Alexander Yassouridis - Academia.edu (original) (raw)

Papers by Alexander Yassouridis

Research paper thumbnail of Toll-like receptor-4 is expressed in menin- giomas and mediates the antiproliferative action of paclitaxel

International Journal of Cancer

Meningiomas are the second most common type of brain and CNS tumors by histology. Surgery and rad... more Meningiomas are the second most common type of brain and CNS tumors by histology. Surgery and radiotherapy are main treatment options, but meningiomas may be impossible to adequately resect or may regrow after surgery. In spite of many experimental attempts, there is no generally accepted chemotherapeutic approach. We have studied in a series of meningiomas the expression of the Toll-like receptor 4 (TLR4), which apart from its major role as a key factor of the innate immune system, is believed to play a role in tumorigenesis. All meningiomas studied expressed TLR4 mRNA and protein at variable degree. Paclitaxel, a ligand of TLR4, exhibited a dose-and time-dependent growth suppression in both monolayer and spheroid meningioma cell cultures. The knockdown of TLR4 with siRNA in meningioma cell cultures abrogated the inhibitory effect of paclitaxel. The suppressive action of paclitaxel on meningioma cell growth was enhanced in the presence of fluvastatin or the mitogen-actvated protein kinase (ERK1/2) inhibitor PD98059. At least part of the growth suppressive effect was mediated by the induction of apoptosis in meningioma cells by paclitaxel alone or in combination with fluvastatin. In conclusion, our in vitro results suggest that paclitaxel alone or in combination with other inhibitors of cell growth (statins, MAPK inhibitors) could provide a potential tool for the treatment of TLR4 expressing meningiomas.

Research paper thumbnail of Differences in polysomnography between patients suffering from Conn's syndrome in comparison with a control group

Experimental and Clinical Endocrinology & Diabetes

Research paper thumbnail of Copeptin – A surrogate marker of CCK-4-induced panic?

Psychoneuroendocrinology, 2015

Research paper thumbnail of Hippocampal mineralocorticoid receptors inhibit the hypothalamus-pituitary-adrenal axis: A new metyrapone-fludrocortisone test and effect of age

Research paper thumbnail of Overnight suppression of HPA axis after mineraolocorticoid receptor stimulation: A sleep endocrine study

Psychiatry research, Jan 24, 2015

Nocturnal hyperactivity of hypothalamic-pituitary-adrenal axis (HPA) indicates decreased feedback... more Nocturnal hyperactivity of hypothalamic-pituitary-adrenal axis (HPA) indicates decreased feedback inhibition with stress-related conditions such as major depression and sleep disorders. To characterize the role of mineralocorticoid (MR) in regulation of HPA axis activity during nocturnal sleep and involvement in sleep architecture, we investigated sleep endocrine effects of the MR agonist fludrocortisone in healthy men after pretreatment with metyrapone to minimize the impact of endogenous cortisol. Subjects (n=8) were treated on three occasions in a single-blinded design in random order with a) metyrapone, b) fludrocortisone after metyrapone, and c) placebo. Polysomnography was recorded and blood samples were drawn for determination of adrenocorticotropic hormone (ACTH) and cortisol during the entire night. After metyrapone administration ACTH was significantly enhanced, while overall nocturnal cortisol secretion remained largely unchanged. Whereas administration of fludrocortisone...

Research paper thumbnail of Ghrelin enhances the nocturnal secretion of cortisol and growth hormone in young females without influencing sleep

Psychoneuroendocrinology

Ghrelin was shown to increase slow wave sleep (SWS) and the secretion of growth hormone (GH) and ... more Ghrelin was shown to increase slow wave sleep (SWS) and the secretion of growth hormone (GH) and cortisol in young males. In terms of sleep, such information for females, however, is lacking. Therefore, polysomnographies were recorded (23:00-07:00 h) and nocturnal (20:00-07:00 h) secretion profiles of GH and cortisol were determined in 10 healthy females (24.9+/-2.4 years, body mass index: 21.2+/-1.1) twice, receiving four boluses of 50 microg ghrelin or placebo at 22:00, 23:00, 00:00, and 01:00 h, in this single-blind, randomized, cross-over study. No significant differences of conventionally or quantitatively analyzed sleep were observed between ghrelin and placebo condition. First administration of ghrelin caused a marked mean increase of GH by 53.3 to 64.4+/-14.2 ng/ml (placebo: 5.9+/-1.5 ng/ml) and cortisol by 54.2 to 96.4+/-15.3 ng/ml (placebo: 27.5+/-4.7 ng/ml). The following ghrelin injections were associated with smaller increases of GH and cortisol. In the ghrelin conditio...

Research paper thumbnail of A follow-up study for estimating the effectiveness of a cross-gender hormone substitution therapy on transsexual patients

Archives of sexual behavior, 1998

This follow-up study was carried out to validate the effectiveness of cross-gender hormone therap... more This follow-up study was carried out to validate the effectiveness of cross-gender hormone therapy embedded in a multistep treatment concept for transsexual patients. This therapy described in detail by the authors elsewhere and presented briefly below provides cross-gender hormone substitution to obtain an assimilation of secondary sex characteristics to the desired sex as quickly as possible. Personal and social background data of 46 male-to-female (M-to-F) and 42 female-to-male (F-to-M) patients passing through different stages of the treatment concept were included. In the Endocrinological Outpatient Clinic of the Max-Planck-Institute/Munich the effectiveness of cross-gender hormone replacement therapy as well as frequency and distribution of side effects were examined by follow-up examination of endocrinological parameters. Cross-gender hormones were administered either parenterally or orally. Blood samples were collected routinely after 2 to 6 months depending on the duration ...

Research paper thumbnail of Central administration of IL-1 reduces anxiety and induces sickness behaviour in rats

Pharmacology, biochemistry, and behavior, 1997

In the present study, we examined the effects of various doses of recombinant human interleukin-1... more In the present study, we examined the effects of various doses of recombinant human interleukin-1beta on anxiety-like behaviour, on body temperature, and on behavioural changes typical of sick animals. First, we assessed the behaviour of rats in the elevated plus-maze before and 20 min after intracerebroventricular injection of IL-1 at six doses ranging from 0.001 to 100 ng. After treatment with 0.1 and 100 ng IL-1, animals exhibited different anxiety levels. The dose effect on behavioural performance in the plus-maze appears to be nonlinear (parabolic function), with the highest effects near a 0.1-ng dose and the lowest near doses of 0.0 and 100 ng. In a second set of experiments, we examined the effects of doses of 0.1 and 100 ng IL-1 (which had the most pronounced effects on performance in the plus-maze) on physical parameters over a 24-h period. Using radiotelemetry we measured body temperature, locomotor activity, food intake, and water consumption: a) in animals kept under bas...

Research paper thumbnail of Differential Impact of Tetratricopeptide Repeat Proteins on the Steroid Hormone Receptors

PLoS ONE, 2010

Background: Tetratricopeptide repeat (TPR) motif containing co-chaperones of the chaperone Hsp90 ... more Background: Tetratricopeptide repeat (TPR) motif containing co-chaperones of the chaperone Hsp90 are considered control modules that govern activity and specificity of this central folding platform. Steroid receptors are paradigm clients of Hsp90. The influence of some TPR proteins on selected receptors has been described, but a comprehensive analysis of the effects of TPR proteins on all steroid receptors has not been accomplished yet.

Research paper thumbnail of Mental Health in Offspring of Traumatized Refugees with and without Post-traumatic Stress Disorder

Stress and Health, 2014

Intergenerational transmission of psychological trauma and the impact of parental post-traumatic ... more Intergenerational transmission of psychological trauma and the impact of parental post-traumatic stress disorder (PTSD) on offspring are controversially discussed. We studied 50 offspring (36 women and 14 men, mean age 42.1 years) of refugees who were severely traumatized as children at the end of World War II. From these, 25 of the refugees currently suffered from chronic PTSD, and 25 had no PTSD. Parental PTSD status did not significantly influence mental health [as per the Symptom Checklist (SCL)-90-R] or quality of life (assessed by the 36-item Short-form Health Survey) in their children. In the entire sample, frequency of talking with the mother about the flight correlated with phobic anxiety (r = 0.67, p = 0.03). Interestingly, the stated burden of having a parent with a history of flight significantly (p < 0.05) correlated with almost all subscales of the SCL-90-R. These results in a non-clinical sample do not support a specific role of parental PTSD in intergenerational trauma transmission. Our other remarkable, but preliminary, results need to be studied in larger samples using more subtle interaction or schema analyses. Copyright © 2014 John Wiley & Sons, Ltd.

Research paper thumbnail of Ghrelin administered in the early morning increases secretion of cortisol and growth hormone without affecting sleep

Psychoneuroendocrinology, 2007

Ghrelin and growth hormone (GH) releasing hormone (GHRH) both stimulate GH secretion and slow wav... more Ghrelin and growth hormone (GH) releasing hormone (GHRH) both stimulate GH secretion and slow wave sleep (SWS), whereas ghrelin increases, and GHRH decreases cortisol in males. However, GHRH's effect on sleep and cortisol was abolished, on GH mitigated, when administered in the early morning, possibly due to counteracting corticotropin releasing hormone (CRH). Aim of this study was to investigate ghrelin's influence on sleep, GH and cortisol when administered in the early morning. Nocturnal (2000-1000 h) GH and cortisol patterns and polysomnography (2300-1000 h) were determined in 12 healthy males (25.3+/-3.2 yr) twice, receiving 50 microg ghrelin or placebo at 0400, 0500, 0600, and 0700 h, in this single-blind, randomized, cross-over study. The first ghrelin bolus caused the strongest (38.7+/-6.5 ng/ml, placebo: 0.4+/-1.1 ng/ml), second and third smaller, the fourth no GH peak. GH levels remained significantly (p<0.05) higher from 0420-0740 h in the ghrelin condition. Comparably, the first ghrelin bolus caused the strongest cortisol response (156.0+/-12.6 ng/ml; placebo: 78.0+/-10.5 ng/ml). Cortisol was significantly higher from 0440 to 0540 and at 0720 h and decreased thereafter to significantly lower levels (0820-0840 h). Sleep variables did not differ in both conditions. In contrast to GHRH, ghrelin's stimulatory effects were apparently not counteracted (GH), and enhanced (cortisol), respectively, by high CRH in the second half of night.

Research paper thumbnail of Systemic growth hormone-releasing hormone (GHRH) impairs sleep in healthy young women

Psychoneuroendocrinology, 2007

In young male subjects peripherally administered growth hormone-releasing hormone (GHRH) enhances... more In young male subjects peripherally administered growth hormone-releasing hormone (GHRH) enhances GH and slow wave sleep (SWS) and blunts cortisol. In contrast, in a sample of females 19-76-year old, GHRH impairs sleep and enhances adrenocorticotropic hormone (ACTH) and cortisol. In the latter study, the days of investigation were not adapted to the menstrual cycle and premenopausal and postmenopausal women as well were included. Placebo and GHRH were given during consecutive nights. In order to confirm or reject the sexual dimorphism of the effects of GHRH on sleep we applied an improved study design. In the present study we examined the effect of pulsatile administration of two dosages of GHRH (4x25 or 4x50 microg intravenously, respectively) on sleep electroencephalogram (EEG) and nocturnal hormone secretion in healthy young women according to a randomized schedule. To rule out the influence of gonadal hormone activity, the study was adapted to the phase of the menstrual cycle and was performed at 4-6th day of menstrual cycle. A carry-over effect was excluded by the interval of at least 4 weeks between examinations. Compared to placebo rapid-eye-movement sleep decreased during the first half of the night after 4x25 microg GHRH and sleep stage 4 decreased after 4x50 microg GHRH. After both dosages GH increased whereas ACTH and cortisol remained unchanged. This study confirms that systemic GHRH impairs sleep in women.

Research paper thumbnail of Non-response of cortisol during stressful exposure therapy in patients with obsessive-compulsive disorder—Preliminary results

Psychiatry Research, 2012

Exposure with response prevention (ERP) is an established treatment for patients with obsessive-c... more Exposure with response prevention (ERP) is an established treatment for patients with obsessive-compulsive disorder (OCD) and also an interesting model to characterize neuroendocrine response to psychological stress. However, so far few studies have assessed hypothalamic-pituitary-adrenocortical (HPA) function during ERP and results are inconsistent. In 15 patients with OCD we repeatedly measured salivary cortisol and subjective units of distress (SUD) on two consecutive afternoons. The first day served as a comparison condition; on the second day the very first session of ERP took place. While SUD were significantly increased during ERP versus the comparison day, salivary cortisol was statistically indistinguishable between ERP and comparison conditions before, during and after ERP. Thus, despite considerable psychological stress no increase of cortisol was observed. This response pattern to ERP in OCD patients needs further research.

Research paper thumbnail of Prognostic and Symptomatic Aspects of Rapid Eye Movement Sleep in a Mouse Model of Posttraumatic Stress Disorder

Frontiers in Behavioral Neuroscience, 2013

Not every individual develops Posttraumatic Stress Disorder (PTSD) after the exposure to a potent... more Not every individual develops Posttraumatic Stress Disorder (PTSD) after the exposure to a potentially traumatic event. Therefore, the identification of pre-existing risk factors and early diagnostic biomarkers is of high medical relevance. However, no objective biomarker has yet progressed into clinical practice. Sleep disturbances represent commonly reported complaints in PTSD patients. In particular, changes in rapid eye movement sleep (REMS) properties are frequently observed in PTSD patients. Here, we examined in a mouse model of PTSD whether (1) mice developed REMS alterations after trauma and (2) whether REMS architecture before and/or shortly after trauma predicted the development of PTSD-like symptoms. We monitored sleep-wake behavior via combined electroencephalogram/electromyogram recordings immediately before (24 h pre), immediately after (0-48 h post) and 2 months after exposure to an electric foot shock in male C57BL/6N mice (n = 15). PTSD-like symptoms, including hyperarousal, contextual, and generalized fear, were assessed 1 month post-trauma. Shocked mice showed early onset and sustained elevation of REMS compared to non-shocked controls. In addition, REMS architecture before trauma was correlated with the intensity of acoustic startle responses, but not contextual fear, 1 month after trauma. Our data suggest REMS as prognostic (pre-trauma) and symptomatic (post-trauma) marker of PTSD-like symptoms in mice. Translated to the situation in humans, REMS may constitute a viable, objective, and non-invasive biomarker in PTSD and other trauma-related psychiatric disorders, which could guide pharmacological interventions in humans at high risk.

Research paper thumbnail of Monthly intravenous methylprednisolone in relapsing-remitting multiple sclerosis - reduction of enhancing lesions, T2 lesion volume and plasma prolactin concentrations

Intravenous methylprednisolone (IV-MP) is an established treatment for multiple sclerosis (MS) re... more Intravenous methylprednisolone (IV-MP) is an established treatment for multiple sclerosis (MS) relapses, accompanied by rapid, though transient reduction of gadolinium enhancing (Gd+) lesions on brain MRI. Intermittent IV-MP, alone or with immunomodulators, has been suggested but insufficiently studied as a strategy to prevent relapses. In an open, single-cross-over study, nine patients with relapsing-remitting MS (RR-MS) underwent cranial Gd-MRI once monthly for twelve months. From month six on, they received a single i.v.-infusion of 500 mg methylprednisolone (and oral tapering for three days) after the MRI. Primary outcome measure was the mean number of Gd+ lesions during treatment vs. baseline periods; T2 lesion volume and monthly plasma concentrations of cortisol, ACTH and prolactin were secondary outcome measures. Safety was assessed clinically, by routine laboratory and bone mineral density measurements. Soluble immune parameters (sTNF-RI, sTNF-RII, IL1-ra and sVCAM-1) and neuroendocrine tests (ACTH test, combined dexamethasone/CRH test) were additionally analyzed. Comparing treatment to baseline periods, the number of Gd+ lesions/scan was reduced in eight of the nine patients, by a median of 43.8% (p = 0.013, Wilcoxon). In comparison, a pooled dataset of 83 untreated RR-MS patients from several studies, selected by the same clinical and MRI criteria, showed a non-significant decrease by a median of 14% (p = 0.32). T2 lesion volume decreased by 21% during treatment (p = 0.001). Monthly plasma prolactin showed a parallel decline (p = 0.027), with significant cross-correlation with the number of Gd+ lesions. Other hormones and immune system variables were unchanged, as were ACTH test and dexamethasone-CRH test. Treatment was well tolerated; routine laboratory and bone mineral density were unchanged. Monthly IV-MP reduces inflammatory activity and T2 lesion volume in RR-MS.

Research paper thumbnail of Differential effects to CCK-4-induced panic by dexamethasone and hydrocortisone

World Journal of Biological Psychiatry, 2012

Peripheral administration of the cholecystokinin (CCK) receptor agonist CCK-4 generates panic and... more Peripheral administration of the cholecystokinin (CCK) receptor agonist CCK-4 generates panic and activates the hypothalamic-pituitary-adrenal (HPA) axis. Direct effects at the pituitary and CCK-HPA interactions at higher regulatory sites have been suggested. According to preliminary data, ACTH response to CCK receptor agonists may differ from its response to exogenous CRH by its resistance to cortisol feedback inhibition. To further explore this resistance and to better characterize CCK-4 sites of action, the effects of different glucocorticoid pretreatments on CCK-4-induced panic were compared. Using a double-blind placebo-controlled design we pretreated healthy males with either dexamethasone (peripheral action) or hydrocortisone (central-peripheral action) each followed by a CCK-4 challenge. Blood levels of ACTH and cortisol were analyzed and panic symptoms were assessed. We found a blunted response of ACTH release following CCK-4 injection only after hydrocortisone pretreatment. Dexamethasone however did not affect CCK-4-induced ACTH release relative to baseline. In contrast to dexamethasone, hydrocortisone reduced the severity of CCK-4-induced panic as measured by the Acute Panic Inventory on a trend level. Findings suggest that CCK-4-induced stress hormone release seems susceptible to cortisol-feedback inhibition and argues for a suprapituitary site of CCK action. Effects on panic anxiety were weak but congruent with studies showing that CCK-4-induced HPA axis inhibition is accompanied by a reduction of anxiety after CCK-4.

Research paper thumbnail of Langzeitfolgen von in der Kindheit am Ende des II. Weltkrieges erlebter Flucht und Vertreibung

PPmP - Psychotherapie · Psychosomatik · Medizinische Psychologie, 2011

Little is known about long-term consequences of flight and expulsion during childhood. The aim of... more Little is known about long-term consequences of flight and expulsion during childhood. The aim of this study was to interview aging former refugee children about their recollection of traumatic experiences and to screen for full and partial posttraumatic stress disorder (PTSD) and their differential impact on today's quality of life and mental health. In 502 participants from the former German eastern territories who were displaced as children at the end of World War II (at the age of 5-12 years) we examined traumatic experiences, posttraumatic stress symptoms (PDS), comorbid symptoms (SCL-90-R), depressive symptoms (BDI) and quality of life (SF-36). 31.5% participants reported posttraumatic stress symptoms indicating current full PTSD, and 33.7% fulfilled the criteria of a current partial PTSD. Participants with full and partial PTSD reported a significantly reduced quality of life, often depressive and comorbid symptoms and were compromised in their well-being compared to participants without PTSD. The study demonstrates the long-term consequences of flight and expulsion during childhood in aging former refugee children more than 60 years later. Posttraumatic stress symptoms play a prominent role for quality of life and well-being in this population.

Research paper thumbnail of Influence of clonidine on psychopathological, endocrine and respiratory effects of cholecystokinin tetrapeptide in patients with panic disorder

Psychopharmacology, 1997

The influence of clonidine pretreatment on psychopathological, endocrine and respiratory effects ... more The influence of clonidine pretreatment on psychopathological, endocrine and respiratory effects of cholecystokinin tetrapeptide (CCK-4) was characterized. Patients with panic disorder (DSM-III-R) were given 50 micrograms CCK-4 i.v. at 1100 hours on 2 separate study days. In a randomized double-blind design they were additionally infused with 150 micrograms clonidine or placebo from 1040 to 1110 hours. After CCK-4 all patients experienced symptom attacks. No effects of clonidine on panic psychopathology or blood gas parameters were observed. After CCK-4, in the clonidine condition the pituitary release of adrenocorticotropin (ACTH) and prolactin was seemingly enhanced compared to placebo. Our results suggest that CCK-4-induced panic attacks are not suppressible by presynaptic alpha-2 receptor stimulation. Moreover, they point to a synergistic postsynaptic action of clonidine to CCK-4 upon pituitary hormone secretion. The diverging sites of action might possibly explain the discrepancies of psychopathological alterations and stress hormone secretion.

Research paper thumbnail of Effects of a metabotropic glutamate2/3 receptor agonist (LY544344/LY354740) on panic anxiety induced by cholecystokinin tetrapeptide in healthy humans: preliminary results

Psychopharmacology, 2005

Preclinical findings have repeatedly shown an anxiolytic-like action of agonists at metabotropic ... more Preclinical findings have repeatedly shown an anxiolytic-like action of agonists at metabotropic glutamate receptors type II, such as LY354740. We aimed to investigate the effect of LY544344, the prodrug of LY354740, upon experimental panic anxiety in humans. Twelve healthy human volunteers were treated orally with 80 mg bid LY544344 for 1 week in a randomized placebo-controlled cross-over study before 50 mug cholecystokinin tetrapeptide (CCK-4) was injected intravenously. We assessed CCK-induced panic and anxiety symptoms and measured stress hormone release. While no significant treatment effect emerged in the entire sample, a significant reduction of the number of CCK-4-induced panic symptoms and of CCK-4-induced subjective anxiety ratings was detected after removing two subjects who did not show decreased CCK-4-elicited adrenocorticotropin (ACTH) release after LY544344 compared to placebo treatment. Further studies are needed to clarify the potential of LY544344 as a new anxiolytic or antipanic drug.

Research paper thumbnail of Ghrelin alone or co-administered with GHRH or CRH increases non-REM sleep and decreases REM sleep in young males

Psychoneuroendocrinology, 2008

Ghrelin activates the somatotropic and the hypothalamic-pituitary-adrenal axes, being crucially i... more Ghrelin activates the somatotropic and the hypothalamic-pituitary-adrenal axes, being crucially involved in sleep regulation. Simplified, growth hormone releasing hormone (GHRH) increases slow-wave sleep and REM sleep in males, whilst corticotropin-releasing hormone (CRH) increases wakefulness and decreases REM sleep. Ghrelin's role in sleep regulation and particularly its interactions with GHRH and CRH are not entirely clear. We aimed to elucidate the interactions between ghrelin, GHRH and CRH in sleep regulation and the secretion of cortisol and GH. Nocturnal GH and cortisol secretion and polysomnographies were determined in 10 healthy males (25.7+/-3.0 years) four times, receiving placebo (A), ghrelin (B), ghrelin and GHRH (C), or ghrelin and CRH (D) at 22:00, 23:00, 00:00, and 01:00h, in this single-blind, randomized, cross-over study. Non-REM sleep was significantly (p<0.05) increased in all verum conditions (mean+/-SEM: B: 355.3+/-7.4; C: 365.4+/-8.1; D: 371.4+/-3.9min) compared to placebo (336.3+/-6.8min). REM sleep was decreased (B: 84.3+/-4.2 [p<0.1]; C: 74.2+/-7.0 [p<0.05]; D: 80.4+/-2.7min [p<0.05]) compared to placebo (100.9+/-8.3). CRH+ghrelin decreased the time spent awake and enhanced the sleep efficiency; furthermore, the REM latency was decreased compared to the other treatment conditions. CRH enhanced the ghrelin-induced cortisol secretion but had no relevant effect on GH secretion. In turn, GHRH enhanced the ghrelin-induced GH secretion but had no effect on cortisol secretion. In conclusion, ghrelin exhibited distinct sleep effects, which tended to be enhanced by both GHRH and CRH. CRH had sleep-improving and REM permissive effects when co-administered with ghrelin, being in contrast to the effect of CRH alone in previous studies.

Research paper thumbnail of Toll-like receptor-4 is expressed in menin- giomas and mediates the antiproliferative action of paclitaxel

International Journal of Cancer

Meningiomas are the second most common type of brain and CNS tumors by histology. Surgery and rad... more Meningiomas are the second most common type of brain and CNS tumors by histology. Surgery and radiotherapy are main treatment options, but meningiomas may be impossible to adequately resect or may regrow after surgery. In spite of many experimental attempts, there is no generally accepted chemotherapeutic approach. We have studied in a series of meningiomas the expression of the Toll-like receptor 4 (TLR4), which apart from its major role as a key factor of the innate immune system, is believed to play a role in tumorigenesis. All meningiomas studied expressed TLR4 mRNA and protein at variable degree. Paclitaxel, a ligand of TLR4, exhibited a dose-and time-dependent growth suppression in both monolayer and spheroid meningioma cell cultures. The knockdown of TLR4 with siRNA in meningioma cell cultures abrogated the inhibitory effect of paclitaxel. The suppressive action of paclitaxel on meningioma cell growth was enhanced in the presence of fluvastatin or the mitogen-actvated protein kinase (ERK1/2) inhibitor PD98059. At least part of the growth suppressive effect was mediated by the induction of apoptosis in meningioma cells by paclitaxel alone or in combination with fluvastatin. In conclusion, our in vitro results suggest that paclitaxel alone or in combination with other inhibitors of cell growth (statins, MAPK inhibitors) could provide a potential tool for the treatment of TLR4 expressing meningiomas.

Research paper thumbnail of Differences in polysomnography between patients suffering from Conn's syndrome in comparison with a control group

Experimental and Clinical Endocrinology & Diabetes

Research paper thumbnail of Copeptin – A surrogate marker of CCK-4-induced panic?

Psychoneuroendocrinology, 2015

Research paper thumbnail of Hippocampal mineralocorticoid receptors inhibit the hypothalamus-pituitary-adrenal axis: A new metyrapone-fludrocortisone test and effect of age

Research paper thumbnail of Overnight suppression of HPA axis after mineraolocorticoid receptor stimulation: A sleep endocrine study

Psychiatry research, Jan 24, 2015

Nocturnal hyperactivity of hypothalamic-pituitary-adrenal axis (HPA) indicates decreased feedback... more Nocturnal hyperactivity of hypothalamic-pituitary-adrenal axis (HPA) indicates decreased feedback inhibition with stress-related conditions such as major depression and sleep disorders. To characterize the role of mineralocorticoid (MR) in regulation of HPA axis activity during nocturnal sleep and involvement in sleep architecture, we investigated sleep endocrine effects of the MR agonist fludrocortisone in healthy men after pretreatment with metyrapone to minimize the impact of endogenous cortisol. Subjects (n=8) were treated on three occasions in a single-blinded design in random order with a) metyrapone, b) fludrocortisone after metyrapone, and c) placebo. Polysomnography was recorded and blood samples were drawn for determination of adrenocorticotropic hormone (ACTH) and cortisol during the entire night. After metyrapone administration ACTH was significantly enhanced, while overall nocturnal cortisol secretion remained largely unchanged. Whereas administration of fludrocortisone...

Research paper thumbnail of Ghrelin enhances the nocturnal secretion of cortisol and growth hormone in young females without influencing sleep

Psychoneuroendocrinology

Ghrelin was shown to increase slow wave sleep (SWS) and the secretion of growth hormone (GH) and ... more Ghrelin was shown to increase slow wave sleep (SWS) and the secretion of growth hormone (GH) and cortisol in young males. In terms of sleep, such information for females, however, is lacking. Therefore, polysomnographies were recorded (23:00-07:00 h) and nocturnal (20:00-07:00 h) secretion profiles of GH and cortisol were determined in 10 healthy females (24.9+/-2.4 years, body mass index: 21.2+/-1.1) twice, receiving four boluses of 50 microg ghrelin or placebo at 22:00, 23:00, 00:00, and 01:00 h, in this single-blind, randomized, cross-over study. No significant differences of conventionally or quantitatively analyzed sleep were observed between ghrelin and placebo condition. First administration of ghrelin caused a marked mean increase of GH by 53.3 to 64.4+/-14.2 ng/ml (placebo: 5.9+/-1.5 ng/ml) and cortisol by 54.2 to 96.4+/-15.3 ng/ml (placebo: 27.5+/-4.7 ng/ml). The following ghrelin injections were associated with smaller increases of GH and cortisol. In the ghrelin conditio...

Research paper thumbnail of A follow-up study for estimating the effectiveness of a cross-gender hormone substitution therapy on transsexual patients

Archives of sexual behavior, 1998

This follow-up study was carried out to validate the effectiveness of cross-gender hormone therap... more This follow-up study was carried out to validate the effectiveness of cross-gender hormone therapy embedded in a multistep treatment concept for transsexual patients. This therapy described in detail by the authors elsewhere and presented briefly below provides cross-gender hormone substitution to obtain an assimilation of secondary sex characteristics to the desired sex as quickly as possible. Personal and social background data of 46 male-to-female (M-to-F) and 42 female-to-male (F-to-M) patients passing through different stages of the treatment concept were included. In the Endocrinological Outpatient Clinic of the Max-Planck-Institute/Munich the effectiveness of cross-gender hormone replacement therapy as well as frequency and distribution of side effects were examined by follow-up examination of endocrinological parameters. Cross-gender hormones were administered either parenterally or orally. Blood samples were collected routinely after 2 to 6 months depending on the duration ...

Research paper thumbnail of Central administration of IL-1 reduces anxiety and induces sickness behaviour in rats

Pharmacology, biochemistry, and behavior, 1997

In the present study, we examined the effects of various doses of recombinant human interleukin-1... more In the present study, we examined the effects of various doses of recombinant human interleukin-1beta on anxiety-like behaviour, on body temperature, and on behavioural changes typical of sick animals. First, we assessed the behaviour of rats in the elevated plus-maze before and 20 min after intracerebroventricular injection of IL-1 at six doses ranging from 0.001 to 100 ng. After treatment with 0.1 and 100 ng IL-1, animals exhibited different anxiety levels. The dose effect on behavioural performance in the plus-maze appears to be nonlinear (parabolic function), with the highest effects near a 0.1-ng dose and the lowest near doses of 0.0 and 100 ng. In a second set of experiments, we examined the effects of doses of 0.1 and 100 ng IL-1 (which had the most pronounced effects on performance in the plus-maze) on physical parameters over a 24-h period. Using radiotelemetry we measured body temperature, locomotor activity, food intake, and water consumption: a) in animals kept under bas...

Research paper thumbnail of Differential Impact of Tetratricopeptide Repeat Proteins on the Steroid Hormone Receptors

PLoS ONE, 2010

Background: Tetratricopeptide repeat (TPR) motif containing co-chaperones of the chaperone Hsp90 ... more Background: Tetratricopeptide repeat (TPR) motif containing co-chaperones of the chaperone Hsp90 are considered control modules that govern activity and specificity of this central folding platform. Steroid receptors are paradigm clients of Hsp90. The influence of some TPR proteins on selected receptors has been described, but a comprehensive analysis of the effects of TPR proteins on all steroid receptors has not been accomplished yet.

Research paper thumbnail of Mental Health in Offspring of Traumatized Refugees with and without Post-traumatic Stress Disorder

Stress and Health, 2014

Intergenerational transmission of psychological trauma and the impact of parental post-traumatic ... more Intergenerational transmission of psychological trauma and the impact of parental post-traumatic stress disorder (PTSD) on offspring are controversially discussed. We studied 50 offspring (36 women and 14 men, mean age 42.1 years) of refugees who were severely traumatized as children at the end of World War II. From these, 25 of the refugees currently suffered from chronic PTSD, and 25 had no PTSD. Parental PTSD status did not significantly influence mental health [as per the Symptom Checklist (SCL)-90-R] or quality of life (assessed by the 36-item Short-form Health Survey) in their children. In the entire sample, frequency of talking with the mother about the flight correlated with phobic anxiety (r = 0.67, p = 0.03). Interestingly, the stated burden of having a parent with a history of flight significantly (p < 0.05) correlated with almost all subscales of the SCL-90-R. These results in a non-clinical sample do not support a specific role of parental PTSD in intergenerational trauma transmission. Our other remarkable, but preliminary, results need to be studied in larger samples using more subtle interaction or schema analyses. Copyright © 2014 John Wiley & Sons, Ltd.

Research paper thumbnail of Ghrelin administered in the early morning increases secretion of cortisol and growth hormone without affecting sleep

Psychoneuroendocrinology, 2007

Ghrelin and growth hormone (GH) releasing hormone (GHRH) both stimulate GH secretion and slow wav... more Ghrelin and growth hormone (GH) releasing hormone (GHRH) both stimulate GH secretion and slow wave sleep (SWS), whereas ghrelin increases, and GHRH decreases cortisol in males. However, GHRH's effect on sleep and cortisol was abolished, on GH mitigated, when administered in the early morning, possibly due to counteracting corticotropin releasing hormone (CRH). Aim of this study was to investigate ghrelin's influence on sleep, GH and cortisol when administered in the early morning. Nocturnal (2000-1000 h) GH and cortisol patterns and polysomnography (2300-1000 h) were determined in 12 healthy males (25.3+/-3.2 yr) twice, receiving 50 microg ghrelin or placebo at 0400, 0500, 0600, and 0700 h, in this single-blind, randomized, cross-over study. The first ghrelin bolus caused the strongest (38.7+/-6.5 ng/ml, placebo: 0.4+/-1.1 ng/ml), second and third smaller, the fourth no GH peak. GH levels remained significantly (p<0.05) higher from 0420-0740 h in the ghrelin condition. Comparably, the first ghrelin bolus caused the strongest cortisol response (156.0+/-12.6 ng/ml; placebo: 78.0+/-10.5 ng/ml). Cortisol was significantly higher from 0440 to 0540 and at 0720 h and decreased thereafter to significantly lower levels (0820-0840 h). Sleep variables did not differ in both conditions. In contrast to GHRH, ghrelin's stimulatory effects were apparently not counteracted (GH), and enhanced (cortisol), respectively, by high CRH in the second half of night.

Research paper thumbnail of Systemic growth hormone-releasing hormone (GHRH) impairs sleep in healthy young women

Psychoneuroendocrinology, 2007

In young male subjects peripherally administered growth hormone-releasing hormone (GHRH) enhances... more In young male subjects peripherally administered growth hormone-releasing hormone (GHRH) enhances GH and slow wave sleep (SWS) and blunts cortisol. In contrast, in a sample of females 19-76-year old, GHRH impairs sleep and enhances adrenocorticotropic hormone (ACTH) and cortisol. In the latter study, the days of investigation were not adapted to the menstrual cycle and premenopausal and postmenopausal women as well were included. Placebo and GHRH were given during consecutive nights. In order to confirm or reject the sexual dimorphism of the effects of GHRH on sleep we applied an improved study design. In the present study we examined the effect of pulsatile administration of two dosages of GHRH (4x25 or 4x50 microg intravenously, respectively) on sleep electroencephalogram (EEG) and nocturnal hormone secretion in healthy young women according to a randomized schedule. To rule out the influence of gonadal hormone activity, the study was adapted to the phase of the menstrual cycle and was performed at 4-6th day of menstrual cycle. A carry-over effect was excluded by the interval of at least 4 weeks between examinations. Compared to placebo rapid-eye-movement sleep decreased during the first half of the night after 4x25 microg GHRH and sleep stage 4 decreased after 4x50 microg GHRH. After both dosages GH increased whereas ACTH and cortisol remained unchanged. This study confirms that systemic GHRH impairs sleep in women.

Research paper thumbnail of Non-response of cortisol during stressful exposure therapy in patients with obsessive-compulsive disorder—Preliminary results

Psychiatry Research, 2012

Exposure with response prevention (ERP) is an established treatment for patients with obsessive-c... more Exposure with response prevention (ERP) is an established treatment for patients with obsessive-compulsive disorder (OCD) and also an interesting model to characterize neuroendocrine response to psychological stress. However, so far few studies have assessed hypothalamic-pituitary-adrenocortical (HPA) function during ERP and results are inconsistent. In 15 patients with OCD we repeatedly measured salivary cortisol and subjective units of distress (SUD) on two consecutive afternoons. The first day served as a comparison condition; on the second day the very first session of ERP took place. While SUD were significantly increased during ERP versus the comparison day, salivary cortisol was statistically indistinguishable between ERP and comparison conditions before, during and after ERP. Thus, despite considerable psychological stress no increase of cortisol was observed. This response pattern to ERP in OCD patients needs further research.

Research paper thumbnail of Prognostic and Symptomatic Aspects of Rapid Eye Movement Sleep in a Mouse Model of Posttraumatic Stress Disorder

Frontiers in Behavioral Neuroscience, 2013

Not every individual develops Posttraumatic Stress Disorder (PTSD) after the exposure to a potent... more Not every individual develops Posttraumatic Stress Disorder (PTSD) after the exposure to a potentially traumatic event. Therefore, the identification of pre-existing risk factors and early diagnostic biomarkers is of high medical relevance. However, no objective biomarker has yet progressed into clinical practice. Sleep disturbances represent commonly reported complaints in PTSD patients. In particular, changes in rapid eye movement sleep (REMS) properties are frequently observed in PTSD patients. Here, we examined in a mouse model of PTSD whether (1) mice developed REMS alterations after trauma and (2) whether REMS architecture before and/or shortly after trauma predicted the development of PTSD-like symptoms. We monitored sleep-wake behavior via combined electroencephalogram/electromyogram recordings immediately before (24 h pre), immediately after (0-48 h post) and 2 months after exposure to an electric foot shock in male C57BL/6N mice (n = 15). PTSD-like symptoms, including hyperarousal, contextual, and generalized fear, were assessed 1 month post-trauma. Shocked mice showed early onset and sustained elevation of REMS compared to non-shocked controls. In addition, REMS architecture before trauma was correlated with the intensity of acoustic startle responses, but not contextual fear, 1 month after trauma. Our data suggest REMS as prognostic (pre-trauma) and symptomatic (post-trauma) marker of PTSD-like symptoms in mice. Translated to the situation in humans, REMS may constitute a viable, objective, and non-invasive biomarker in PTSD and other trauma-related psychiatric disorders, which could guide pharmacological interventions in humans at high risk.

Research paper thumbnail of Monthly intravenous methylprednisolone in relapsing-remitting multiple sclerosis - reduction of enhancing lesions, T2 lesion volume and plasma prolactin concentrations

Intravenous methylprednisolone (IV-MP) is an established treatment for multiple sclerosis (MS) re... more Intravenous methylprednisolone (IV-MP) is an established treatment for multiple sclerosis (MS) relapses, accompanied by rapid, though transient reduction of gadolinium enhancing (Gd+) lesions on brain MRI. Intermittent IV-MP, alone or with immunomodulators, has been suggested but insufficiently studied as a strategy to prevent relapses. In an open, single-cross-over study, nine patients with relapsing-remitting MS (RR-MS) underwent cranial Gd-MRI once monthly for twelve months. From month six on, they received a single i.v.-infusion of 500 mg methylprednisolone (and oral tapering for three days) after the MRI. Primary outcome measure was the mean number of Gd+ lesions during treatment vs. baseline periods; T2 lesion volume and monthly plasma concentrations of cortisol, ACTH and prolactin were secondary outcome measures. Safety was assessed clinically, by routine laboratory and bone mineral density measurements. Soluble immune parameters (sTNF-RI, sTNF-RII, IL1-ra and sVCAM-1) and neuroendocrine tests (ACTH test, combined dexamethasone/CRH test) were additionally analyzed. Comparing treatment to baseline periods, the number of Gd+ lesions/scan was reduced in eight of the nine patients, by a median of 43.8% (p = 0.013, Wilcoxon). In comparison, a pooled dataset of 83 untreated RR-MS patients from several studies, selected by the same clinical and MRI criteria, showed a non-significant decrease by a median of 14% (p = 0.32). T2 lesion volume decreased by 21% during treatment (p = 0.001). Monthly plasma prolactin showed a parallel decline (p = 0.027), with significant cross-correlation with the number of Gd+ lesions. Other hormones and immune system variables were unchanged, as were ACTH test and dexamethasone-CRH test. Treatment was well tolerated; routine laboratory and bone mineral density were unchanged. Monthly IV-MP reduces inflammatory activity and T2 lesion volume in RR-MS.

Research paper thumbnail of Differential effects to CCK-4-induced panic by dexamethasone and hydrocortisone

World Journal of Biological Psychiatry, 2012

Peripheral administration of the cholecystokinin (CCK) receptor agonist CCK-4 generates panic and... more Peripheral administration of the cholecystokinin (CCK) receptor agonist CCK-4 generates panic and activates the hypothalamic-pituitary-adrenal (HPA) axis. Direct effects at the pituitary and CCK-HPA interactions at higher regulatory sites have been suggested. According to preliminary data, ACTH response to CCK receptor agonists may differ from its response to exogenous CRH by its resistance to cortisol feedback inhibition. To further explore this resistance and to better characterize CCK-4 sites of action, the effects of different glucocorticoid pretreatments on CCK-4-induced panic were compared. Using a double-blind placebo-controlled design we pretreated healthy males with either dexamethasone (peripheral action) or hydrocortisone (central-peripheral action) each followed by a CCK-4 challenge. Blood levels of ACTH and cortisol were analyzed and panic symptoms were assessed. We found a blunted response of ACTH release following CCK-4 injection only after hydrocortisone pretreatment. Dexamethasone however did not affect CCK-4-induced ACTH release relative to baseline. In contrast to dexamethasone, hydrocortisone reduced the severity of CCK-4-induced panic as measured by the Acute Panic Inventory on a trend level. Findings suggest that CCK-4-induced stress hormone release seems susceptible to cortisol-feedback inhibition and argues for a suprapituitary site of CCK action. Effects on panic anxiety were weak but congruent with studies showing that CCK-4-induced HPA axis inhibition is accompanied by a reduction of anxiety after CCK-4.

Research paper thumbnail of Langzeitfolgen von in der Kindheit am Ende des II. Weltkrieges erlebter Flucht und Vertreibung

PPmP - Psychotherapie · Psychosomatik · Medizinische Psychologie, 2011

Little is known about long-term consequences of flight and expulsion during childhood. The aim of... more Little is known about long-term consequences of flight and expulsion during childhood. The aim of this study was to interview aging former refugee children about their recollection of traumatic experiences and to screen for full and partial posttraumatic stress disorder (PTSD) and their differential impact on today's quality of life and mental health. In 502 participants from the former German eastern territories who were displaced as children at the end of World War II (at the age of 5-12 years) we examined traumatic experiences, posttraumatic stress symptoms (PDS), comorbid symptoms (SCL-90-R), depressive symptoms (BDI) and quality of life (SF-36). 31.5% participants reported posttraumatic stress symptoms indicating current full PTSD, and 33.7% fulfilled the criteria of a current partial PTSD. Participants with full and partial PTSD reported a significantly reduced quality of life, often depressive and comorbid symptoms and were compromised in their well-being compared to participants without PTSD. The study demonstrates the long-term consequences of flight and expulsion during childhood in aging former refugee children more than 60 years later. Posttraumatic stress symptoms play a prominent role for quality of life and well-being in this population.

Research paper thumbnail of Influence of clonidine on psychopathological, endocrine and respiratory effects of cholecystokinin tetrapeptide in patients with panic disorder

Psychopharmacology, 1997

The influence of clonidine pretreatment on psychopathological, endocrine and respiratory effects ... more The influence of clonidine pretreatment on psychopathological, endocrine and respiratory effects of cholecystokinin tetrapeptide (CCK-4) was characterized. Patients with panic disorder (DSM-III-R) were given 50 micrograms CCK-4 i.v. at 1100 hours on 2 separate study days. In a randomized double-blind design they were additionally infused with 150 micrograms clonidine or placebo from 1040 to 1110 hours. After CCK-4 all patients experienced symptom attacks. No effects of clonidine on panic psychopathology or blood gas parameters were observed. After CCK-4, in the clonidine condition the pituitary release of adrenocorticotropin (ACTH) and prolactin was seemingly enhanced compared to placebo. Our results suggest that CCK-4-induced panic attacks are not suppressible by presynaptic alpha-2 receptor stimulation. Moreover, they point to a synergistic postsynaptic action of clonidine to CCK-4 upon pituitary hormone secretion. The diverging sites of action might possibly explain the discrepancies of psychopathological alterations and stress hormone secretion.

Research paper thumbnail of Effects of a metabotropic glutamate2/3 receptor agonist (LY544344/LY354740) on panic anxiety induced by cholecystokinin tetrapeptide in healthy humans: preliminary results

Psychopharmacology, 2005

Preclinical findings have repeatedly shown an anxiolytic-like action of agonists at metabotropic ... more Preclinical findings have repeatedly shown an anxiolytic-like action of agonists at metabotropic glutamate receptors type II, such as LY354740. We aimed to investigate the effect of LY544344, the prodrug of LY354740, upon experimental panic anxiety in humans. Twelve healthy human volunteers were treated orally with 80 mg bid LY544344 for 1 week in a randomized placebo-controlled cross-over study before 50 mug cholecystokinin tetrapeptide (CCK-4) was injected intravenously. We assessed CCK-induced panic and anxiety symptoms and measured stress hormone release. While no significant treatment effect emerged in the entire sample, a significant reduction of the number of CCK-4-induced panic symptoms and of CCK-4-induced subjective anxiety ratings was detected after removing two subjects who did not show decreased CCK-4-elicited adrenocorticotropin (ACTH) release after LY544344 compared to placebo treatment. Further studies are needed to clarify the potential of LY544344 as a new anxiolytic or antipanic drug.

Research paper thumbnail of Ghrelin alone or co-administered with GHRH or CRH increases non-REM sleep and decreases REM sleep in young males

Psychoneuroendocrinology, 2008

Ghrelin activates the somatotropic and the hypothalamic-pituitary-adrenal axes, being crucially i... more Ghrelin activates the somatotropic and the hypothalamic-pituitary-adrenal axes, being crucially involved in sleep regulation. Simplified, growth hormone releasing hormone (GHRH) increases slow-wave sleep and REM sleep in males, whilst corticotropin-releasing hormone (CRH) increases wakefulness and decreases REM sleep. Ghrelin's role in sleep regulation and particularly its interactions with GHRH and CRH are not entirely clear. We aimed to elucidate the interactions between ghrelin, GHRH and CRH in sleep regulation and the secretion of cortisol and GH. Nocturnal GH and cortisol secretion and polysomnographies were determined in 10 healthy males (25.7+/-3.0 years) four times, receiving placebo (A), ghrelin (B), ghrelin and GHRH (C), or ghrelin and CRH (D) at 22:00, 23:00, 00:00, and 01:00h, in this single-blind, randomized, cross-over study. Non-REM sleep was significantly (p<0.05) increased in all verum conditions (mean+/-SEM: B: 355.3+/-7.4; C: 365.4+/-8.1; D: 371.4+/-3.9min) compared to placebo (336.3+/-6.8min). REM sleep was decreased (B: 84.3+/-4.2 [p<0.1]; C: 74.2+/-7.0 [p<0.05]; D: 80.4+/-2.7min [p<0.05]) compared to placebo (100.9+/-8.3). CRH+ghrelin decreased the time spent awake and enhanced the sleep efficiency; furthermore, the REM latency was decreased compared to the other treatment conditions. CRH enhanced the ghrelin-induced cortisol secretion but had no relevant effect on GH secretion. In turn, GHRH enhanced the ghrelin-induced GH secretion but had no effect on cortisol secretion. In conclusion, ghrelin exhibited distinct sleep effects, which tended to be enhanced by both GHRH and CRH. CRH had sleep-improving and REM permissive effects when co-administered with ghrelin, being in contrast to the effect of CRH alone in previous studies.