Abstract not available

Thesis (Ph. D.)--Auburn University. / Abstract. Vita. Includes bibliographical references.

Thesis (M.S.)--Brigham Young University. Dept. of Physiology and Developmental Biology, 2007. / Includes bibliographical references (p. 38-40).

Thesis (M.S.)--The University of North Carolina at Greensboro, 2009. / Directed by Keith Erikcon; submitted to the Dept. of Nutrition. Title from PDF t.p. (viewed Jun. 4, 2010). Includes bibliographical references (p. 65-86).

Alzheimer's disease is a progressive neurodegenerative disorder, in which there is a marked decline in neurotransmitters, especially those of the cholinergic pathways. One of the approaches to the symptomatic treatment of Alzheimer's disease is the inhibition of the breakdown of the neurotransmitter acetylcholine, using an acetylcholinesterase inhibitor. One such drug tested, is the organophosphate, metrifonate. Any drug used for the treatment of neurodegenerative disorders should preferably not induce further neurological damage. Thus, in the present study, we investigated whether or not metrifonate is neuroprotective. The in vivo and in vitro effect of this drug on free radicals generation shows that metrifonate increases the level ofthese reactive species. Lipid peroxidation induced using quinolinic acid (QA) and iron (II) and show that metrifonate increased the peroxidative damage induced by using quinolinic acid. Metrifonate is also able to induce lipid peroxidation both in vivo and in vitro. This was reduced in vitro in the presence of melatonin. Using iron (II), in vi/ro, there was no significant difference in the level of lipid peroxidation in the presence of this drug. An investigation of the activity of the mitochondrial electron transport chain and complex I of the electron transport chain in the presence of metrifonate revealed that metrifonate reduces the activity of the electron transport chain at the level of complex I. The activity of the mitochondrial electron transport chain was restored in the presence of melatonin. Pineal organ culture showed that metrifonate does not increase melatonin production. Histological and apoptosis studies show that tissue necrosis and apoptosis respectively, occur in the presence of this agent, which is reduced in the presence of melatonin. Metal binding studies were performed USing ultraviolet spectroscopy, and electrochemical analysis to examine the interaction of metrifonate with iron (II) and iron (III). No shift in the peak was observed in the ultraviolet spectrum when iron (ll) was added to metrifonate. Electrochemical studies show that there may be a very weak or no ligand formed between the metal and drug. This study shows that while drugs such as metrifonate may be beneficial in restoring cognitive function in Alzheimer's disease, it could also have the potential to enhance neurodegeneration, thus worsening the condition, in the long term. / KMBT_363 / Adobe Acrobat 9.54 Paper Capture Plug-in

The crotoxin complex protein is the major neurotoxic component in the venom of the Brazilian rattlesnake, Crotalus durissus terrificus. The purified protein can be crystallized in the form of thin platelets (less than 500 Å thick) suitable for electron crystallography and image processing techniques. The unit cell dimensions of the crystal are a = 38.8 Å, b = 38.8 Å, c = 256 Å, and α = β = γ = 90°. These crystals can grow in layers. For a three-dimensional image reconstruction this necessitates the determination of the crystal thickness in order to combine information from low dose images of crystals of the same thickness. In the past, the highest resolution image (to 3.9 Å) recorded from a crotoxin complex crystal on the electron microscope was from a crystal embedded in glucose. However, since glucose cannot be removed in order to accurately determine the crystal thickness, a different embedding technique (amorphous ice embedding) and tried. It was determined that high resolution image information (to 3.9 Å) can be recorded from crotoxin complex crystals embedded in amorphous ice. Five images of crystals preserved in amorphous ice, all exhibiting resolution to at least 9 Å, were first processed by a global averaging method from which two-dimensional projection maps were calculated. These maps were not interpretable due to variations in the images as demonstrated by a second processing method. In the second processing method the images were divided into smaller areas, or patches, and these patches were averaged. The patchwork images produced from the second process indicate that there is variation across the original images. The most likely explanation for the variation is the bending, or lack of flatness, of the crystals on the grid. The determination of mass thickness of the crystals from optical density differences between the crystals and the carbon support in images of freeze-dried crystals was explored. It was found that this method could not determine the mass thickness of crotoxin complex crystals to within one layer (64 Å), but could clearly distinguish between one and three overlapping layers of freeze-dried purple membrane which was used as a test specimen.

The dinoflagellate Karenia brevis is one organism responsible for harmful algal blooms (HABs) that severely impact marine life. K. brevis produces a suite of neurotoxins referred to as brevetoxins (PbTx) which bind to voltage-gated sodium channels (VGSCs) in excitable tissues, affecting cellular permeability leading to a suite of symptoms and potentially cell death. Brevetoxicosis is difficult to treat in sea turtles as the physiological impacts have not been investigated and the magnitude and duration of brevetoxin exposure are generally unknown. Due to their threatened and endangered status, experimental exposures cannot be performed to determine the fate of brevetoxin in sea turtle tissues, making it difficult to design appropriate treatments. The freshwater turtle, Trachemys scripta, was utilized as a model for brevetoxin exposure in turtles. Turtles were exposed to intratracheal instillation (10.53μg/kg) or oral dosing (33.48μg/kg) of PbTx-3 3x weekly over a period of 2-4 weeks. Tissues and fluids were collected for ELISA to determine PbTx-3 uptake and distribution, routes of excretion and rates of clearance (1h-1wk post-exposure). Tissues were also preserved for histopathology. Primary turtle neuronal cell cultures were exposed to PbTx-3 in the presence and absence of various agonists and antagonists to determine brevetoxin’s mode of action. PbTx-3 was widely distributed in all tissues and fluids following both intratracheal and oral exposures, but was largely cleared from the system within 24 hours; PbTx-3 moved into the bile and feces over 48h post exposure indicating that this is the main route of excretion. While exposed animals showed clear behavioral symptoms of toxicity including muscle twitching, swimming in circles, and ataxia, there was no evident tissue pathology. Despite the evident behavioral effects, turtle neurons are surprisingly resistant to PbTx-3, with an EC50 significantly higher than is seen in mammalian neurons. While PbTx-3 exposure resulted in significant Ca2+ influx, various antagonists prevented Ca2+ influx when added with PbTx-3 confirming the mechanism of action through VGSCs. Upregulation of Hsp72 in the turtle brain could be enhancing cell survival. Based on results, intralipid treatment post PbTx-3 exposure rapidly decreases symptoms and proves to be a suitable treatment for toxin exposure. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2017. / FAU Electronic Theses and Dissertations Collection

A exposição a agentes químicos neurotóxicos pode concorrer para o desenvolvimento ou potencialização de dificuldades de aprendizagem. A investigação dos níveis de concentração de metais pesados em escolares com tais dificuldades pode auxiliar no planejamento terapêutico, bem como orientar órgãos de saúde competentes para promoção de prevenção e de desintoxicação. Foi realizado um estudo com o objetivo de verificar as concentrações remotas de chumbo em escolares com dificuldades de aprendizagem, a fim de avaliar a prevalência de exposição precoce a este agente, bem como correlacionar os níveis encontrados com resultados de desempenhos em avaliações de processamento fonológico, leitura, escrita e aritmética, além de descrever estatisticamente a amostra quanto a aspectos relevantes do histórico clínico e identificar os bairros de origem ao nascimento. Participaram escolares na faixa etária de 9 a 14 anos, regularmente matriculados no Ensino Básico de instituições públicas ou privadas do município de Bauru (SP) e região, em atendimento na Clínica de Linguagem Escrita da FOB-USP. Foram utilizadas amostras de esmalte dentário superficial como biomarcador de exposição remota ao chumbo. Foram realizadas análises por espectrometria de absorção atômica de forno de grafite (GF AAS) para determinação do chumbo e espectrometria de emissão óptica com plasma indutivamente acoplado (ICP OES) para determinação do fósforo, necessário para o cálculo da massa de esmalte. O estudo teve 17 participantes. Os resultados indicam a prevalência de 100% de exposição precoce ao chumbo, média da concentração de 46,56 g Pb/g esmalte, DP = 47,09. Não houve correlações estatisticamente significativas com os desempenhos avaliados. Quanto ao perfil amostral, as meninas representam 17,6% e os meninos 82,4%. Um total de 35,3% dos participantes sofreram intercorrências gestacionais ou neonatais, 23,5% tem QI limítrofe ou rebaixado, 94,1% tem histórico de distúrbios de linguagem oral, 41,2% alterações psicomotoras, 5,9% diagnosticados com TDAH. A análise descritiva qualitativa dos bairros de origem revela que a distribuição dos mesmos está dispersa pelo município, além de participantes de outras localidades da região. / Exposure to neurotoxic chemical agents may contribute to the development or enhancement of learning disabilities. The investigation of concentration levels of heavy metals in schoolchildren with such difficulties can aid in therapeutic planning as well as guide competent health agencies to promote prevention and detoxification. A study was carried out with the objective of verifying the remote concentrations of lead in students with learning disabilities in order to evaluate the prevalence of early exposure to this agent, as well as to correlate the levels found with results of performances in phonological processing evaluations, reading, writing and arithmetic, in addition to statistically describing the sample regarding relevant aspects of clinical history and identifying origin neighborhoods at birth. Participants were students aged 9 to 14 years, regularly enrolled in Basic Education of public or private institutions of the municipality of Bauru (SP) and region, attending the Clinic of Written Language of FOB-USP. Surface dental enamel samples were used as a biomarker for remote lead exposure. Analyzes were performed by atomic absorption spectrometry of graphite furnace (GF AAS) for determination of lead and inductively coupled plasma optical emission spectrometry (ICP OES) for determination of phosphorus, necessary for the calculation of enamel mass. The study had 17 participants. The results indicate the prevalence of 100% early exposure to lead, mean concentration of 46.56 g Pb / g enamel, SD = 47.09. There were no statistically significant correlations with the evaluated performances. The sample profile reveals that girls represent 17.6% and boys 82.4%. A total of 35.3% of the participants had gestational or neonatal intercurrences, 23.5% had borderline or reduced IQ, 94.1% had a history of oral language disorders, 41.2% had psychomotor disturbances, 5.9% had ADHD. The qualitative descriptive analysis of the origin neighborhoods reveals that its distribution is dispersed by the municipality, besides participants of other localities of the region.

Abstract not available

Thesis (M.Sc. (Pharmacy)) - Rhodes University, 2008.