Dissertations / Theses on the topic 'Antidepressants Mechanisms of action'
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Mann, Catherine. "Mechanisms of action of antidepressant drugs: Presynaptic and postreceptor mechanisms." Thesis, University of Ottawa (Canada), 1992. http://hdl.handle.net/10393/10600.
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The etiology of clinical depression is unknown, but thought to be related to an impairment in brain transmission of monoamines. Depression is treated with antidepressant drugs which, regardless of classification, ultimately result in increased efficacy of aminergic transmission. Tricyclic antidepressants are known to inhibit the presynaptic uptake of amines. [3H]Imipramine, the prototype tricyclic antidepressant and a potential biological marker in depression, binds to both high- and a low-affinity sites in the brain. The high-affinity binding of [3H]imipramine to its binding site on the serotonin (5-HT) neuronal transporter has been shown to be a sodium-dependent process. However, that of [3H]paroxetine, a novel and selective 5-HT uptake inhibitor, has not yet been investigated. Because of a discrepancy between the onset of uptake-blocking effect and alleviation of depressive symptoms, the blockage of uptake is probably not the only pharmacological action of antidepressants underlying their clinical effect. Recent studies have reported decreases in beta-adrenoceptor and 5-HT2 receptor numbers following long-term treatment with antidepressants, and suggested that an adaptive change in amine receptors may be more relevent for the clinical effect. However, not all 5-HT uptake inhibitors elicit this downregulation. Recent research has thus centred on elucidating changes in the signal transduction apparatus of aminergic neurons. The 5-HT2 receptor in the brain is coupled to the phosphoinositide turnover cascade and protein kinase C (PKC) activity. The subcellular distribution of PKC following chronic antidepressant treatment has not yet been investigated. This study was undertaken (1) To compare the sodium dependence of [3H]paroxetine binding and [3H]5-HT uptake in rat diencephalon in order to confirm whether paroxetine binds to the 5-HT recognition site on the transporter, and (2) to investigate the effects of both acute and chronic antidepressant treatment on PKC location and activity (both basal and 5-HT2 receptor agonist (DOI)-challenged) in rat cortex and hippocampus. Results indicate that, antidepressant drugs induce differing but significant effects on PKC activity in the subcellular fractions of neurons both after acute and chronic treatment. These changes in PKC activity may alter transduction of cellular signals evoked by the binding of 5-HT to receptors. (Abstract shortened by UMI.)
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Tabaka, John. "Mechanisms of action of antidepressants and their combination for major depressive disorder treatment: a theoretical and clinical approach." Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=121186.
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Background: Annually, an estimated 8.2% of Canadians aged 18 or older are affected by major depressive disorder (MDD). Nearly half of those suffering from MDD will fail to achieve remission while also having an inadequate response to an initial and continuous 6-week single antidepressant treatment. This failure to remit or respond to monotherapy, referred to as treatment-resistant depression (TRD), affects more than 30% of those suffering from MDD. The addition of a second antidepressant to improve upon the effects or alleviate the side-effects of the initial antidepressant has repeatedly shown encouraging therapeutic benefits. Unfortunately, the use of combination therapy in clinical settings has remained relatively low. Objective: With knowledge and understanding of the mechanisms of action of each of the seven different classes of antidepressants attained from preclinical studies (in vitro and in vivo electrophysiology) conducted at the Neurobiological Psychiatry Unit (NPU) at McGill University, the therapeutic efficacy of combination therapy can be maximized and adverse interactions and events minimized. The main goal of this thesis was to review the extensive literature concerning antidepressant studies conducted at the NPU as well as the clinical literature from PubMed and OvidSP in order to discern the most efficacious antidepressants and antidepressant combination treatments. The data collected from the literature was critically compared with the clinical database of the Mood Disorders Clinic (MDC) at the McGill University Health Centre (MUHC), in order to establish the clinical pertinence of using antidepressant combinations. Methods: A literature review was conducted to discern the most frequently prescribed antidepressants and efficacious antidepressant combination treatments. Subsequently, we analyzed the database of the MUHC; 133 outpatients with a current DSM-IV diagnosis of MDD aged 18 years or older were included in this study. Sociodemographic and clinical information of each patient was obtained during his or her initial diagnostic evaluation by a multidisciplinary team and chart review. Patients were also asked to complete a self-reported BDI-II questionnaire in order to assess the severity of depressive symptoms. Statistical analyses between prescribed antidepressant combinations and symptom severity were performed to determine effectiveness. A critical comparison of the findings from the literature with the clinical information obtained from patients referred to the MDC was conducted. Results: Significantly more women than men were diagnosed with MDD. Within the six months of their initial diagnostic evaluation, 87.2% of the patients had been prescribed an antidepressant. The most frequently prescribed antidepressant was a selective serotonin reuptake inhibitor (SSRI), followed by a serotonin-norepinephrine reuptake inhibitor (SNRI) and bupropion. Consistent with the literature, the most frequent antidepressant combination treatments were i) SSRI + bupropion, ii) SNRI + bupropion, and iii) SNRI + mirtazapine. No significant difference was found between antidepressant combination treatments and mean total BDI-II scores. Conclusions: Clinical findings were generally consistent with the literature. The literature supported the use of antidepressant combinations for effective and time-efficient treatment of MDD, particularly at the beginning of treatment, yet psychiatrists still appeared hesitant on using this approach. The combinations of bupropion with an SSRI or SNRI were found to be the most efficacious combinations, receiving frequent support in the literature and in this study. Limitations: Low completion rate of the BDI-II resulted in the powers of performed tests to be lower than the desired powers, thus reducing the likelihood of detecting a difference when one may have actually existed. A larger cohort of patients could allow for clinically meaningful differences to be observed.Contexte: Chaque année, on estime que 8.2% des Canadiens âgés de 18 ans ou plus sont touchés par un trouble dépressif majeur (TDM). Près de la moitié des personnes souffrant de TDM ne parviendra pas à atteindre la rémission tout en ayant une réponse inadéquate au premier traitement antidépresseur pris seul durant 6 semaines continues. Ce défaut de rémission ou de répondre à la monothérapie, appelée dépression résistante au traitement (DRT), affecte plus de 30% des personnes souffrant de TDM. L'ajout d'un second antidépresseur pour améliorer les effets du médicament ou atténuer les effets secondaires de l'antidépresseur a montré à maintes reprises d'encourageants avantages thérapeutiques. Malheureusement, l'utilisation de la thérapie de combinaison dans les milieux cliniques reste relativement faible. Objectif: L'objectif principal de ce travail de recherche était de revisiter la littérature scientifique, à partir des études précliniques menées sur les antidépresseurs chez l'unité de Psychiatrie Neurobiologique à l'université McGill et des études cliniques à partir de PubMed/OvidSP, afin de comprendre le mécanisme d'action des antidépresseurs et les combinaisons possibles les plus efficaces. Ces données de la littérature ont été ensuite comparées avec une banque de données cliniques du programme de troubles de l'humeur du centre universitaire de santé McGill (CUSM), qui est un centre de soins tertiaires psychiatriques, avec le but d'établir la pertinence clinique de l'utilisation des combinaisons d'antidépresseurs. Méthodes: Une revue des études publiés dans la littérature a été effectuée pour discerner les antidépresseurs les plus prescrits et les combinaisons d'antidépresseurs les plus efficaces. Par la suite, nous avons analysé la banque de données du CUSM; 133 patients en consultation externe ayant un diagnostic du DSM-IV de TDM âgés de 18 ans ou plus ont été inclus dans cette étude. Les renseignements sociodémographiques et cliniques de chaque patient ont été obtenus au cours de sa première évaluation diagnostique par une équipe pluridisciplinaire et examen des dossiers. Les patients ont également été invités à remplir un questionnaire d'auto-évaluation de BDI-II afin d'évaluer la sévérité des symptômes dépressifs. Des analyses statistiques entre les combinaisons d'antidépresseurs prescrits et la sévérité des symptômes ont été effectuées. Une comparaison critique de ces résultats de la littérature avec les données cliniques de la banque du CUSM a été réalisée. Résultats: Beaucoup plus de femmes que d'hommes ont été diagnostiqués avec TDM. Dans les six mois suivant leur diagnostic initial, 87.2% des patients avaient été prescrit un antidépresseur. L'antidépresseur le plus prescrit est un ISRS, suivi par un IRSNa et le bupropion. Conformément à la documentation, les traitements combinés d'antidépresseurs les plus fréquents étaient i) ISRS + bupropion, ii) IRSNa + bupropion, et iii) IRSNa + mirtazapine. Aucune différence significative n'a été observée entre les traitements de combinaisons d'antidépresseurs et la moyenne totale des résultats du BDI-II. Conclusions: Les résultats cliniques étaient généralement conformes aux études passées. Les études sont favorables à l'utilisation de combinaisons d'antidépresseurs pour le traitement efficace et plus rapide de TDM, en particulier au début du traitement, mais les psychiatres semblaient encore hésitants sur l'utilisation de cette approche. Les combinaisons de bupropion avec un ISRS ou IRSNa se sont révélées être les combinaisons les plus efficaces, bénéficiant d'un soutien fréquent dans les études passées et dans cette étude. Limitations:Le faible taux d'achèvement du questionnaire BDI-II ont abouti à des pouvoirs de tests effectués à être plus faible que les pouvoirs voulus, réduisant ainsi la probabilité de détecter une différence qui peut avoir réellement existé. Une cohorte plus importante de patients pourrait permettre d'observer des différences cliniquement significatives.
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Mustafa, M. R. "Involvement of noradrenergic mechanisms in the antidepressant action of rolipram." Thesis, Cardiff University, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.378451.
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Coull, Moyra Ann. "Signal transduction mechanisms in affective disorders and antidepressant drug action." Thesis, St George's, University of London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393163.
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Petermann, Markus. "Identifying the mechanisms of antidepressant drug action in mice lacking brain serotonin." Doctoral thesis, Humboldt-Universität zu Berlin, 2021. http://dx.doi.org/10.18452/23035.
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Serotonin gilt als Hauptangriffsstelle gängiger Antidepressiva bei schweren Depressionen, wie bspw. selektive Serotonin-Wiederaufnahmehemmer (SSRI), und -Enhancer (SSRE). Es bleibt offen, ob SSRI / E ausschließlich über die Manipulation des Serotoninspiegels wirken, oder ob alternative Signalwege daran beteiligt sind. Ansatzpunkte hierfür sind beispielsweise die neurotrophen Signalwege (spez. Brain derived neurotophic factor, BDNF) oder die Hypothalamus-Hypophysen-Nebennieren- (HPA) – Signalwege des Stressachsensystems. Ebenfalls wurde in Nagetiermodellen beobachtet, dass mit der Dysregulation des zentralen Serotoninsystems bei schweren Depressionen, ein Rückgang der Neurogenese im Gyrus dentatus des Hippocampus einhergeht. Ziel dieser Arbeit war, das Zusammenspiel von Serotonin, BDNF, adulter Neurogenese und der Stressachse zu untersuchen. Zentrum der Studien ist ein Mausmodell, mit einer genetischen Depletion des zentralen Serotonin-synthetisierenden Enzyms Tryptophanhydroxylase 2 (sog. Tph2-/- Mäuse). Es wurden die physiologische Reaktionen auf die Behandlung mit gängigen Antidepressiva abhängig von der Abwesenheit von Serotonin untersucht, um mögliche alternative Signalwege aufzeigen zu können. Die bekannte Zunahme der Neurogenese nach SSRI/SSRE-Behandlung wurde in Wildtyptieren beobachtet, während die Therapie in Tph2-/- Mäusen keine direkte kausale Wirkung zeigte. Im Gegensatz dazu waren die BDNF-Spiegel in depressionsrelevanten Hirnregionen in Tph2-/- Mäusen nach SSRI, signifikant verringert. Auch zeigen die Studien eine neurobiologische Relevanz von Serotonin im ZNS, bei den antidepressiven Mechanismen einer Elektrokonvulsiven Krampftherapie. Ebenfalls deuten erhöhte Neurogeneseraten bei lebenslanger Abwesenheit von Serotonin im ZNS, Therapiemethoden-unabhängig, möglicherweise auf eine modulierte Stressreaktion hin. Untersuchungen der Parameter des HPA-Stressachsensystems, wiesen auf einen grundlegend veränderten Stresshormonspiegel in Tph2-/- Mäusen hin.Serotonin, the "molecule of happiness" is an important target for antidepressants. The mainly prescribed drugs in major depression are selective serotonin re-uptake inhibitors (SSRI); but recently, SSR-enhancer (SSRE) have also attracted clinical attention. However, only a quarter of patients responds to treatment. It needs to be determined, whether SSRI/E act solely via manipulating serotonin levels or whether other pathways are involved, e.g. neurotrophic signaling (brain-derived neurotrophic factor, BDNF) or the hypothalamus-pituitary-adrenal (HPA)-axis. Furthermore, in major depression, dysregulation of central serotonin signaling is accompanied with a decline in hippocampal neurogenesis, as has been observed in rodent models. At the center of this thesis is a mouse model deficient in the central serotonin-synthesizing enzyme, tryptophan hydroxylase 2 (Tph2-/- mice). I have investigated physiological responses to antidepressant treatment in the absence of brain serotonin, and the possible role of alternative pathways. I observed the typical increase in neurogenesis upon SSRI treatment in WT mice, while it had no effect in Tph2-/- mice. In contrast, BDNF levels were significantly decreased in Tph2-/- mice after treatment with no effect in WT control mice. Furthermore, my results show a critical role of brain serotonin in the neurobiological effects of electroconvulsive seizure. Surprisingly, in animals lacking central serotonin, increased neurogenesis was observed independently of the treatment. The gathered data indicated an altered stress response; therefore, parameters of the HPA-axis have been studied, indicating a downregulated HPA system in Tph2-/-animals in baseline state, but showed no difference in treatment or feedback control. This thesis gives insight into the mechanisms of antidepressant action and reveals ideas for novel pathways involved in the process that could be used as targets in therapeutic approaches and further research in major depression.
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Petermann, Markus [Verfasser]. "Identifying the mechanisms of antidepressant drug action in mice lacking brain serotonin / Markus Petermann." Berlin : Humboldt-Universität zu Berlin, 2021. http://d-nb.info/1237268524/34.
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Pariante, Carmine Maria. "The in vitro effects of antidepressants on the glucocorticoid receptor and the potential relevance for the mechanism of action of this class of drugs." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406497.
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Abdel-Razaq, Wesam. "Molecular mechanisms of monoamine neurotransmitter modulatory antidepressant actions." Thesis, University of Nottingham, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.435767.
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Neves, António Luís Alexandre. "Tratamento farmacológico da depressão." Master's thesis, [s.n.], 2015. http://hdl.handle.net/10284/5309.
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Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências FarmacêuticasAs organizações mundias de saúde consideram a depressão uma desordem de humor apresentando muitas facetas e uma variedade de possíveis etiologias que provoca forte impacto na qualidade de vida do doente e dos seus familiares. A depressão é um problema de saúde pública, tendo em vista o aumento no número de casos e as suas consequências sociais. Uma elevada percentagem dos doentes com depressão desenvolvem a tendências para o suicídio e podem evoluir para tentativa do mesmo. A doença ocorre em todas as faixas etárias, desde os jovens até aos idosos. A prevalência média da depressão na população geral é mais comum nas mulheres com idade compreendida entre os 15 e os 29 anos e menos prevalente nos indivíduos com 50 ou mais anos. A depressão é um problema médico, passível de tratamento e, nas últimas cinco décadas, a psicofarmacologia da depressão evoluiu muito e rapidamente aumentando o número de fármacos disponíveis no mercado. Assim, atualmente o mercado dispõe de diversos antidepressivos com eficácia para o tratamento da depressão. Apesar das diferenças estruturais e do mecanismo de ação, os antidepressivos apresentam, de um modo geral, a mesma eficácia entre as diferentes classes. No entanto, a farmacocinética das substâncias podem alterar a biodisponibilidade e os efeitos adversos das mesmas, tornando-se um fator preponderante para a não adesão à terapia. A escolha do antidepressivo deverá ser baseada em vários fatores tais como: o tipo de sintomatologia, a idade, o uso concomitantes com outras terapias e a história clínica do doente. Este trabalho procura fazer uma revisão bibliográfica no âmbito do tratamento farmacológico da depressão, bem como do mecanismo de ação, da farmacocinética, dos efeitos laterais e das interações farmacológicas das diferentes classes de antidepressivos.
The mundial health organizations consider depression a mood disorder presenting many facets and a variety of possible etiologies that causes strong impact on quality of life of patients and their families. Depression is a public health problem, given the increase in the number of cases and its social consequences. A high percentage of patients with depression develop tendencies towards suicide and may progress to attempt the same. The disease occurs in all age groups, from the young to the elderly. The average prevalence of depression in the general population is more common among women aged 15 to 29 years and less prevalent in individuals with 50 or more years. The depression is a medical condition, treatable and in the last five decades the psychopharmacology of depression has evolved very quickly and increasing the number of drugs available in the market. Currently, the market offers many antidepressants effectively for the treatment of depression. Despite the structural differences and their mechanism of action, the antidepressants generally have the same efficacy between different classes. However, the pharmacokinetics of substances can alter the bioavailability and adverse effects of the same, becoming an important factor for non-adherence to therapy. The choice of the antidepressant should be based on various factors such as the type of symptoms, age, concomitant use with other therapies, and patient history. This paper seeks to make a literature review about the pharmacology of antidepressants particularly the pharmacological treatment of depression and the mechanism of action, pharmacokinetics, side effects and drug interactions thereof.
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Schroeder, Frederick Albert. "A Role for Histone Modification in the Mechanism of Action of Antidepressant and Stimulant Drugs: a Dissertation." eScholarship@UMMS, 2007. https://escholarship.umassmed.edu/gsbs_diss/370.
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Depression and stimulant drug addiction each result in massive losses of health, productivity and human lives every year. Despite decades of research, current treatment regimes for depression are ineffective in approximately half of all patients. Therapy available to stimulant drug addicts is largely ineffective and moreover, dedicated treatments for drug dependence (including abuse of cocaine) are non-existent. Thus, there is a pressing need to further understanding of the molecular mechanisms underlying these disorders in order to develop novel, targeted therapeutic strategies.
Chromatin remodeling, including changes in histone acetylation, has been proposed to play a role in both the etiology and treatment of depression and stimulant abuse. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate numerous cellular processes, including transcription, cell cycle progression and differentiation. Moreover, histone acetylation has been shown to regulate hippocampal neurogenesis, a cellular response associated with the pathogenesis and treatment of depression and stimulant abuse (Hsieh et al., 2004, Yamaguchi et al., 2004, Fischer et al., 2007). Ultimately, such basic cellular processes impact higher order function, namely cognition and emotion.
Indeed, recent studies suggest that HDAC activity in selected forebrain regions, including ventral striatum and hippocampus, modulate stimulant- and antidepressantinduced behavior (Kumar et al., 2005, Tsankova et al., 2006a, Fischer et al., 2007). These reports highlight an association between chromatin remodeling and diverse behavioral changes, including changes induced by the pleiotropic HDAC inhibitor, sodium butyrate (SB), (Kumar et al., 2005, Tsankova et al., 2006a, Fischer et al., 2007). However, behavioral, brain-metabolic and molecular effects of SB treatment in the context of rodent models of depression, dopaminergic sensitization and repeated cocaine administration remained unclear.
The work described in this thesis illustrates the potential for chromatin modifying drugs in mechanisms underlying the experimental pharmacology of depression and stimulant addiction. Specifically, the data presented here support the view that treatment with the short chain fatty acid, sodium butyrate enhances: (1) antidepressant-like behavioral effects of the selective serotonin reuptake inhibitor (SSRI), fluoxetine (2) locomotor sensitization induced by repeated administration of the dopamine D1/D5 receptor agonist SKF82958; and(3) brain metabolic activation upon repeated cocaine administration as evidenced by fMRI in awake rats.
Furthermore, this report provides evidence that these treatment paradigms will result in chromatin modification changes associated with active transcription, in addition to increased mRNA levels of plasticity-associated genes, including brain-derived neurotrophic factor (BDNF) at key brain regions implicated in the pathogenesis of depression and stimulant addiction.
To date, little is known regarding the underlying mechanisms of action mediating the enhancing effects of sodium butyrate on the various antidepressant- and stimulantrelated paradigms. Our findings underscore the potential of chromatin-modifying drugs to profoundly affect the behavioral response of an animal to antidepressant and stimulant drugs and warrants consideration in the context of developing novel therapeutic strategies.
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Haddjeri, Nasser. "Auto- and heteromodulation of the rat brain 5-HT system : involvement in the mechanism of action of antidepressant drugs." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ36978.pdf.
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Phillips, Marc Antony. "An investigation of monoaminergic mechanisms in the regulation of pupil size and the acoustic startle reflex in man." Thesis, University of Nottingham, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324546.
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Yon, Daniel. "Sensory prediction mechanisms in action." Thesis, Birkbeck (University of London), 2018. http://bbktheses.da.ulcc.ac.uk/362/.
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When we produce an action we generate predictions about the sensory consequences that are likely to ensue. This thesis tests a series of claims about the functional contribution these predictions make to perception, the role that such predictions play in processing the reactions of others, and the range of sensory inputs that these prediction mechanisms operate over. Chapter 1 outlines the theoretical background to each of these claims, alongside the previous literature that motivates subsequent experiments. The first three empirical chapters focus on claims about the functional role of sensory predictions during action: that they act to 'cancel' perception of expected action outcomes. Chapter 2 investigates this hypothesis in the context an intensity judgement task, Chapter 3 tests the hypothesis in the context of a signal detection task and Chapter 4 assess how predictions generated during action influence multivariate measures of visual brain activity, recorded via functional magnetic resonance imaging. Chapter 5 investigates the claim that sensory predictions during action support the processing of imitative reactions in others. Two psychophysical experiments are reported which investigate whether sensory predictions generated during action have temporal properties needed to support processing of others' reactions. Chapter 6 investigates whether sensory predictions generated during action influence the 'when' - as well as the 'what' - of perception. Four psychophysical experiments investigate whether the temporal features of executed actions are incorporated into duration perception. Chapters 7 and 8 report preliminary investigations into the mechanism underlying these effects. Chapter 7 assesses whether these influences arise through a mechanism that is primarily tuned to biological action outcomes. Chapter 8 investigates whether these effects arise as a result of statistical learning about the relationship between actions and outcomes. Chapter 9 summarises the studies presented in the thesis, and outlines their implications for thinking about sensory prediction during action.
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Tyrrell, Toby. "Computational mechanisms for action selection." Thesis, University of Edinburgh, 1993. http://hdl.handle.net/1842/20257.
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Imagine a zebra in the African savannah. At each moment in time this zebra has to weigh up alternative courses of action before deciding which will be most beneficial to it. For instance, it may want to graze because it is short of food, or it may want to head towards a water hole because it is short of water, or it may want to remain motionless in order to avoid detection by the predator it can see lurking nearby. This is an example of the problem of action selection: how to choose, at each moment in time, the most appropriate out of a repertoire of possible actions. This thesis investigates action selection in a novel way and makes three main contributions. Firstly, a description is given of a simulated environment which is an extensive and detailed simulation of the problem of action selection for animals. Secondly, this simulated environment is used to investigate the adequacy of several theories of action selection such as the drive model, Lorenz's hydraulic model and Maes' spreading activation network. Thirdly, a new approach to action selection is developed which determines the most appropriate action in a principled way, and which does not suffer from the inherent shortcomings found in other methods.
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Prabhu, G. "Neural mechanisms of object-oriented action." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1445241/.
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The ventral premotor cortex (area F5, in the macaque monkey) plays an important role in the control of hand shape during object grasp. F5 neurones can encode the selection of different grasps, and are excited by vision of graspable objects. However, it is not clear how F5 influences the motor outputs to the hand and arm that control hand shape. By using linked neurophysiological studies in macaque monkeys and humans, this thesis examined, firstly, how visual information for action is encoded in area F5 and, secondly, the transmission of this information from F5 to the primary motor cortex (Ml). The relationship of F5 activity to the observation and movement stages of a visuomotor grasping task was examined. Single units from Ml and F5 and electromyographic (EMG) activity were recorded from macaque monkeys. Recordings from F5 revealed evidence for object- and grasp-related activity, suggesting that initially neurones are activated by the visual characteristics of the object and later represent the specific hand configuration for grasp of the object. Ml activity was consistent with encoding of grasp, but was uninfluenced by object. Secondly, using the same task, the pathways used to transmit visuomotor information from F5 to Ml were investigated by intracortical myostimulation of these cortical regions. The facilitation and suppression of the Ml test response from F5 conditioning was highly specific, evoked only in particular muscles and certain object-grasp combinations. Furthermore, the timing of the evoked response supports late I-wave pathways mediating F5-M1 interactions in visuomotor grasp. In the final set of experiments a paired-pulse transcranial magnetic stimulation paradigm, previously shown to enhance the late I-wave components of the corticospinal volley, was used to examine object-orientated grasp in healthy human subjects. The results suggest excitability of cortico-cortical inputs to Ml was transient and contributed to action selection only when immediate sensory information specified which action to make. Results from this thesis expand our knowledge of the role of F5 in visuomotor grasp, by showing F5 single unit activity is compatible with encoding the physical properties of an object to be grasped as well as the motor prototype used for grasp. Evidence is also provided for a possible route for transmission of visuomotor information from F5 to Ml. Overall, there was a highly specific task-related pattern of object/grasp-related activity present in F5 and Ml single units and the EMG activity evoked from stimulation of these regions during the preparation and execution stages of visuomotor grasp.
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Richer, Maxime. "Characterization of the serotonergic and noradrenergic systems in mice lacking the 5-HTA receptor and its relevance to the mechanism of action of antidepressant drugs." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=33831.
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The implication of central noradrenergic and serotonergic systems in the control of mood has been known for forty years. Indeed, the different classes of molecules prescribed in the treatment of major depression directly interfere with the transmission mediated by these amines, either at the level of the synthesis, the release, the stimulation of receptors, the reuptake or the degradation. According to the leading theory in the field, the increase in serotonergic transmission is the final convergence point of currently prescribed antidepressant drugs.Pharmacological and electrophysiological studies have shown the essential role of the somatodendritic 5-HT1A autoreceptor in the control of dorsal raphe 5-HT neuronal firing frequency and release; these characteristics make this receptor an extremely interesting target for adjuvant drugs that potentiate or even accelerate the effect of actual antidepressants molecules. In fact, augmentation of synaptic levels of 5-HT, thought to be necessary for the beneficial action of antidepressants in mood, does not immediately occur subsequent to acute administration of those molecules but depends on the desensitization of 5-HT1A somatodendritic autoreceptors located in the dorsal raphe, a phenomenom temporally correlated with the onset of action of all antidepressant classes.
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Ainsworth, Kerri. "Neuropharmacological studies of antidepressant action on brain dopamine systems." Thesis, University of Oxford, 1998. http://ora.ox.ac.uk/objects/uuid:15c300a8-1395-4a8c-be8e-474c42c5a5b5.
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Barkhem, Tomas. "Molecular mechanisms of estrogen and antiestrogen action /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-359-7/.
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Fox, Stephanie. "Measles and Vitamin A : mechanisms of action." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=32992.
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Measles virus (MV) infects an estimated 30 million individuals each year, leading to ∼880,000 deaths. The mechanisms that underlie both MV-associated immunosuppression and the dramatic benefit of vitamin A remain poorly understood. Vitamin A supplements are also important for the eradication of vitamin A deficiency, which is implicated in the death of ∼1 million children each year, due to blindness and severe infections. In recent years, there has been increasing pressure to include vitamin A supplements in "universal" childhood vaccination programs in the developing world (e.g.: EPI). In this thesis, three studies dealing with the relationship between measles virus, vitamin A and the immune system are presented. First, the induction of PBMC apoptosis by MV is described and correlated with viral output and proliferation of these cells. In the second study, the results from a large trial of vitamin A supplementation at the time of MV vaccination are presented. Finally, as part of ongoing studies into the mechanism underlying the beneficial effect of vitamin A supplementation in MV infections, changes in the retinoid (vitamin A) signaling cascade during MV infection of a monocytic cell line (U937) were measured. (Abstract shortened by UMI.)
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Craven, Robert Anthony. "Execution mechanisms for the action language C+." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.445886.
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Chivers, Joanna Elizabeth. "Mechanisms of glucocortical action in epithelial cells." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415076.
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Harrison, Julian Earle. "Mechanisms of action of transdermal penetration enhancement." Thesis, Cardiff University, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321746.
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Hassan, Lobna Mohammed Saber Abdel. "Intracellular mechanisms of action of cardioprotective agents." Thesis, University of Sunderland, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338350.
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Kwok, Rebecca Martha. "Visual mechanisms subserving perceptual judgement and action." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408703.
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Di, Daniel Elena. "Mechanisms of action of mood-stabilizing drugs." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1445413/.
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Bipolar disorder or manic-depression is a severe and common psychiatric illness that is often treated with mood-stabilizing drugs. Several molecular targets and signalling pathways have been implicated in the pathophysiology of the illness and in the mechanism of action of these drugs. However, the precise targets that are responsible for the therapeutic action and side-effects of the drugs are not known. In this PhD thesis we have analysed some of the potential drug targets, in particular extracellular signal-regulated kinase mitogen-activated protein kinase (ERK/MAPK) and glycogen synthase kinase-3 (GSK.3). which mood stabilizers are believed to regulate. We showed, using cell and biochemical assays, that the effects of lithium, valproate or carbamazepine on ERIC MAPK are not always observed in a given cell type. In addition, only lithium inhibits GSK3 directly and modulation of this kinase with potent and selective inhibitors does not mimic the effects of mood stabilizers on cortical and sensory neuron growth cone morphology. A major part of my thesis focused on the enzyme prolyl oligopeptidase (PO), which is thought to modulate the phosphatidylinositol pathway, as shown from studies in Dictyostelium discoideum and human astroglioma cells. PO inhibitors alone have no effect on sensory neuron growth cone morphology, but reverse the growth cone changes induced by mood stabilizers, mimicking addition of/m-o-inositol to the culture media. We studied PO null-mutant mice and analysed the effects of mood stabilizers on the morphology of growth cones from these mice. Unexpectedly, the PO null-mutant phenotype itself resembled wild-type neurons treated with a mood stabilizer and each drug had no further effect on growth cone morphology. These results show that PO is a critical component of signalling pathways involved in mood-stabilizing drug action on growth cones. Using viral delivery of native or catalytically-dead PO, we showed that each restored the wild-type phenotype. In order to better understand PO function, a yeast-tvvo-hybrid screen (Y2H) was also performed at Gla.xoSmithK.line to determine protein interactors for PO, and we analysed one of these interactors, namely GAP43. We showed that both the native and the catalytically-dead PO co-precipitate with the neuronal protein GAP43. These results show that there are additional biological effects of PO independent of its catalytic domain.
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Duan, Xuchen. "Physiological and biological mechanisms of bisphosphonate action." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:36b0439d-2f89-4c1e-8bb3-941b4e6ee847.
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Bisphosphonates (BPs) are stable analogues of pyrophosphate widely used for the treatment of bone diseases characterised by increased bone resorption. Studies over the years have shown that the pharmacological potencies of BPs are dependent both on their binding affinities for bone mineral and on their inhibitory actions on osteoclasts. In addition, potential effects on other cell types present locally in the environment of skeletal tissues have been reported. The present study systematically evaluated the relative mineral-binding affinities of individual BPs of clinically relevance in mixtures of these compounds and the changes with elution pH by using column chromatography with ceramic hydroxyapatite and fluoroapatite combined with mass spectrometric identification and quantitation of the individual BPs. The results indicate that pH has a profound effect on the ionisation of the phosphonate and R2 functional groups, with BPs having greater affinities at lower pH as shown by increased retention times. Moreover, two other approaches, namely using Langmuir adsorption isotherms and competition assays based on fluorescent BP, have been developed to assess the mineral-binding capacities and dissociation constants of BPs. These results suggest that there are substantial differences among BPs in their binding to hydroxyapatite. From the cellular aspect of my study, I present evidence for the anti-apoptotic effects of BPs in osteocytes and osteoblasts. However, the study of prosurvival signalling pathways involved in these cells needs to be optimised. The work described in this thesis provides novel insights into the physiological and biological mechanisms of BP action. My project has provided a better knowledge of the physicochemical properties of BPs, which are highly relevant to their differential distributions within bone, their biological potencies, and their durations of action. Additionally, the cell culture studies may provide new information on the cellular effects of BPs on osteocytes and osteoblasts.
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Quested, Digby John. "Serotonin receptor mechanisms in anti-depressant action." Master's thesis, University of Cape Town, 2003. http://hdl.handle.net/11427/12577.
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Bibliography: leaves 221-270.Serotonin neurones have been implicated in the pathophysiology and treatment of clinical depression to a greater degree than any other neurotransmitter. Additionally, serotonin pathways may playa role in the pathophysiology and treatment of eating disorders, anxiety states and schizophrenia. Molecular biological studies have confirmed pharmacological evidence suggesting the existence of multiple serotonin receptor subtypes and the genes for these receptors, as well as that of the serotonin transporter, have common polymorphic variants. To investigate the effect of repeated treatment with selective serotonin fe-uptake inhibitors (SSRI's) on the function of central 5-HT2C receptors. To assess the effect of polymorphic variation in the 5-HT2c receptor and serotonin transporter on functional responses to selective pharmacological challenge. To determine whether polymorphic variation in the 5-HT receptor and serotonin transporter influence the clinical response of patients with major depression to treatment with serotonergic antidepressants. To assess the effect of repeated treatment with selective serotonin re-uptake inhibitors (SSRI's) on the function of central 5-HT2c receptors I used the 5-HT2C receptor agonist, m-chlorophenylpiperazine (m-CPP) as a 5-HT2c probe in a neuroendocrine challenge paradigm. I used the same approach to assess whether polymorphic variation in the 5-HT2c receptor (serine vs cysteine substitution) was associated with differences in functional response to 5-HT2C receptor challenge. I then studied whether polymorphic variation in the serotonin transporter promotor region (long versus short form) was associated with differing functional responses to acute challenge with clomipramine, a tricyclic antidepressant with a high affinity for the serotonin transporter. Finally, I studied whether either of these polymorphic variants influenced the clinical response of patients with major depression to treatment with SSRI's and clomipramine. SSRI treatment significantly lowered the sensitivity of 5-HT2c receptors as predicted from animal experimental studies. However polymorphic variation in the 5-HTzc receptor did not significantly influence functional responses to m-CPP challenge. In contrast polymorphic variation in the serotonin transporter was associated with differing neuroendocrine responses to acute clomipramine challenge with greater prolactin release being seen in subjects with the long polymorphic variant. Neither the 5-HTzc nor the transporter polymorphisms correlated with clinical response to SSRI and clomipramine treatment in patients with major depression. The ability of SSRI's to produce a functional down-regulation of 5-HTzc receptors may be relevant to certain of their therapeutic effects. Polymorphic variation in the 5-HT2c receptor (serine vs cysteine) seems unlikely to explain functional differences in responses to 5-HTzc receptor challenge or antidepressant responses to SSRI treatment. In contrast variation in the serotonin transporter promotor is associated with differing functional responses to acute serotonin re-uptake blockade. However, this did not correlate with clinical response to longer-term SSRI treatment.
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SHEELER, CAMERON Q. "MECHANISMS OF ACTION OF THE ESTROGEN RECEPTOR." University of Cincinnati / OhioLINK, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=ucin982955523.
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Norman, Jane Elizabeth. "Menstrual induction : methods and mechanisms of action." Thesis, University of Edinburgh, 1992. http://hdl.handle.net/1842/20065.
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One hundred and ninety five thousand abortions were performed in Britain in 1989, a rate of 13 per 1000 women of reproductive age. Data from England and Wales indicates that 35% of women undergoing abortion in 1989 were at less than nine weeks gestation when menstrual induction can readily be performed. The method of abortion in almost all these women was vacuum aspiration, but there is increasing interest in menstrual induction, whereby early pregnancy can be terminated medically without the need for surgical intervention. The development of the progesterone antagonist mifepristone offers the possibility of a safe method of menstrual induction (in combination with a prostaglandin), which is effective and has minimal side effects. The minimum effective dose, and the mechanism of action of mifepristone are however unknown. The work in this thesis has investigated these two questions further. When the efficacy and side effects of three different doses of mifepristone: 200mg, 400mg and 600mg followed 48 hrs later by 1mg gemeprost in women of ≤56 days amenorrhoea were compared, all three regimes were equally effective, with a mean complete abortion rate of 98% . There were no differences in the incidence of side effects between the three groups. In contrast a lower complete abortion rate of 87% was seen in women at the same gestation following gemeprost alone (1mg 6 hrly to a total of 3mg) (p< 0.01). In a randomised comparison between the two methods, there was a significantly greater requirement for analgesia following the use of gemeprost alone (p< 0.02). The effects of a new prostaglandin (misoprostol) which could be used in combination with mifepristone were also studied. A significant increase in uterine tone was observed 30-120 minutes after 200-600μg misoprostol alone (p&60 0.01); in women pretreated 48 hours earlier with 200mg mifepristone, an increase in uterine contractility measured in Montivideo units was observed 30 minutes after 200-600μg misoprostol (p< 0.01). Eighteen out of twenty one women aborted using 200mg mifepristone followed 48 hours later by 200-1000μg misoprostol.
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Bakunina, Nataliia Sergeevna. "Modelling oxidative stress in human hippocampal progenitor cells : insight into the pathogenesis of depression and antidepressants action." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/modelling-oxidative-stress-in-human-hippocampal-progenitor-cells-insight-into-the-pathogenesis-of-depression-and-antidepressants-action(eeb5d246-5d69-4d5f-bb53-8e09ac5cab93).html.
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Recent findings suggest that oxidative stress (OS) has an important role in the pathophysiology of major depressive disorder (MDD), however the underlying molecular mechanisms are still poorly understood. In this project, I set up an experimental in vitro OS model, using a human hippocampal progenitor cell line HPC0A07/03C capable of neurogenesis, to study molecular mechanisms potentially involved in the pathogenesis of this disorder and to evaluate the possible antioxidative properties of compounds with antidepressant properties. Alterations of redox homeostasis were induced by treatment of the cells with a range of concentrations of tert-butyl hydroperoxide (t-BHP); higher doses were cytotoxic and lower doses led to major changes in neurogenesis and activation of the transcription factors Nrf2 and NF-κB in a dose-dependent manner. Potential redoxsignalling pathways involved in regulating neurogenesis were studied. Inhibition of the t-BHP–induced ERK1/2 activation abrogated the increased differentiation of progenitor cells into mature neurons observed upon oxidative stimulus. I tested various compounds for their antioxidative properties and found that the omega-3 fatty acid eicosapentaenoic acid (EPA), as well as the conventional antioxidants N-acetylcysteine (NAC) and glutathione (GSH) prevented the oxidative damage inflicted by t- BHP, with no effects observed for sertraline, venlafaxine, ketamine or docosahexaenoic acid (DHA). Both EPA and GSH differentially regulated the expression of genes involved in the OS response, including Keap1, HMOX1, SLC7A11 and SLC1A1. Data obtained in this research project indicate that depending on the dose ROS can have detrimental effects on the viability and molecular profile of human hippocampal progenitor cells or facilitate neurobiological processes that are essential for normal cellular functioning and adaptation of the organism to environmental stimuli. Remarkably, EPA, known to exhibit antidepressant properties, elicited favourable effects in my OS in vitro model and appears to be a promising compound for further research in developing novel antidepressants targeting OS.
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Browning, Michael. "The mechanisms and effects of modifying attentional biases to threatening information." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:26959079-8f02-4347-b398-1b8347b64a92.
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Patients with both depression and anxiety show an increased tendency to deploy attention towards negative information. Cognitive models of the illnesses predict that these negative attentional biases are causally related to the symptoms of the disorders. Consistent with this, modifying attentional bias using either antidepressant medication or simple, computer based training tasks has previously been associated with altered symptomatology in both non-clinical and clinical populations. The current thesis aimed to investigate the mechanisms by which attentional bias training tasks alter attention. The investigations were conducted within an experimental neuroscience framework which has previously been successfully deployed in studies of antidepressant medication. The thesis then sought to use these initial results to improve the basic understanding of attentional control processes and, ultimately, guide the development of novel treatment strategies. The initial studies of the thesis characterised the behavioural and neural effects of attentional bias training. Behaviourally, a high degree of generalisation of the training effect was found across a range of emotional stimuli. Neurally, training was found to alter activity in a network of prefrontal regions known to be involved in the control of attention. Further analysis, utilising a computational learning model, suggested that the attentional control systems identified in this study could be understood in terms of expectation based processes. These studies therefore indicated that, in contrast to the predominately limbic effects of antidepressant medication, training initially altered the response of frontal control circuitry. The later studies of the thesis investigated possible strategies for extending the use of attentional bias training. Firstly, combining training with antidepressant medication was found to produce an interference effect on emotional memory suggesting that administering both interventions concurrently is likely to erode their cognitive impact. Lastly, attentional bias training was found not to alter attention in patients with bipolar disorder, with the results of the study indicating that standard assessments of attentional bias in this clinical population are likely to be unreliable. Overall, these studies indicate that attentional bias training may be used to alter the top-down control of attention to emotional information and suggest that such effects may interfere with the bottom-up effects of antidepressant drugs. More generally the work demonstrates the utility of using a cognitive-neuroscientific framework to explore the mechanisms and impact of novel therapeutic strategies.
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Ostrowski, Stephen M. "Pleiotropic mechanisms of statin action in Alzheimer's Disease." Cleveland, Ohio : Case Western Reserve University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1190669698.
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Johnston, H. P. "The mechanisms of action of thiopurine nucleotide prodrugs." Thesis, University of East Anglia, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.356608.
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Jenkinson, Stephen. "Molecular mechanisms of lithium action on phosphoinositide signalling." Thesis, University of Leicester, 1993. http://hdl.handle.net/2381/35263.
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The work described in this thesis examines the phosphoinositide (PI) signalling system and its disruption by the anti-manic agent lithium. The effects of lithium upon the accumulation of labelled and unlabelled inositol (poly) phosphates in muscarinic cholinoceptor-stimulated rat brain slices and Chinese hamster ovary (CHO) cells expressing the human M1-muscarinic receptor subtype (CHO-Ml) were examined. Similarly, the effects of this ion on other intermediates of this second messenger signalling system were examined in order to give an overall picture of the action of lithium. These included the accumulation of CMP-phosphatidic acid (CMP-PA), a precursor of the (poly) phosphoinositide lipids, and the agonist-stimulated levels of the (poly) phosphoinositide lipids. Initial experiments examined phosphoinositide metabolism in cortex, hippocampus and striatum to determine whether there were regional variations in both this signalling system and the effects which lithium had upon it. Both cortical and hippocampal PI metabolism were similar, however, striatum was significantly different such that in the continued presence of agonist this region was unable to maintain the initial elevated levels of Ins(l,3,4,S)P4, unlike the other regions examined. Lithium appeared to have a similar disruptive effect on PI metabolism in all regions, with statistically similar EC50 values for the accumulation of InsP1 in all regions. The effects of lithium upon PI metabolism stimulated by a variety of different agonists was examined to determine whether the action of lithium was agonist dependent Lithium appeared to have a similar disruptive effect upon PI metabolism stimulated by these various agonists. Studies examining the effects of lithium upon the carbachol-stimulated accumulation of the inositol (poly) phosphate isomers revealed the presence of a lithium-sensitive accumulation of the inositol bisphosphate Ins(4,5)P2. This study was unable to determine the source of this isomer, however, the formation of this isomer in both cerebral cortex slices and CHO cells suggests the possibility that Ins(4,5)P2 may be a dephosphorylation product of Ins(l,4,5)P3. The lithium-sensitivity of the accumulation of this isomer also suggests that a novel Uthium- sensitive 4- or 5-phosphatase activity may be present in these preparations. The effects of lithium on phosphoinositide metabolism in CHO cells expressing the human M1-muscarinic receptor subtype was also examined to determine whether this cell line would represent a suitable model of cerebral PI metabolism. It was hoped that the use of this cell-line would result in clearer more interpretable data. Indeed, a definitive analysis of PI metabolism in this cell line clearly demonstrated that the addition of lithium to agonist-stimulated cells resulted in a decrease in the intracellular myo-inositol reserves within the cell which resulted in a decrease in the (poly)phosphoinositide precursor of Ins(l,4,5)P3, PtdIns(4,5)P2. In turn this resulted in a time-dependent decrease in the agonist-stimulated levels of Ins(l,4,5)P3 after a lag period of 5-10 min, similar to that observed in cerebral cortex slices. The data demonstrate that the CHO-Ml cell-line is a valuable tool in elucidating the actions of lithium upon PI signalling. In conclusion, the results described in this thesis clearly demonstrate the profound effects that this monovalent ion has on phosphoinositide signalling in the preparations examined. The main action of lithium appears to be the inhibition of the inositol monophosphatase, however, this agent may also have other more subtle effects upon this complex system. These possibilities and their implications are also discussed.
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Ostrowski, Stephen M. "Pleiotropic Mechanisms of Statin Action in Alzheimer's Disease." Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1190669698.
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Smyth, Christopher David. "Paracrine mechanisms of gonadotrophin action on the ovary." Thesis, University of Edinburgh, 1994. http://hdl.handle.net/1842/20805.
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This thesis describes a study of the role of local regulators in the modulation of gonadotrophin action. It was found that in vivo FSH stimulated granulosa cell proliferation and increased ovarian weight, but was incapable of stimulating granulosa cells to proliferate in vitro. This suggests that the action of FSH in vivo is mediated through another factor. However, in the presence of LH, FSH also stimulated the expression of differentiated functions (progesterone and oestradiol production) both in vivo and in vitro demonstrating a direct effect of FSH. In the absence of LH or aromatase substrate, FSH induced the potential for aromatisation but did not increase uterine weight, a marker of oestradiol production. Therefore it is concluded that FSH is the primary stimulus for follicular development but that LH is also required for co-ordinated follicular development. There is a growing body of indirect evidence to suggest that factors of FSH-stimulated granulosa cell origin may regulate adjacent thecal/interstitial cells. Cytochrome P45017α (17-hydroxylase/C17-20 lyase) in thecal/interstitial cells is a LH-responsive steroidogenic enzyme vital for androgen production. To obtain direct evidence for FSH-stimulated paracrine signalling in the ovary a rat thecal/interstitial cell culture system was validated for the study of the control of androgen production. Using this system and Northern hybridisation the control of androgen production by gonadotrophins and granulosa cell derived factors was studied. The 2.0 kb P45017α mRNA signal in ovarian total RNA from intact animals was dose-dependently increased by treatment with recombinant human FSH (rh-FSH). Treatment of hypophysectomised animals with rh-FSH did not consistently alter ovarian P45017α mRNA levels, though in the presence of low levels of LH, FSH increased P45017α mRNA expression.
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Dagli, Deniz. "Laboratory Investigations of Frost Action Mechanisms in Soils." Licentiate thesis, Luleå tekniska universitet, Geoteknologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:ltu:diva-64184.
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Phase change of the water in the soil skeleton under cold climate conditions (also known as frost action in soils) affects soil properties and can be responsible for serious alterations in a soil body; causing damages (due to the volumetric expansion known as frost heave) to structures on or below the ground surface such as foundations, roads, railways, retaining walls and pipelines, etc. In order to improve the current design methods for roads against frost action, the Swedish Transport Administration (Trafikverket) has initiated a research program. The main goals of the program are to revise the existing frost heave estimation methods and improve the frost susceptibility classification system for subgrade soils. Literature was reviewed to gather the details of different freezing test equipment around the world and to identify common trends and practices for laboratory freezing tests. Based on the literature review and the collaboration with the University of Oulu, Finland an experimental apparatus was assembled for studying frost action in the laboratory. A detailed description of the experimental apparatus is given. Top to down freezing of specimens (of 10cm height and diameter) can be monitored while keeping track of water intake, vertical displacements (heave) and the temperature profile within the sample. Loads can be applied at the top of the sample to study the effects of overburden. Moreover, the test setup was modified with a camera system to have the option of recording the experiments. Disturbed samples of two different soil types were tested. Experiments with fixed and varying temperature boundary conditions were conducted to assess the validity of the assumptions for the frost heave estimation methods currently in use in Sweden. To this end, a qualitative relationship between frost heave and heat extraction rates based on theoretical equations was established. It was shown that there is a significant difference between the preliminary findings of the experimental work and the current system being used in Sweden to quantify heave. Image analysis techniques were used on two experiments that were recorded by the camera system. Image recording and correlation analyses provided detailed information about frost front penetration and ice lens formation(s) under varying temperature boundary conditions. Thawing has also been regarded in further studies. Results of the image analyses were compared to readings from conventional displacement measurements during the same test. Significant agreement between the results of image analyses and displacement measurements has been found. Image analysis was shown to be a viable method in further understanding of frost heave mechanisms. Shortcomings and disadvantages of utilizing the theoretical equations as well as the image analysis techniques were discussed. Potential remedies for overcoming the drawbacks associated with each approach are suggested. The work is concluded by discussing the potential improvements, planned upgrades (addition of pore pressure transducers) and the future experiments to be conducted.
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Dvorakova, Katerina. "Mechanisms of imexon action in human myeloma cells." Diss., The University of Arizona, 2000. http://hdl.handle.net/10150/289132.
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Imexon is an iminopyrrolidone derivative that has selective antitumor activity in multiple myeloma. The exact mechanism of imexon action is unknown. In human 8226 myeloma cells, the cytotoxicity of imexon was schedule dependent and long exposures ( ≥ 48 hours) to low concentrations of imexon were most effective at inducing cytotoxicity. Our data suggest that imexon does not affect DNA, but it can alkylate thiols by binding to the sulfhydryl group. We have also shown by HPLC studies that in human 8226 myeloma cells, imexon depletes cellular stores of cysteine and glutathione (GSH). Oxidative stress in myeloma cells exposed to imexon was detected by staining with dihydroethidium (HE) and flow cytometry, and by immunohistochemical staining with a monoclonal antibody to 8-hydroxydeoxyguanosine (8-OHdG) followed by confocal microscopy. This antibody can also recognize 8-hydroxyguanine and 8-hydroxyguanosine. The images showed increased levels of oxidized nucleotides in the cytoplasm of cells treated with imexon. Interestingly, 8-OHdG staining was not observed in the nucleus of imexon treated cells, in contrast to the diffuse staining seen with t-butyl hydroperoxide. Myeloma cells exposed to imexon showed classic morphologic features of apoptosis on electron microscopy and phosphatidylserine exposure detected as Annexin-V binding on the cell surface. Mitochondrial enlargement was observed by electron microscopy in the cells treated with 90 μM imexon at as early as 4 hours. Morphometric studies indicated that mitochondrial volume significantly increased from 14.1% in control cells to 18.7% in cells treated with 45 μM imexon for 24 hours. In flow cytometric experiments it was shown that the increase in levels of ROS (measured by staining with dihydroethidium) in myeloma cells exposed to imexon precedes the loss of Δψ(m) (detected by MitoTracker Red labeling). Damage of mitochondrial DNA was detected by semiquantitative PCR assay in myeloma cells treated with imexon; however nuclear DNA remained unaffected by imexon treatment. Moreover, release of cytochrome c from mitochondria to cytosol was observed in imexon treated cells. Partial protection of myeloma cells against imexon cytotoxicity was achieved by treatment with theonyltrifluoroacetone, an inhibitor of superoxide production at mitochondrial complex 11. Myeloma cell line was developed that is stably resistant to imexon. This cell line shows an increase in the expression of mitochondrial proteins (e.g. Bcl-2, thioredoxin 2) with antioxidant properties. These changes are consistent with drug-induced mitochondrial oxidation and apoptotic signaling.
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Ruzvidzo, Oziniel. "Plant Natriuretic Peptides - Elucidation of the Mechanisms of Action." Thesis, University of the Western Cape, 2009. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_5854_1285860491.
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Several lines of cellular and physiological evidence have suggested the presence of a novel class of systemically mobile plant molecules that are recognized by antibodies generated against vertebrate atrial natriuretic peptides (ANPs). Functional characterization of these immunoanalogues, referred to as immunoreactive plant natriuretic peptides (irPNPs) or plant natriuretic peptides (PNPs), has shown that they play important roles in a number of cellular processes crucial for plant growth and maintenance of cellular homeostasis. Although the various biological roles of PNPs in plants are known, their exact mode of action remains elusive. To elucidate the mechanisms of action for these immunoanalogues, we have prepared a biologically active recombinant PNP from Arabidopsis thaliana (AtPNP-A) and the biological activity was demonstrated by showing its ability to induce water uptake into Arabidopsis thaliana protoplasts. In addition, the molecule was shown to downregulate photosynthesis while at the same time up-regulating respiration, transpiration as well as net water uptake and retention capacities in the sage Plectranthus ecklonii. Further analysis of the recombinant AtPNP-A indicated that the peptide can induce systemic response signalling though the phloem. A recombinant Arabidopsis wall associated kinase-like protein (AtWAKL10) that has a domain organization resembling that of vertebrate natriuretic peptide (NP) receptors was also partially characterized as a possible receptor for the recombinant AtPNP-A. Vertebrate NP receptors contain an extracellular ligand-binding domain and an intracellular guanylate cyclase (GC)/kinase domain and signal through the activity of their GC domain that is capable of generating intracellular cGMP from GTP. The structural resemblance of AtWAKL10 to vertebrate NP receptors could suggest a functional homology with receptor molecules and it is conceivable that such a receptor may recognize PNPs as ligands. The characterization of the recombinant AtWAKL10 showed that the molecule functions as both a GC and a kinase in vitro. This strengthened the suggestion that AtWAKL10 could be a possible AtPNP-A receptor especially considering the fact that AtPNP-A applications to plant cells also
trigger cGMP transients. Furthermore, a bioinformatic analysis of the functions of AtPNP-A and AtWAKL10 has inferred both molecules in plant pathogen responses and defense mechanisms, thus indirectly functionally linking the two proteins.
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Ntanios, Fady Y. "Cholesterol lowering efficacy of plant sterols : mechanisms of action." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0018/NQ44534.pdf.
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Rousseaux, Maxime. "Understanding Parkinson's Disease: Mechanisms of Action of DJ-1." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/22904.
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Parkinson’s disease (PD) is the most common movement neurodegenerative disease affecting approximately 1% of the population over 60. Though originally thought to be sporadic in nature, a genetic component is increasingly being linked to the disease. Of these genes, mutations in DJ-1 (PARK7) cause early onset autosomal recessive PD. Initial workup of the DJ-1 protein has suggested that it may act in the cell by combatting oxidative stress though the mechanism by which it does so is unclear. Thus, though much work has attempted to elucidate a function at the biochemical, cellular and organismal level, the overt physiological role of DJ-1 remains elusive. In this dissertation, we explore the mechanisms through which DJ-1 confers neuroprotection, particularly in the case of oxidative stress insult. We demonstrate that DJ-1 acts through the pro-survival protein AKT to accomplish its neuroprotective function. Moreover, we note that DJ-1 likely serves its role as an antioxidant through the NRF2 master antioxidant regulator pathway a pathway that is, itself, likely to be regulated by AKT. Together, our results demonstrate that neuroprotection by DJ-1 is done through a signaling pathway involving both AKT and NRF2 and that disruption of the former in PD likely results in abolishing this signaling pathway. Finally, to generate a better animal model of PD, we demonstrate that backcrossing DJ-1 null mice - which originally did not demonstrate any gross histopathological or behavioral phenotypes – display unilateral dopaminergic degeneration that progresses to bilateral degeneration with aging, a feature reminiscent of classical PD progression. Collectively, this thesis takes a two-sided approach to address the biochemical and physiological functions of DJ-1 within the cell and the mouse in hopes of elucidating mechanisms of neuronal death to devise better translational therapies.
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Fox, Mary Elizabeth. "Mechanisms of action of anticancer DNA topoisomerase II poisons." Thesis, University of Cambridge, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239716.
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Lloyd, Jeffrey Douglas. "The mechanisms of action of boron containing wood preservatives." Thesis, Imperial College London, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284132.
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Roelofs, Anke. "Anti-tumour mechanisms of action bisphosphonates and bisphosphonate analogues." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.436994.
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McClelland, David. "Mechanisms of action of pregabalin on cultured sensory neurones." Thesis, University of Aberdeen, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408955.
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In this study, the whole-cell patch clamp technique and fura-2 calcium (Ca2+) imaging techniques were employed to investigate and compare the effects of the novel antiepileptic/ antihyperalgesic drugs pregabalin and gabapentin. Investigations were done on cultured dorsal root ganglion neurones as they form a neuronal system that is a potential target for gabapentin/pregabalin pain control. The effects of pregabalin on the action potential properties of hyperexcitable multiple-firing cells were similar to those previously found for gabapentin. The changes on action potential properties suggested that pregabalin and gabapentin inhibition of repetitive firing of action potential spikes in DRG neurones is due to inhibition of Ca2+ dependent K+ currents as a result of Ca2+ current attenuation. Pregabalin and gabapentin inhibited voltage-activated Ca2+ currents to a similar maximal level and no additive inhibition was seen during simultaneous application of both drugs, suggesting a common site of action. The current inhibited was not conducted by L-type voltage-activated Ca2+ channels and was not due to a shift in the voltage dependence of activation. The continual presence of GABA or the GABAB receptor antagonist CGP52432 or intracellular photorelease of GTP-g-S had no effect on pregabalin-induced inhibition of Ca2+ currents. Inhibition of voltage-dependent Ca2+ current by pregabalin did not involve the actions a G-protein coupled receptor sensitive to the selective modulator SCH-202676 and unlike previous findings for gabapentin, pertussis toxin pre-treatment did not effect inhibition of Ca2+ currents. Ca2+-imaging techniques supported the magnitude of inhibition produced by pregabalin but also indicated the possibility of pregabalin having other actions that could produce an apparent increase in intracellular Ca2+ flux. This research indicates that pregabalin reduces excitatory properties of cultured DRG neurones by modulating both voltage-activated Ca2+ and K+ channels and its pharmacological activity is similar to that of gabapentin.
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Morrow, Dympna Mary Paula. "Tumour promotion : mechanisms of action and modes of prevention." Thesis, University of Ulster, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322414.
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Petroff, Brian Kelli. "Mechanisms of Hormone Action in the Porcine Corpus Luteum /." The Ohio State University, 1996. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487934589976858.
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Berger, Olivier. "Synthesis of antimalarial agents with new mechanisms of action." Thesis, Montpellier 2, 2010. http://www.theses.fr/2010MON20034.
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L'objectif de mon travail de thèse a été la synthèse de nouveaux agents antipaludiques afin de développer une nouvelle chimiothérapie pour lutter contre l'émergence de résistance multi-drogues de Plasmodium falciparum. Notre choix s'est porté sur le développement de trois nouvelles séries de composés: les quinolones qui inhibent le processus de respiration des mitochondries, les benzamidines qui inhibent la formation de l'hémozoïne et les alkylamidines qui bloquent le métabolisme phospholipidique. Dans le groupe du professeur O'Neill à Liverpool, la première partie de mon travail a été concentrée sur la synthèse de dérivés de 4-quinolone en faisant varier la chaîne latérale (chapitre II). La seconde partie de mon travail a été la synthèse de dérivés dibenzamidines en variant le linker hétérocyclique (chapitre III). Pour ce travail, le linker a été modifié: la chaîne alkoxy de la pentamidine a été remplacée par l'hétérocycle correspondant pour fournir les différentes séries de composés (thiazole, triazole, furane ou aziridine). Trois différents paramètres ont été étudiés pour ces dérivés: la position de la fonction amidine sur le cycle aromatique, l'angle entre les deux benzamidines et la position de l'hétérocycle au sein de la molécule. Pour tous ces composés, les activités antipaludiques in vivo ont été déterminées. Dans le groupe du professeur Durand à Montpellier, la première partie de mon travail a été la synthèse de dérivés alkylamidines en faisant varier le linker et en introduisant un noyau aromatique dans la tête polaire des reversed amidines. Le but était d'étudier l'influence du noyau aromatique sur l'activité antipaludique des drogues ainsi que le développement de leurs prodrogues (chapitre IV). Pour tous ces composés, les activités antipaludiques in vitro et in vivo ont été mesurées. La seconde partie de mon travail a été la réalisation des essais de stabilité et de bioconversion des différentes prodrogues dissymétriques (chapitre V). Les différentes conditions utilisées ont été optimisées sur la pentamidoximeThe objective of my PhD work was the synthesis of new antimalarial agents in order to develop a new chemotherapy to fight the emerging multi-drug resistant strains of Plasmodium falciparum malaria. Our choice has been the development of three new series of drugs: quinolones which inhibit the mitochondrial respiration process, benzamidines which inhibit hemozoin formation and alkylamidines which block phospholipid metabolism. Within the O'Neill group (Liverpool), the first part of my work has been focussed on the synthesis of 4-quinolone derivatives, varying the side chain (chapter II). The second part of my work has been the synthesis of dibenzamidine derivatives, varying the heterocyclic linker (chapter III). Within this work, the linker was modified in the following ways: alkoxy chain of pentamidine was replaced by the corresponding heterocycle to give four different series of compounds (thiazole, triazole, furane or aziridine). Three different parameters were studied for these derivatives: position of the amidine function on the aromatic ring, the angle between the two benzamidines and the position of the heterocyclic ring in the molecule. For these drugs, in vitro antimalarial activities have been measured. Within the Durand group (Montpellier), the first part of my work has been focussed on the synthesis of derivatives varying the linker of the bis-C-alkylamidines and introducing an aromatic ring in the polar head of the reversed amidines. The aim was to study the influence of the aromatic ring on the antimalarial activity of the drugs as well as the development of their prodrugs (chapter IV). For all these drugs and prodrugs, in vitro and in vivo antimalarial activities have been measured. The second part of my work has been based on the stability and bioconversion studies of different asymmetrical prodrugs (chapter V). The different conditions used for these studies have been optimised on the pentamidoxime
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Simmons, Michele LeAnn. "Mechanisms of dynorphin release and action in the hippocampus /." Thesis, Connect to this title online; UW restricted, 1996. http://hdl.handle.net/1773/6306.
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Vainio, Petri. "Molecular mechanisms of action and activation of lipoprotein lipase." Helsinki : Societas Scientiarum Fennica, 1985. http://catalog.hathitrust.org/api/volumes/oclc/23065316.html.
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