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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

PRECLINICAL DEVELOPMENT OF PHYTOCANNABINOID- AND ENDOCANNABINOID- BASED PHARMACOTHERAPIES FOR THE TREATMENT OF ETHANOL-INDUCED NEURODEGENERATION

Liput, Daniel J 01 January 2013 (has links)
Excessive ethanol consumption, characteristic of alcohol use disorders (AUDs), is associated with widespread neurodegeneration and cognitive and behavioral impairments that may contribute to the chronic and relapsing nature of alcoholism. Therefore, identifying novel targets that can afford neuroprotection will undoubtedly aid current treatment strategies for AUDs. The cannabinoids have been shown to provide neuroprotection in a variety of preclinical models of neurodegeneration; however minimal data is available regarding the use of cannabinoid-based pharmacotherapies for treating ethanol-induced neurodegeneration. Therefore, the current dissertation examined the overarching hypothesis: the cannabinoids are a therapeutic strategy to afford neuroprotection in the context of ethanol-induced neurodegeneration. Importantly, this overarching hypothesis was approached with translational considerations in mind. Specifically, the use of many cannabinoids in the clinic is hindered due to multiple unfavorable pharmacokinetic/pharmacodynamic profiles, including high first pass metabolism and untoward psychoactivity. Therefore, the studies herein were designed to circumvent these PK/PD obstacles. The first set of studies examined whether transdermal delivery of the phytocannabinoid, cannabidiol (CBD), could attenuate binge ethanol induced neurodegeneration. Transdermal CBD afforded neuroprotection in the entorhinal cortex and neuroprotection was similar in magnitude as intraperitoneal administration. The second set of studies found that binge ethanol treatment transiently down-regulated the main CNS cannabinoid receptor, CB1R. Interestingly, these changes were not accompanied by alterations in one of the major endogenous ligands, anandamide (AEA), or other related n-acylethanolamides (NAEs). The latter finding is in contrast to other literature reports demonstrating that endocannabinoid content is substantially elevated in response to a CNS insult. Nevertheless, studies were carried out to determine if administration of the AEA and NAE catabolism inhibitor, URB597, could attenuate binge ethanol induced neurodegeneration. URB597 failed to produce neuroprotection in the entorhinal cortex and dentate gyrus of the hippocampus. However, additional studies found that URB597 failed to elevate AEA in the entorhinal cortex, and in general the biological activity of URB597 was impaired by ethanol exposure. Therefore, with further drug discovery/development efforts, it may be feasible to optimize such treatment strategies. In conclusion, the studies within the current dissertation demonstrated the feasibility of using some cannabinoid-based agents to prevent ethanol-induced neurodegeneration.
2

MICROGLIA ACTIVATION IN A RODENT MODEL OF AN ALCOHOL USE DISORDER: THE IMPORTANCE OF PHENOTYPE, INITIATION, AND DURATION OF ACTIVATION

Marshall, Simon A 01 January 2013 (has links)
Chronic ethanol exposure results in neuroadaptations that drive the progression of an alcohol use disorder (AUD). One such driving force is alcohol-induced neurodegeneration. Neuroinflammation has been proposed as a mechanism underlying this damage. Although neuroinflammation is a physiological response to damage, overactivation of its pathways can lead to neurodegeneration. A hallmark indicator of neuroinflammation is microglial activation, but microglial activation is a heterogeneous continuum of phenotypes that can promote or inhibit neuroinflammation. Furthermore acute microglial activation is necessary to restore homeostasis, but prolonged activation can exacerbate damage. The diversity of microglia makes both the level and timecourse of activation vital to understanding their role in damage and/or recovery. The current set of experiments examines the effects of ethanol on microglia within the hippocampus and entorhinal cortex in a binge model of alcohol-induced neurodegeneration. In the first set of experiments, the phenotype of microglia activation was assessed using Raivich’s 5-stages of activation that separates pro- and anti-inflammatory forms of microglia. Morphological and functional assessments suggest that ethanol does not elicit classical microglial activation but instead induces partially activated microglia. In the second set of experiments, the earliest signs of microglial activation were determined to understand the initiation of microglial activation. Experiments indicated that activation occurred subsequent to previous evidence of neuronal damage; however, activation was accompanied by a loss of microglia and the discovery of dystrophic microglia. The final set of experiments examined whether alcohol-induced partial activation of microglia would show a differential response with further alcohol exposure. Experiments showed that animals previously exposed to ethanol showed a greater response to a second ethanol insult. Overall, these studies suggest that although alcohol may initially interrupt the normal microglia response, during abstinence from ethanol a partial activation phenotype appears that may contribute to recovery. Once activated, however, data suggest that these microglia are primed and upon subsequent exposure show an increased response. This heterogeneous microglial response with respect to time does not necessarily reflect a neuroinflammatory response that would be neurodegenerative but does imply that chronic ethanol consumption affects the normal neuroimmune system.
3

Drug consumption and stressful experiences in adolescent mice: behavioural, neorotoxic and neurochemical responses

Ros i Simó, Clara, 1984- 15 March 2013 (has links)
Adolescence is a critical developmental period in which the brain emerges from an immature state to adulthood. This process of brain development is associated to greater cognitive capacity but also to altered emotional behaviour, such as anxiety and depressive symptoms; as well as increased sensation-seeking and risk taking behaviour. The proper development of brain and behaviour into adulthood can be negatively affected by external factors such as drug abuse and environmental conditions. This work consists firstly on, studying the impact of binge ethanol, 3, 4-Methylenedioxymethamphetamine (MDMA) and its combination in adolescent mice. Secondly, study the consequences of early-life stressful experiences (social isolation) into adulthood. Main results obtained from the first objective are that the combination of binge ethanol and MDMA induces emotional-like alterations. These alterations can be prevented by antidepressant treatment. In addition, MDMA induces memory impairments that may be associated to oxidative damage to specific proteins in the hippocampus. Neuroinflammation is also present after MDMA treatment, but not after binge ethanol treatment, in mice striatum. Metabolomic studies indicate that brain metabolism is altered after binge ethanol, MDMA or its combination. Even though these are only preliminary results, these alterations might be due to an imbalance in tryptophan metabolism. Regarding the second objective, our findings indicate that social isolation during adolescence induces an altered response to novel and stressful situations. These alterations are probably due to altered HPA axis activity. / L'adolescència és un període crític en el desenvolupament de l’individu en el qual el cervell va d’un estat immadur a l’edat adulta. Aquest procés va acompanyat d’una elevada capacitat cognitiva però també de freqüents alteracions de tipus emocional, com l’ansietat o els símptomes depressius, així com la cerca de sensacions de risc. Un bon desenvolupament del cervell i del comportament es pot veure negativament afectat per factors externs com són l’abús de drogues i les condicions ambientals desfavorables. Aquest projecte consisteix en primer lloc, a estudiar l'impacte de l’alcohol en excés, la 3, 4-Metilendioximetamfetamina (MDMA) i la seva combinació en ratolins adolescents. En segon lloc, estudiar les conseqüències en l’edat adulta d’experiències estressants durant l’adolescència. Els principals resultats obtinguts referents al primer objectiu són que la combinació d'alcohol en excés i MDMA provoca alteracions de tipus emocional. Aquestes alteracions poden ser previngudes pel tractament amb antidepressius. A més, la MDMA indueix un deteriorament de la memòria que pot estar associada amb el dany oxidatiu a proteïnes específiques de l'hipocamp. També s’ha observat una resposta neuroinflamatòria en el cos estriat dels ratolins després del tractament amb MDMA, però no després del tractament amb etanol en excés. Finalment, estudis de metabolòmica indiquen que el metabolisme cerebral es veu alterat després de l’alcohol en excés, la MDMA o la seva combinació. Tot i que només són resultats preliminars, aquestes alteracions poden ser conseqüència d'un desequilibri en el metabolisme del triptòfan. Referent al segon objectiu, els nostres resultats indiquen que l'aïllament social durant l’adolescència indueix una resposta alterada a situacions novelles i estressants. Aquestes respostes anormals són probablement conseqüència d’alteracions en l’activitat de l’eix HPA.

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