ORCID Profile
0000-0001-6409-0664
Current Organisations
Leibniz-Institut zur Analyse des Biodiversitätswandels
,
Friedrich-Alexander-Universität Erlangen-Nürnberg
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Publisher: Elsevier BV
Date: 10-2004
Publisher: Springer Science and Business Media LLC
Date: 25-03-2021
DOI: 10.1038/S41598-021-85656-X
Abstract: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin gene. The neuropathology of HD is characterized by the decline of a specific neuronal population within the brain, the striatal medium spiny neurons (MSNs). The origins of this extreme vulnerability remain unknown. Human induced pluripotent stem cell (hiPS cell)-derived MSNs represent a powerful tool to study this genetic disease. However, the differentiation protocols published so far show a high heterogeneity of neuronal populations in vitro. Here, we compared two previously published protocols to obtain hiPS cell-derived striatal neurons from both healthy donors and HD patients. Patch-cl experiments, immunostaining and RT-qPCR were performed to characterize the neurons in culture. While the neurons were mature enough to fire action potentials, a majority failed to express markers typical for MSNs. Voltage-cl experiments on voltage-gated sodium (Nav) channels revealed a large variability between the two differentiation protocols. Action potential analysis did not reveal changes induced by the HD mutation. This study attempts to demonstrate the current challenges in reproducing data of previously published differentiation protocols and in generating hiPS cell-derived striatal MSNs to model a genetic neurodegenerative disorder in vitro.
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.BRAINRESBULL.2006.01.003
Abstract: Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a CAG repeat expansion in the HD gene. Excitotoxic cell damage by excessive stimulation of glutamate receptors has been hypothesized to contribute to the pathogenesis of HD. Transgenic mouse models of HD have shown variable sensitivity to excitotoxicity. The models differ in the genetic background, the type and length of the promoter driving the transgene expression, the CAG repeat length and/or the HD gene construct length. Furthermore, one has to differentiate whether transgenic or knock-in models have been used. All these factors may be involved in determining the responsiveness to an excitotoxic insult. Here, we explored the responsiveness to excitotoxic damage using a transgenic HD rat model carrying 22% of the rat HD gene which is driven by the rat HD promoter and which harbors 51 CAG repeats. 3 and 18 months old transgenic HD rats and their wild-type littermates received unilateral intrastriatal injections of the glutamate analogue quinolinic acid. Lesion size was assessed 7 days later using the degenerative stain Fluoro-Jade and by immunohistochemistry for the neuronal protein NeuN. No difference in susceptibility to excitotoxicity was found between the groups. Our study supports mouse data showing maintained susceptibility to excitotoxicity with the expression of around 25% of the full HD gene. Differences in sensitivity to excitotoxicity between genetic animal models of HD may be dependent on the length of the expressed HD gene although additional factors are also likely to be important.
Publisher: Springer Science and Business Media LLC
Date: 23-07-2018
DOI: 10.1038/S41380-018-0114-5
Abstract: Antipsychotic drugs are effective interventions in schizophrenia. However, the efficacy of these agents often decreases over time, which leads to treatment failure and symptom recurrence. We report that antipsychotic efficacy in rat models declines in concert with extracellular striatal dopamine levels rather than insufficient dopamine D2 receptor occupancy. Antipsychotic efficacy was associated with a suppression of dopamine transporter activity, which was reversed during failure. Antipsychotic failure coincided with reduced dopamine neuron firing, which was not observed during antipsychotic efficacy. Synaptic field responses in dopamine target areas declined during antipsychotic efficacy and showed potentiation during failure. Antipsychotics blocked synaptic vesicle release during efficacy but enhanced this release during failure. We found that the pharmacological inhibition of the dopamine transporter rescued antipsychotic drug treatment outcomes, supporting the hypothesis that the dopamine transporter is a main target of antipsychotic drugs and predicting that dopamine transporter blockers may be an adjunct treatment to reverse antipsychotic treatment failure.
Publisher: Elsevier BV
Date: 07-2003
DOI: 10.1016/S0091-3057(03)00154-0
Abstract: Dipeptidyl-peptidase IV (DPPIV/CD26) is involved in several physiological functions by cleavage of dipeptides with a Xaa-Pro or Xaa-Ala sequence of regulatory peptides such as neuropeptide Y (NPY). Cleavage of NPY by DPPIV results in NPY(3-36), which lacks affinity for the Y(1) but not for other NPY receptor subtypes. Among other effects, the NPY Y(1) receptor mediates anxiolytic-like effects of NPY. In previous studies with F344 rat substrains lacking endogenous DPPIV-like activity we found a reduced behavioral stress response, which might be due to a differential degradation of NPY. Here we tested this hypothesis and administered intracerebroventricularly two different doses of NPY (0.0, 0.2, 1.0 nmol) in mutant and wildtype-like F344 substrains. NPY dose-dependently stimulated food intake and feeding motivation, decreased motor activity in the plus maze and social interaction test, and exerted anxiolytic-like effects. More important for the present hypothesis, NPY administration was found to be more potent in the DPPIV-negative substrains in exerting anxiolytic-like effects (increased social interaction time in the social interaction test) and sedative-like effects (decreased motor activity in the elevated plus maze). These data demonstrate for the first time a differential potency of NPY in DPPIV-deficient rats and suggest a changed receptor-specificity of NPY, which may result from a differential degradation of NPY in this genetic model of DPPIV deficiency. Overall, these results provide direct evidence that NPY-mediated effects in the central nervous system are modulated by DPPIV-like enzymatic activity.
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.NEUBIOREV.2012.11.012
Abstract: Kratom (or Ketum) is a psychoactive plant preparation used in Southeast Asia. It is derived from the plant Mitragyna speciosa Korth. Kratom as well as its main alkaloid, mitragynine, currently spreads around the world. Thus, addiction potential and adverse health consequences are becoming an important issue for health authorities. Here we reviewed the available evidence and identified future research needs. It was found that mitragynine and M. speciosa preparations are systematically consumed with rather well defined instrumentalization goals, e.g. to enhance tolerance for hard work or as a substitute in the self-treatment of opiate addiction. There is also evidence from experimental animal models supporting analgesic, muscle relaxant, anti-inflammatory as well as strong anorectic effects. In humans, regular consumption may escalate, lead to tolerance and may yield aversive withdrawal effects. Mitragynine and its derivatives actions in the central nervous system involve μ-opioid receptors, neuronal Ca²⁺ channels and descending monoaminergic projections. Altogether, available data currently suggest both, a therapeutic as well as an abuse potential.
Publisher: SAGE Publications
Date: 04-2006
DOI: 10.1258/002367706776319015
Abstract: Stress causes a rise in body temperature in laboratory animals (stress-induced hyperthermia). However, the direct effect of common stressors in animal research, i.e. transportation between holding and test rooms or isolation of animals, on body temperature has not been investigated to its full extent. To address this question, it is important to have a reliable and simple monitoring technique, which does not induce stress itself. In the present study, we investigated stress-related changes in body temperature of F344/Hw rats after (1) moving the cage within the holding room, (2) moving the cage from the holding room to another test room and (3) social deprivation (isolation). A combination of two different body temperature recording methods was used to clarify their accuracy and stress-inductive character: rectal temperature recording and peritoneal implanted temperature sensors (Thermochron iButtons). The results demonstrate that (1) different stressors induce a significant rise in body temperature, (2) which is detectable for more than 60 min and (3) it is of importance to standardize temperature recording methods in order to avoid confounding effects of the recording method itself. Furthermore, Thermochron iButtons are more accurate and reliable for body temperature studies than rectal recordings.
Publisher: Proceedings of the National Academy of Sciences
Date: 16-08-2004
Abstract: Neuropeptide Y (NPY) is pivotal in the coordinated regulation of food intake, growth, and reproduction, ensuring that procreation and growth occur only when food is abundant and allowing for energy conservation when food is scant. Although emotional and behavioral responses from the higher brain are known to be involved in all of these functions, understanding of the coordinated regulation of emotion/behavior and physiological functions is lacking. Here, we show that the NPY system plays a central role in this process because ablation of the Y1 receptor gene leads to a strong increase in territorial aggressive behavior. After exposure to the resident-intruder test, expression of c-fos mRNA in Y1-knockout mice is significantly increased in the medial amygdala, consistent with the activation of centers known to be important in regulating aggressive behavior. Expression of the serotonin [5-hydroxytryptamine (5-HT)] synthesis enzyme tryptophan hydroxylase is significantly reduced in Y1-deficient mice. Importantly, treatment with a 5-HT-1A agonist, (±)-8-hydroxy-2-(di- n -propylamino)tetralin hydrobromide, abolished the aggressive behavior in Y1-knockout mice. These results suggest that NPY acting through Y1 receptors regulates the 5-HT system, thereby coordinately linking physiological survival mechanisms such as food intake with enabling territorial aggressive behavior.
Publisher: Elsevier BV
Date: 2003
Abstract: The evaluation of behavioral effects is an important component for the in vivo screening of drugs or potentially toxic compounds in mice. Ideally, such screening should be composed of monitoring general health, sensory functions, and motor abilities, right before specific behavioral domains are tested. A rational strategy in the design and procedure of testing as well as an effective composition of different well-established and reproducible behavioral tests can minimize the risk of false positive and false negative results in drug screening. In the present review we describe such basic considerations in planning experiments, selecting strains of mice, and propose groups of behavioral tasks suitable for a reliable detection of differences in specific behavioral domains in mice. Screening of general health and neurophysiologic functions (reflexes, sensory abilities) and motor function (pole test, wire hang test, beam walking, rotarod, accelerod, and footprint) as well as specific hypothesis-guided testing in the behavioral domains of learning and memory (water maze, radial maze, conditioned fear, and avoidance tasks), emotionality (open field, hole board, elevated plus maze, and object exploration), nociception (tail flick, hot plate), psychiatric-like conditions (porsolt swim test, acoustic startle response, and prepulse inhibition), and aggression (isolation-induced aggression, spontaneous aggression, and territorial aggression) are described in further detail. This review is designed to describe a general approach, which increases reliability of behavioral screening. Furthermore, it provides an overview on a selection of specific procedures suitable for but not limited to behavioral screening in pharmacology and toxicology.
Publisher: Elsevier BV
Date: 10-2003
DOI: 10.1016/S0031-9384(03)00229-4
Abstract: The enzyme and binding protein dipeptidyl peptidase IV (DPPIV/CD26) has a unique enzymatic specificity in cleaving dipeptides from neuropeptides, chemokines, and hormones. Thus, DPPIV is potentially involved in the regulation of functions of the immune, endocrine, and nervous systems. In the present study, we compared DPPIV-deficient, mutant Japanese [F344/DuCrj(DPPIV-)] and German [F344/Crl(Ger/DPPIV-)] F344 rat substrains with a wild-type-like F344 substrain [F344/Crl(Por)] from the United States in a multitiered strategy using a number of different behavioral tests. General health, neurological and motor functions, and sensory abilities of the different F344 substrains were not different. A reduced body weight and a reduced water consumption were observed in mutant animals. DPPIV-deficient rats exhibited increased pain sensitivity in a non-habituated hot plate test, indicative of a reduced stress-induced analgesia. In line with this finding, reduced stress-like responses in tasks like the open field (OF), social interaction (SI), and passive avoidance test were found. Differences in DPPIV-like activity appear to be involved in neurophysiological processes because DPPIV-deficient animals were less susceptible to the sedative effects of ethanol. The varying phenotypes of the F344 substrains are likely to be mediated by differential degradation of DPPIV substrates such as substance P, glucagon-like peptide (GLP)-1, enterostatin, and especially neuropeptide Y (NPY). Potentially, DPPIV-deficient substrains represent an important tool for biomedical research, focusing on the involvement of DPPIV and its substrates in behavioral and physiological processes.
Publisher: Oxford University Press (OUP)
Date: 14-12-2004
DOI: 10.1111/J.1365-2249.2005.02666.X
Abstract: CD26 truncates several chemokines as well as neuropeptides and influences immune responses via modulation of cell adhesion and T cell activation, suggesting an involvement of CD26 in asthmatic and airway inflammation. Therefore, Fischer 344 (F344), Brown Norway (BN) and Lewis (LEW) rat strains, which differ in their CD26-like enzymatic activity, were compared using an asthma model. Additionally, two CD26-deficient mutant F344 rat substrains were included and compared to the wild-type F344 substrain. Immunization was performed twice with ovalbumin (OVA), and 2 weeks later the rats were challenged with OVA intratracheally Flow cytometry (FACS) analysis of different leucocyte subsets as well as enzyme-linked immunosorbent assay (ELISA) for IgE levels in the blood and bronchoalveolar lavage (BAL) were performed 24 h after challenge. LEW rats with the lowest CD26 activity among the rat strains investigated here displayed significantly reduced CD4+ T cell numbers in the BAL compared to wild-type F344 and BN rats. Moreover, in asthma, the ratio of CD26+ to CD26– T cell receptor (TCR)-positive cells increased significantly in F344 and LEW but not BN rats. Most intriguingly, in both CD26-deficient F344 rat substrains the number of CD4+ T lymphocytes was markedly reduced compared to wild-type F344. The decrease in T cell recruitment observed in the CD26-deficient rats was associated with significantly reduced OVA-specific IgE-titres. This is the first report to show a remarkably reduced T cell recruitment in rat strains that either lack or exhibit reduced CD26-like enzymatic activity, suggesting a role for CD26 in the pathogenesis of asthma via T cell-dependent processes such as antibody production.
Publisher: Elsevier BV
Date: 11-2002
DOI: 10.1016/S0165-5728(02)00278-3
Abstract: Sympathetic nervous system (SNS) activation mobilizes blood leukocytes. Under these circumstances, both epinephrine (EPI) and neuropeptide Y (NPY) are released. Therefore, we investigated a possible interaction between these transmitters during leukocyte mobilization, using intravenous catheterization of male adult Lewis rats. Intravenous application of NPY followed by EPI, dose-dependently facilitated, intensified and inhibited EPI-induced leukocytosis with subset-specificity for NK-cells, monocytes, and B-lymphocytes. Pharmacological assessment of NPY receptors involved revealed a Y-1R-mediated inhibition and a Y-5R-mediated facilitation. RT-PCR on peripheral blood mononuclear cells (PBMC) detected Y-1R mRNA only, suggesting direct Y-1R-mediated effects on leukocytes and indirect effects via the Y-5R. Thus, via a specific Y-1R/Y-5R interplay, NPY acts as a neuroimmune co-transmitter in vivo.
Publisher: Elsevier BV
Date: 09-2003
DOI: 10.1016/S0167-0115(03)00149-6
Abstract: Dipeptidyl-peptidase IV (DPPIV) is involved in endocrine and immune functions via cleavage of regulatory peptides with a N-terminal proline or alanine such as incretins, neuropeptide Y, or several chemokines. So far no systematic investigations on the localization and transmission of the Dpp4 gene or the natural variations of DPPIV-like enzymatic function in different rat strains have been conducted. Here we mapped the Dpp4 gene to rat chromosome 3 and describe a semi-dominant mode of inheritance for Dpp4 in a mutant F344/DuCrj(DPPIV-) rat substrain lacking endogenous DPPIV-like activity. This mutant F344/DuCrj(DPPIV-) rat substrain constantly exhibits a nearly complete lack of DPPIV-like enzymatic activity, while segregation of DPPIV-like enzymatic activity was observed in another DPPIV-negative F344/Crl(Ger/DPPIV-) rat substrain. Screening of 12 different inbred laboratory rat strains revealed dramatic differences in DPPIV-like activity ranging from 11 mU/microl (LEW/Ztm rats) to 40 mU/microl (BN/Ztm and DA/Ztm rats). A lack of DPPIV-like activity in F344 rats was associated with an improved glucose tolerance and blunted natural killer cell function, which indicates the pleiotropic functional role of DPPIV in vivo. Overall, the variations in DPPIV-like enzymatic activity probably represent important confounding factors in studies using rat models for research on regulatory peptides.
Publisher: Elsevier BV
Date: 07-2001
DOI: 10.1016/S0165-5728(01)00328-9
Abstract: Sympathetic nervous system activation mobilizes leukocytes but it is unknown whether the concomitant neuropeptide Y (NPY)-release also alters blood leukocyte counts. Using chronic intravenous (i.v.) cannulation of freely moving rats and flow cytometry, time-, dose- and subset-specific effects of NPY on blood leukocytes were investigated 1-15 min after injection: High-dose NPY increases leukocytes numbers by preferentially mobilizing CD4(+) T-cells, activated NKR-P1A(+) monocytes and NK-cells. Low-dose NPY significantly decreases B-lymphocyte and NK-cell numbers. Furthermore, NPY dose-dependently mobilizes a previously undetected IgM(low)CD5(+)CD11b(+) B-cell subpopulation in rats ("B1-like" B-lymphocytes). These data suggest a role for the sympathetic neurotransmitter NPY in neuroimmune alterations in vivo.
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1016/J.PEPTIDES.2006.07.029
Abstract: Although it is broadly accepted that the immune system and the nervous system functionally interact with each other at various levels, many aspects of this crosstalk still remain unclear. One player in this interaction is neuropeptide Y (NPY), a sympathetic neurotransmitter, which has been demonstrated to regulate a broad variety of immune functions. In this review we will outline key findings on the effects NPY exerts on phagocytosis by neutrophils and monocytes/macrophages and its relevance to the elimination of invading pathogens. Furthermore, we will discuss the implications of these findings for antigen presentation by dendritic cells and the induction of adaptive immune responses.
Publisher: Informa UK Limited
Date: 25-04-2019
Publisher: Oxford University Press (OUP)
Date: 08-2010
DOI: 10.1002/IBD.21241
Abstract: We have previously demonstrated that inhibition of dipeptidyl peptidase (DP) activity partially attenuates dextran sulfate sodium (DSS) colitis in mice. The aim of this study was to further investigate the mechanisms of this protection. Wildtype (WT) and DPIV(-/-) mice consumed 2% DSS in drinking water for 6 days to induce colitis. Mice were treated with saline or the DP inhibitors Ile-Pyrr-(2-CN)*TFA or Ile-Thia. DP mRNA and enzyme levels were measured in the colon. Glucagon-like peptide (GLP)-2 and GLP-1 concentrations were determined by radioimmunoassay, regulatory T-cells (Tregs) by fluorescence activated cell sorting (FACS) on FOXp3+T cells in blood, and neutrophil infiltration assessed by myeloperoxidase (MPO) assay. DP8 and DP2 mRNA levels were increased (P < 0.05) in WT+saline mice compared to untreated WT mice with colitis. Cytoplasmic DP enzyme activity was increased (P < 0.05) in DPIV(-/-) mice at day 6 of DSS, while DP2 activity was increased (P < 0.05) in WT mice with colitis. GLP-1 (63%) and GLP-2 (50%) concentrations increased in WT+Ile-Pyrr-(2-CN)*TFA mice compared to day-0 controls. MPO activity was lower in WT+Ile-Thia and WT+Ile-Pyrr-(2-CN)*TFA treated mice compared to WT+saline (P < 0.001) at day 6 colitis. DP expression and activity are differentially regulated during DSS colitis, suggesting a pathophysiological role for these enzymes in human inflammatory bowel disease (IBD). DP inhibitors impaired neutrophil recruitment and maintenance of the Treg population during DSS-colitis, providing further preclinical evidence for the potential therapeutic use of these inhibitors in IBD. Finally, DPIV appears to play a critical role in mediating the protective effect of DP inhibitors.
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.JNEUROIM.2008.01.012
Abstract: Despite a continuously growing body of evidence highlighting the role of NPY in the immune system, surprisingly little is known about its ability to alter human leukocyte function. We therefore set out to examine NPY receptor expression and functional effects of NPY in freshly isolated human neutrophils. Our results not only demonstrate for the first time the presence of specific NPY receptors on human neutrophils, but also unveil of how these receptors differentially modulate critical functions of neutrophils such as phagocytosis of bacteria as well as the release of reactive oxygen species.
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1016/J.PEPTIDES.2006.09.027
Abstract: N-terminal truncation of NPY has important physiological consequences, because the truncated peptides lose their capability to activate the Y1-receptor. The sources of N-terminally truncated NPY and related peptides are unknown and several proline specific peptidases may be involved. First, we therefore provide an overview on the peptidases, belonging to structural and functional homologues of dipeptidyl peptidase 4 (DP4) as well as aminopeptidase P (APP) and thus, represent potential candidates of NPY cleavage in vivo. Second, applying selective inhibitors against DP4, DP8/9 and DP2, respectively, the enzymatic distribution was analyzed in brain extracts from wild type and DP4 deficient F344 rat substrains and human plasma s les in activity studies as well as by matrix assisted laser desorption/ionisation-time of flight (MALDI-TOF)-mass spectrometry. Third, co-transfection of Cos-1 cells with Dpp4 and Npy followed by confocal lasermicroscopy illustrated that hNPY-dsRed1-N1 was transported in large dense core vesicles towards the membrane while rDP4-GFP-C1 was transported primarily in different vesicles thereby providing no clear evidence for co-localization of NPY and DP4. Nevertheless, the review and experimental results of activity and mass spectrometry studies support the notion that at least five peptidases (DP4, DP8, DP9, XPNPEP1, XPNPEP2) are potentially involved in NPY cleavage while the serine protease DP4 (CD26) could be the principal peptidase involved in the N-terminal truncation of NPY. However, DP8 and DP9 are also capable of cleaving NPY, whereas no cleavage could be demonstrated for DP2.
Publisher: Elsevier BV
Date: 10-2004
Publisher: American Physiological Society
Date: 06-2007
DOI: 10.1152/AJPLUNG.00273.2006
Abstract: The ovalbumin (OVA)-induced airway inflammation in rats is a commonly used model to explore the pathobiology of asthma. However, its susceptibility varies greatly between rat strains, and presently Brown Norway (BN) rats are preferentially used. Since recruitment of T cells to the lungs depends on the CD26 (dipeptidyl peptidase IV, DPPIV) expression, Fischer 344 strain (F344) rats are a highly relevant rat strain, in particular because CD26-deficient substrains are available. To establish a F344 rat model of asthma, we challenged F344 rats using different doses of aerosolized antigen (0%, 1%, 2.5%, 5%, and 7.5% OVA) and compared these effects with intratracheal instillation of OVA (1.5 mg/0.3 ml). Asthmoid responsiveness was determined by analysis of early airway responsiveness (EAR), antigen-specific IgE levels, as well as airway inflammation including the composition of T cell subpopulations in the bronchoalveolar lavage (BAL) and lung tissue with special respect to the T cell activation markers CD25 and CD26. Even low allergen doses caused allergen-specific EAR and increases of antigen-specific IgE levels. However, EAR and IgE levels did not increase dose dependently. Higher concentrations of OVA led to a dose-dependent increase of several immunological markers of allergic asthma including an influx of eosinophils, T cells, and dendritic cells. Interestingly, a dose-dependent increase of CD4 + /CD25 + /CD26 + T cells was found in the lungs. Summarizing, we established a novel F344 rat model of aerosolized OVA-induced asthma. Thereby, we found a dose-dependent recruitment of cellular markers of allergic asthma including the activated CD4 + /CD25 + /CD26 + T cell subpopulation, which has not been described in asthma yet.
Publisher: Elsevier BV
Date: 2003
DOI: 10.1016/S0165-5728(02)00424-1
Abstract: Both cellular and humoral functions of the immune system are modulated by the sympathetic nervous system (SNS). This interaction is mainly mediated by the release of catecholamines (CA) and their receptor-specific action on immune cells. However, neuropeptide Y (NPY), also present in sympathetic nerve terminals, is released upon SNS-stimulation. NPY modulates potent immunological effects in vitro and in vivo, such as differentiation of T helper cells, monocyte mediator release, NK cell activation, and immune cell redistribution. In addition to this direct action within the neuroimmune crosstalk, NPY is also able to modulate the immunomodulatory effects of other neurotransmitters, thereby acting as a neuroimmune co-transmitter. This review will discuss key findings from recent studies, provide implications for the clinical situation, and integrate the pleiotropic functions of NPY in the context of neuroimmune interactions.
Location: Japan
Location: Germany
Location: United States of America
No related grants have been discovered for Stephan von Hörsten.