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dc.contributor.authorGrant, Phillip
dc.date.accessioned2023-03-28T12:43:43Z
dc.date.available2011-12-09T14:24:17Z
dc.date.available2023-03-28T12:43:43Z
dc.date.issued2011
dc.identifier.urihttp://nbn-resolving.de/urn:nbn:de:hebis:26-opus-84954
dc.identifier.urihttps://jlupub.ub.uni-giessen.de//handle/jlupub/15869
dc.identifier.urihttp://dx.doi.org/10.22029/jlupub-15251
dc.description.abstractSigns of neurodegeneration are commonly found in schizophrenic patients, albeit still unclear, why they occur and whether they are a cause or rather an effect of schizophrenia. Although there are numerous studies supporting either theory, the working hypothesis of this thesis is that an overactivity of mesolimbic dopaminergic pathways leads to dopamine neurotoxicity in terms of an increased production of reactive oxygen species (ROS), in time leading to oxidative stress and thereby to so-called atypical neurodegeneration. This in turn negatively influences i.a. frontal glutamate neurotransmission, thereby linking the proposed schizophrenia-models of hyperdopaminergia and hypoglutamatergia. A key player in the body s antioxidant capacity is the peroxisome. This cell organelle is involved in both enzymatic (e.g. through the H2O2-degrading enzyme catalase) as well as non-enzymatic antioxidant metabolism. Its role in schizophrenia has, however, only been poorly examined, even though peroxisomes additionally are the only known source to-date of major enzymes for the degradation of cofactors of NMDA-receptors (including NMDA itself). Changes in peroxisomal metabolism and abundance therefore influence both the brain s capacity to degrade ROS as well as the functionality of its NMDA receptors and vice versa. This thesis therefore examines the reactions of peroxisomes to increased dopamine. Since peroxisomes are involved in a number of other metabolic functions apart from antioxidant defense, their enzyme content is highly heterogeneous. Catalase and ABCD3 are generally used as markers for peroxisomes. Their abundance is, however, highly dependent on metabolic demands and therefore varies extremely between as well as within different organs, tissues and cells. Especially in the brain, both catalase and ABCD3 are barely detectable, thereby leading to a marked underestimation of true peroxisomal abundance and distribution. In the first part of this thesis it was therefore attempted to establish a new peroxisomal marker, peroxin 14 (Pex14p), which is part of a docking complex on the peroxisomal membrane relevant for import of all matrix proteins and therefore independent of individual peroxisomal metabolism. Using various morphological methods in a large variety of organs, tissues and cell types from a number of different species it could be shown that Pex14p is indeed present in the membrane of every healthy peroxisome and is expressed in similarly high levels in tissue sections and cell cultures of different organs and species. As Pex14p is also highly suited as a peroxisomal marker in all neuronal tissue, post mortem brain sections of schizophrenic patients and controls were analyzed regarding the abundance and distribution of peroxisomes as well as catalase. The results were, however, inconclusive, wherefore the reactions of peroxisomes to increased dopamine were analyzed under more controllable conditions within the second part of this thesis. The effects of dopamine in vitro were examined using primary murine neuronal and astrocyte cell cultures and the in vivo-effects in a pharmacological mouse model (through subchronic systemic administration of the selective, non-competitive NMDAR-antagonist MK-801). Analyses of gene expression patterns from the brains of the animals show i.a. an activation of antioxidant pathways in MK-801-treated animals compared to vehicle-treated controls as well as an increase in mRNA copies of enzymes involved in NMDAR-cofactor degradation. Morphological experiments show that dopamine changes peroxisomal reactions and neuronal morphology specifically and only in intact neuron-astrocyte interactions, mimicking the atypical neurodegeneration found in schizophrenic patients. Additionally, increased levels of selected antioxidant enzymes were found to be increased in the brains of MK-801-treated animals. It can therefore be concluded that dopamine does indeed lead to increased ROS production in the brain, which is, however, initially still countered by an increase in antioxidant defense mechanisms. This strengthens the initial hypothesis that oxidative stress (i.e. the state of disequilibrium between ROS production and antioxidant defense) is an effect rather than a cause of schizophrenia. Finally, the dopamine-related increase in the expression of genes encoding for enzymes degrading NMDAR-cofactors, thereby leading to a decrease of NMDAR-mediated neurotransmission, shows that hyperdopaminergia and hypoglutamatergia in schizophrenia are not separate entities, but rather influence, uphold and even exacerbate each other. This led to the proposition of a new integrative model of the etiopathogenesis of schizophrenia, linking both hyperdopaminergia and hypoglutamatergia together.en
dc.description.abstractBezüglich der bei Schizophrenen gefundenen Neurodegeneration ist die Frage nach Ursache und Wirkung unklar. Viele Befunde erlauben jedoch die Hypothese, dass, aufgrund einer Überaktivität des mesolimbischen Dopaminsystems, innerhalb und außerhalb der Neurone eine neurotoxische Wirkung des Dopamins und seiner Metaboliten im Sinne der Produktion reaktiver Sauerstoffspezies (ROS) auftritt.Neben den Mitochondrien und dem Zytoplasma spielt das Peroxisom eine wesentliche Rolle in der enzymatischen (z.B. durch Katalase) und nicht-enzymatischen antioxidativen Abwehr. Die Konzentration des klassischen peroxisomalen Markerenzyms Katalase ist jedoch in Neuronen ausgesprochen niedrig, weshalb im ersten Schritt der Arbeit ein neues Markerprotein für Peroxisomen (Peroxin 14, Pex14p) an einer Vielzahl verschiedener Gewebe und Zellen mittels Proteinlabelingmethoden für Elektronen-, Licht- und Fluoreszenzmiskroskopie etabliert wurde. Über diese neue Methode war es nun möglich, Peroxisomen auch im Nervengewebe unabhängig ihres Katalasegehaltes zu untersuchen.Wir haben daher die Anzahl an Peroxisomen und Katalase an postmortem Hippokampusschnitten von Schizophrenen und Kontrollen verglichen. Aufgrund methodologischer Einschränkungen waren die Befunde jedoch uneindeutig.Im nächsten Schritt wurden Mischkulturen muriner Neurone und Astrozyten mit unterschiedlichen Dopaminkonzentrationen inkubiert, wonach sich eine Erhöhung der Katalasemenge vor allem in Astrozyten, begleitet von einer Umverteilung der Peroxisomen aus den Dendriten in die Somata ohne signifikante Zelltoderhöhung zeigte.Wir wiederholten diese Experimente daher mit reinen Astrozytenkulturen und fanden selbst bei Erhöhung der Dopaminkonzentration und Inkubationsdauer keine Unterschiede zu Vehikel-behandelten Kulturen. Dies spricht für die antitoxische Wirkung der Astrozyten und die Spezifität der Reaktionen aus den ersten Zellkulturen für intakte neuroastrozytäre Verbände.In darauf aufbauenden Tierversuchen untersuchten wir die Erhöhung des mesolimbischen Dopamins in männlichen Wildtypmäusen durch Gabe des NMDAR-Antagonisten MK-801.Im Anschluss an Behandlungsdauern von 1h-72h wurden die Gehirne entnommen und für morphologische Analysen oder Extraktion der RNAs für Expressionsanalysen verwandt. Unsere Befunde stärken die Annahme, dass Dopamin neurodegenerative Veränderungen hervorruft und diese erst im späteren Krankheitsverlauf auftreten und daher vermutlich nicht an der Äthiopathogenese der Schizophrenie beteiligt, sondern eher als Folgeerscheinung der Dopamin-Neurotoxizität anzusehen sind.de_DE
dc.language.isoende_DE
dc.rightsIn Copyright*
dc.rights.urihttp://rightsstatements.org/page/InC/1.0/*
dc.subjectDopaminde_DE
dc.subjectoxidativer Stressde_DE
dc.subjectSchizophreniede_DE
dc.subjectPeroxisomde_DE
dc.subjectMK-801de_DE
dc.subjectdopamineen
dc.subjectoxidative stressen
dc.subjectschizophreniaen
dc.subjectperoxisomeen
dc.subjectMK-801en
dc.subject.ddcddc:150de_DE
dc.titleDopamine neurotoxicity, oxidative stress and schizophrenia : in vitro and in vivo studies of peroxisomal reactions to increased dopamineen
dc.title.alternativeDopamin-Neurotoxizität, oxidativer Stress und Schizophrenie : in vitro und in vivo Studien peroxisomaler Reaktionen auf erhöhtes Dopaminde_DE
dc.typedoctoralThesisde_DE
dcterms.dateAccepted2011-12-08
local.affiliationFB 06 - Psychologie und Sportwissenschaftde_DE
thesis.levelthesis.doctoralde_DE
local.opus.id8495
local.opus.instituteAbt. für Differentielle Psychologie und Persönlichkeitsforschungde_DE
local.opus.fachgebietPsychologiede_DE


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