapine. Furthermore, at-RA and retinol serum levels were significantly lower in patients with schizophrenia compared with matched healthy controls. Patients treated with clozapine exhibited significantly higher at-RA serum levels compared with patients treated with other antipsychotics, while retinol levels did not differ between treatment groups. Similarly, in patients without clozapine treatment, mRNA expression of RA-inducible targets CYP26A and STRA6, as well as at-RA/retinol ratio, were significantly reduced. In contrast, clozapine-treated patients did not differ from healthy controls in this regard. Our findings provide the first evidence for altered peripheral retinoid homeostasis in schizophrenia and suggest modulation of RA catabolism as a novel mechanism of action of clozapine, which may be useful in future antipsychotic drug development

Steroid hormone secretion after stimulation of mineralocorticoid and NMDA receptors and cardiovascular risk in patients with depression

Major depressive disorder (MDD) is associated with altered mineralocorticoid receptor (MR) and glucocorticoid receptor function, and disturbed glutamatergic signaling. Both systems are closely intertwined and likely contribute not only to the pathophysiology of MDD, but also to the increased cardiovascular risk in MDD patients. Less is known about other steroid hormones, such as aldosterone and DHEA-S, and how they affect the glutamatergic system and cardiovascular disease risk in MDD. We examined salivary cortisol, aldosterone, and DHEA-S secretion after stimulation of MR and glutamatergic NMDA receptors in 116 unmedicated depressed patients, and 116 age- and sex-matched healthy controls. Patients (mean age = 34.7 years, SD = ±13.3; 78% women) and controls were randomized to four conditions: (a) control condition (placebo), (b) MR stimulation (0.4 mg fludrocortisone), (c) NMDA stimulation (250 mg D-cycloserine (DCS)), and (d) combined MR/NMDA stimulation (fludrocortisone + DCS). We additionally determined the cardiovascular risk profile in both groups. DCS had no effect on steroid hormone secretion, while cortisol secretion decreased in both fludrocortisone conditions across groups. Independent of condition, MDD patients showed (1) increased cortisol, increased aldosterone, and decreased DHEA-S concentrations, and (2) increased glucose levels and decreased high-density lipoprotein cholesterol levels compared with controls. Depressed patients show profound alterations in several steroid hormone systems that are associated both with MDD pathophysiology and increased cardiovascular risk. Prospective studies should examine whether modulating steroid hormone levels might reduce psychopathology and cardiovascular risk in depressed patients

Intranasal oxytocin administration impacts the acquisition and consolidation of trauma-associated memories: a double-blind randomized placebo-controlled experimental study in healthy women

Intrusive memories are a hallmark symptom of post-traumatic stress disorder (PTSD) and oxytocin has been implicated in the formation of intrusive memories. This study investigates how oxytocin influences the acquisition and consolidation of trauma-associated memories and whether these effects are influenced by individual neurobiological and genetic differences. In this randomized, double-blind, placebo-controlled study, 220 healthy women received either a single dose of intranasal 24IU oxytocin or a placebo before exposure to a trauma film paradigm that solicits intrusive memories. We used a "general random forest" machine learning approach to examine whether differences in the noradrenergic and hypothalamic-pituitary-adrenal axis activity, polygenic risk for psychiatric disorders, and genetic polymorphism of the oxytocin receptor influence the effect of oxytocin on the acquisition and consolidation of intrusive memories. Oxytocin induced significantly more intrusive memories than placebo did (t(188.33) = 2.12, p = 0.035, Cohen's d = 0.30, 95% CI 0.16-0.44). As hypothesized, we found that the effect of oxytocin on intrusive memories was influenced by biological covariates, such as salivary cortisol, heart rate variability, and PTSD polygenic risk scores. The five factors that were most relevant to the oxytocin effect on intrusive memories were included in a Poisson regression, which showed that, besides oxytocin administration, higher polygenic loadings for PTSD and major depressive disorder were directly associated with a higher number of reported intrusions after exposure to the trauma film stressor. These results suggest that intranasal oxytocin amplifies the acquisition and consolidation of intrusive memories and that this effect is modulated by neurobiological and genetic factors. Trial registration: NCT03031405

Cognitive and emotional empathy after stimulation of brain mineralocorticoid and NMDA receptors in patients with major depression and healthy controls

Mineralocorticoid receptors (MR) are predominantly expressed in the hippocampus and prefrontal cortex. Both brain areas are associated with social cognition, which includes cognitive empathy (ability to understand others’ emotions) and emotional empathy (ability to empathize with another person). MR stimulation improves memory and executive functioning in patients with major depressive disorder (MDD) and healthy controls, and leads to glutamate-mediated N-methyl-D-aspartate receptor (NMDA-R) signaling. We examined whether the beneficial effects of MR stimulation can be extended to social cognition (empathy), and whether DCS would have additional beneficial effects. In this double-blind placebo-controlled single-dose study, we randomized 116 unmedicated MDD patients (mean age 34 years, 78% women) and 116 age-, sex-, and education years-matched healthy controls to four conditions: MR stimulation (fludrocortisone (0.4 mg) + placebo), NMDA-R stimulation (placebo + D-cycloserine (250 mg)), MR and NMDA-R stimulation (both drugs), or placebo. Cognitive and emotional empathy were assessed by the Multifaceted Empathy Test. The study was registered on clinicaltrials.gov (NCT03062150). MR stimulation increased cognitive empathy across groups, whereas NMDA-R stimulation decreased cognitive empathy in MDD patients only. Independent of receptor stimulation, cognitive empathy did not differ between groups. Emotional empathy was not affected by MR or NMDA-R stimulation. However, MDD patients showed decreased emotional empathy compared with controls but, according to exploratory analyses, only for positive emotions. We conclude that MR stimulation has beneficial effects on cognitive empathy in MDD patients and healthy controls, whereas NMDA-R stimulation decreased cognitive empathy in MDD patients. It appears that MR rather than NMDA-R are potential treatment targets to modulate cognitive empathy in MDD

Minocycline alters behavior, microglia and the gut microbiome in a trait-anxiety-dependent manner

Major depressive disorder is the main cause of disability worldwide with imperfect treatment options. However, novel therapeutic approaches are currently discussed, from augmentation strategies to novel treatments targeting the immune system or the microbiome-gut-brain axis. Therefore, we examined the potential beneficial effects of minocycline, a tetracycline antibiotic with pleiotropic, immunomodulatory action, alone or as augmentation of escitalopram on behavior, prefrontal microglial density, and the gut microbiome in rats selectively bred for high anxiety-like behavior (HAB). We show that concomitant with their high innate anxiety and depression, HABs have lower microglial numbers in the infralimbic and prelimbic prefrontal cortex and an altered gut microbiota composition compared with controls. Three weeks of minocycline treatment alleviated the depressive-like phenotype, further reduced microglial density, exclusively in male HAB rats, and reduced plasma concentrations of pro-inflammatory cytokines. However, coadministration of escitalopram, which had no effect alone, prevented these minocycline-induced effects. Moreover, minocycline led to a robust shift in cecal microbial composition in both HABs and rats nonselected for anxiety-like behavior. Minocycline markedly increased relative abundance of Lachnospiraceae and Clostridiales Family XIII, families known for their butyrate production, with a corresponding increase and positive correlation in plasma 3-OH-butyrate levels in a trait-dependent manner. Thus, our data suggest that the antidepressant effect of minocycline is sex- and trait-dependent, associated with a reduced microglial number in the prefrontal cortex, and with changes in microbial composition and their metabolites. These results further support the microbiomegut-brain axis as potential target in the treatment of depression

Effects of raf kinase inhibitor protein on neuronal differentiation and its role in ethanol-impaired neuronal development of human SH-SY5Y neuroblastoma cells

Für die Entwicklung und Integrität des Nervensystems stellt die neuronale Differenzierung einen wichtigen Prozess dar, welcher gegenüber schädlichen Umwelteinflüssen wie Alkoholexposition zeitlebens vulnerabel ist. Zur Untersuchung neuronaler Differenzierung zugrunde liegender Prozesse wurde ein humanes, neuronales Zellkulturmodell etabliert. Es wurde auf Ebene der Zellmorphologie, der intrazellulären Signaltransduktion sowie der Expression neuronaler Markerproteine und signaltransduktions-assoziierter Proteine analysiert sowie hinsichtlich dopaminerger Eigenschaften charakterisiert. Insbesondere das Raf kinase inhibitor protein (RKIP), ein möglicherweise auch an der neuronalen Signaltransduktion modulierend beteiligtes Protein, und die Proteinkinase C (PKC) wurden hinsichtlich möglicher Beteiligung an neuronaler Differenzierung sowie ethanolbedingten Differenzierungsschäden untersucht. Hierzu wurden humane Neuroblastomzellen mit Retinsäure bis zu 4 Wochen differenziert, mit Ethanol behandelt und Analysen mittels Phasenkontraszmikroskopie, Immunzytochemie, Western Blot, cAMP-spezifischem ELISA, quantitativer RT-PCR sowie Hochdruck-Flüssig¬keitschromatographie durchgeführt. Weiterhin wurde eine eigene, unabhängig von Ethanoleinflüssen bestehenden Rolle des RKIP bei der neuronalen Differenzierung untersucht. Hierzu wurde RKIP mittels gezielter Transfektion überexprimiert und downreguliert. Unter Ethanolexposition zeigte sich morphologisch eine beeinträchtigte Differenzierung. Entsprechend fanden sich auch im Quotienten der mRNA des prä- und postsynaptischen Dopaminrezeptors eine Störung des differenzierungstypischen Verteilungsmusters sowie eine reduzierte Expression neuronaler Markerproteine. Zudem ergab sich eine signifikant reduzierte Aktivierbarkeit der Mitogen aktivierten Proteinkinase-Kaskade, welche Effekte differenzierungsfördernder Substanzen wie bspw. Brain derived neurotrophic factor (BDNF) vermittelt. Gleichzeitig lag eine signifikant reduzierte PKC- und RKIP-Expression vor. Die Ergebnisse zu ethanolbedingter Reduktion relevanter neuronaler Proteine sowie der assoziierten Signaltransduktion zeigen einerseits allgemeine Mechanismen zellulärer Toleranzentwicklung auf und geben andererseits Aufschluss über Mechanismen der daraus resultierenden Differenzierungsschäden, wie sie bspw. auch in der Maximalvariante am Phänotyp der Alkoholembryopathie beobachtet werden. In Transfektionsexperimenten konnte darüber hinaus erstmals eine eigene Rolle des RKIP in der neuronalen Differenzierung belegt werden: Während die Überexpression von RKIP in verstärkter Signaltransduktion und schließlich beschleunigter neuronaler Differenzierung resultierte, ergab sich nach Downregulation ein glialer Phänotyp bei reduzierter neuronaler Differenzie¬rung.Neuronal differentiation represents a hallmark in neuronal development and has repeatedly been discussed to be altered in several psychiatric conditions. The signal transduction underlying neuronal differentiation is tightly regulated by a variety of proteins, including Raf kinase inhibitor protein (RKIP), which acts as a molecular switch amplifying neurotrophin-mediated signal transduction. Several aspects of RKIP-modulated signal transduction are affected by ethanol exposure. To elucidate the role of the signal transduction modulator RKIP in ethanol-impaired neuronal development and in neuronal differentiation, a human neuronal cell culture model was established including conditions of RKIP overexperssion and gene silencing. Aspects of cellular morphology, intracellular signal transduction mechanisms involving RKIP and the protein kinase C (PKC) and expression of select marker proteins were quantitatively analyzed. Moreover, aspects of dopaminergic differentiation were investigated by high pressure liquid chromatography (HPLC). Ethanol exposure resulted in significantly impaired neuronal differentiation, which was attributable to impaired signal transduction due to reduced RKIP and PKC expression. Transfection studies additionally revealed a role for RKIP in neuronal differentiation. While RKIP overexpression significantly enhanced neuronal differentiation, RKIP knock-down resulted in a glial-like phenotype with impaired neurite outgrowth accompanied by a significant increase in glial marker protein expression. These results suggest a role for RKIP in regulating neuronal differentiation, possibly at the level of fate-determination

A simple approach to optimum pool size for pooled SARS-CoV-2 testing

Systematic, large-scale testing of asymptomatic subjects is an important strategy in the management of the SARS-CoV-2 pandemic. In order to increase the capacity of laboratory-based molecular SARS-CoV-2 testing, it has been suggested to combine several samples and jointly measure them in a sample pool. While saving cost and labour at first sight, pooling efficiency depends on the pool size and the presently experienced prevalence of positive samples. Here we address the question of the optimum pool size at a given prevalence. We demonstrate the relation between analytical effort and pool size and delineate the effects of the target prevalence on the optimum pool size. Finally, we derive a simple-to-use formula and table that allow laboratories performing sample pooling to assess the optimum pool size at the currently experienced target prevalence rate

Effects of Open-Label Placebos on State Anxiety and Glucocorticoid Stress Responses

Stress belongs to the most frequent negative feelings people are confronted with in daily life. Strategies against acute stress include, e.g., relaxation techniques or medications, but it is also known that placebos can successfully reduce negative emotional stress. While it is widely held that placebos require deception to provoke a response, recent studies demonstrate intriguing evidence that placebos may work even without concealment (e.g., against anxiety or pain). Most of these studies are based on self-report questionnaires and do not include physiological measures. Here we report results of a study examining whether placebos without deception reduce acute stress. A total of 53 healthy individuals received either placebos without deception or no pills before participating in a laboratory stress test (Maastricht Acute Stress Test, MAST). We recorded self-report stress measures and cortisol responses before and after the MAST. Results showed no significant differences between the placebo and the control group, but when comparing participants with high relative to low beliefs in the power of placebos we found significant lower anxiety and cortisol responses for the placebo believers. These results show that non-deceptive placebos may successfully reduce acute anxiety and stress, but only in participants who had a strong belief in placebos. We discuss the results by suggesting that open-label placebos might be a possible treatment to reduce stress at least for some individuals