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Dose dependent pharmacokinetics of probenecid following single and repeated dosesSelen, Arzu. January 1900 (has links)
Thesis (Ph. D.)--University of Wisconsin--Madison, 1984. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 243-249).
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Development and Phenotypic Characterisation of a CRISPR/Cas9 Model of Riboflavin Transporter Deficiency in ZebrafishChoueiri, Catherine 12 December 2023 (has links)
Riboflavin transport is mediated, in part, by riboflavin transporter proteins 2 and 3, encoded by SLC52A2 and SLC52A3, respectively. Biallelic mutations in SLC52A2 and SLC52A3 impair riboflavin transporter protein function and riboflavin transport, causing disruptions to mitochondrial metabolism which result in sensory and motor neurodegeneration and give rise to riboflavin transporter deficiency (RTD) in humans. RTD is a rare neurodegenerative disease characterised by respiratory compromise, muscle and limb weakness, and vision and hearing impairments. RTD patients are treated with high-dose riboflavin supplementation which is effective in over 70% of cases but can be ineffective due to rapid excretion of riboflavin when its plasma concentration exceeds 0.5 μM. To address the need for alternative or supplemental RTD treatment, this study generated morpholino-mediated knockdown and CRISPR/Cas9 models of RTD in zebrafish. An RTD-like phenotype is observed in these RTD models including hearing loss, decreased motor axon length, and impaired locomotor activity. The slc52a3 morphant phenotype was found to be specific via coinjection of slc52a3 morpholino/human SLC52A3 mRNA, which achieved effective rescue of the morphant phenotype, as well as slc52a3 morpholino/p53 morpholino coinjection, which maintains the slc52a3 morphant phenotype. In line with clinical findings, riboflavin supplementation resulted in some improvement of the morphant phenotype. Probenecid was selected as a candidate drug due to its inhibitory effect on OAT-3, which mediates riboflavin excretion. However, supplementing riboflavin treatment with probenecid provided no additional benefit to the slc52a3 knockdown model. Further development of CRISPR/Cas9-knockout lines of slc52a2 and slc52a3, as well continued therapeutic screening of riboflavin and probenecid and consideration of alternative therapeutics will provide more opportunities to uncover novel therapeutic strategies to improve RTD treatment.
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A Mechanistic Investigation of Anesthesia-Induced Spatial Learning Deficits in Aged RatsMawhinney, Lana J 29 April 2011 (has links)
Anesthesia-induced spatial learning impairments in aged rats model postoperative cognitive dysfunction (POCD) in the elderly surgical population. Mechanisms underlying both normal age-related cognitive decline and anesthesia-induced spatial learning deficits in aged rats were investigated. With respect to the involvement of inflammasome activation and age-related cognitive decline, I hypothesized that the aged hippocampus exhibits an elevated activation of inflammasome components contributing to elevated levels of IL-1β in the aged brain. Age-related cognitive decline was identified in a subpopulation of male Fischer 344 rats. Activation of the NLRP1 inflammasome was elevated in the aged brain, contributing to spatial learning deficits in aged rats. With respect to anesthesia-induced spatial learning impairment in aged rats, I hypothesized that an increase in NR2B subunit in the hippocampus and cortex during and following isoflurane anesthesia exposure resulting in spatial learning impairment in aged rats via disruption of downstream signaling molecule, extracellular-signal regulated protein kinase (ERK). Anesthesia exposure resulted in chronic spatial learning impairment in aged rats that were previously unimpaired in spatial learning tasks. Additionally, anesthesia induced elevated levels of N-methyl-D-aspartate (NMDA) receptor NR2B subunit protein expression in aged. It was concluded that various factors contribute to age-related spatial impairment including: NLRP1 inflammasome activation and NMDA receptor NR2B protein expression elevation. It was also concluded that anesthesia exposure exacerbates the elevation in NR2B protein expression in the aged brain, with subsequent disruption of ERK activation leading to chronic spatial learning deficits in aged rats. In the final chapter, a relationship for the interplay between inflammation and NMDA receptor function in the aged brain is discussed. In addition, a novel mechanism for anesthesia-induced cognitive deficits is presented. Therapeutic treatments for cognitive decline and anesthesia-induced cognitive deficits are explored. Finally, future lines of research are proposed.
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Estudo do efeito dos antagonistas do receptor P2X7 e Panexina-1 nas células gliais entéricas no protocolo de isquemia e reperfusão intestinal. / Study of the effect of P2X7receptor and Pannexin-1 antagonists on enteric glial cells in the intestinal ischemia and reperfusion protocol.Mendes, Cristina Eusébio 27 March 2017 (has links)
Evidências indicam uma interação na comunicação glia-neurônio. E sabido que a isquemia e reperfusão intestinal (I/R) são eventos clínicos graves. Este projeto visa estudar os efeitos de Brilliant Blue G (BBG) e de Probenecida (PB) nas células gliais entéricas (CGE). Os vasos ileais foram ocluídos por 45 min. Os períodos de reperfusão foram de 24 h, 14 e 28 dias.Os animais foram tratados com BBG, PB ou Salina. Os dados mostraram que o receptor P2X7 estava em CEG e neurônios, que há fenótipos diferentes de CGE e Panx-1 estava em CEG (GFAP). As densidades mostraram diminuição do número de células-IR ao receptor P2X7, Panx-1 e Hu no grupo I/R Salina, porém nos grupos tratados houve recuperação do número dessas células e com as CGE ocorreu um aumento no grupo I/R Salina. A área do perfil celular apresentou alterações em neurônios e CGE. Houve alterações na expressão proteica de P2X7 e Panx-1 e na atividade contrátil do intestino. O uso de BBG e de PB têm sido eficaz na recuperação de CGE e neurônios e podem ser alvos terapêuticos para doenças do trato gastrintestinal. / Evidence indicates an interaction in glia-neuron communication. It is known that intestinal ischemia and reperfusion (I/R) are serious clinical events. This project aims to study the effects of Brilliant Blue G (BBG) and Probenecida (PB) on enteric glial cells (CGE). The ileal vessels were occluded for 45 min. Reperfusion periods were 24 h, 14 and 28 days. Animals were treated with BBG, PB or Saline. The data showed that the P2X7 receptor was in CEG and neurons, that there are different phenotypes of CGE and Panx-1 was in CEG (GFAP). The densities showed a decrease in the number of cells-IR to the P2X7 receptor, Panx-1 and Hu in the Salina I/R group, but in the treated groups there was a recovery in the number of these cells and with the CGE there was an increase in the Salina I/R group. The cell profile area presented changes in neurons and CGE. There were changes in the protein expression of P2X7 and Panx-1 and in the contractile activity of the intestine. The use of BBG and PB has been effective in the recovery of CGE and neurons may be therapeutic targets for diseases of the gastrointestinal tract.
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