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1
Zhou, Yan. "ß-amyloid neurotoxicity." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/nq23974.pdf.
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Al-Mousa, Fawaz Ali F. "Neurotoxicity of environmental pollutants." Thesis, University of Birmingham, 2011. http://etheses.bham.ac.uk//id/eprint/1461/.
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Brominated flame retardants (BFRs) and alkylphenols (APs) are pollutants commonly found within the environment and have human health concerns due to their endocrine disrupting and cytotoxic effects. BFRs are used to reduce the flammability of a variety of consumer products such as foam furnishings, whereas APs are found in plastic products used by the food industry. This study investigated the neurotoxicity of the most commonly used groups of BFRs and APs on SH-SY5Y human neuroblastoma cells. The results presented in this thesis showed (using cell viability assays) that these pollutants are toxic at low concentrations. Some compounds such as hexabromocyclododecane (HBCD) and 4-nonylphenol (4-NP) induce cell death (apoptosis) by caspases activation (Casp-8, Casp-9 and Casp-3) and cytochrome c release at low micromolar concentrations (IC50 ~ 4μM and 6μM, respectively). Consequently this study also showed that these compounds increased intracellular [Ca2+] levels and the production of reactive oxygen species (ROS) within SH-SY5Y cells by causing Ca2+-dependent depolarization of the mitochondria. In support of a Ca2+-mediated mechanism, the data presented here shows that some BFRs and APs inhibit Sarcoplasmic/ Endoplasmic Ca2+-ATPase (SERCA) and to corroborate this over-expressing SERCA1 improved cell viability especially in cells exposed to certain cytotoxic chemicals such as HBCD; this study is the first experiment of this type to be performed. This study also showed that some of these chemicals, at low concentrations had amyloidgenic effects causing the cleavage amyloid precursor protein (APP) into Beta-amyloid (Aβ) and could therefore be implicated in Alzheimer‟s disease (AD).
3
Child, Tim. "The neurotoxicity of acrylamide." Thesis, Aston University, 1996. http://publications.aston.ac.uk/10934/.
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The experiments described in this thesis compared conventional methods of screening for neurotoxins with potential electrophysiological and pharmacological tests in an attempt to improve the sensitivity of detection of progressive distal neuropathy. Adult male albino mice were dosed orally with the neurotoxicant acylamide and subjected to a test of limb strength and co-ordination and a functional observational battery. These methods established a no observable effect level of 10 mg/kg. A dose of 200 mg/kg resulted in abnormalities of gait and reduced limb strength and/or co-ordination. The evoked and spontaneous twitch responses of the hemidiaphragm preparation following in vitro exposure to the organophosphorous anticholinesterase compound ecothiopate were altered by in vivo pre treatment with acrylamide. Acrylamide caused an increase in the time course of the potentiation of stimulated twitches and a decrease in the maximum potentiation. Spontaneous twitches were reduced in amplitude and frequency. These effects occurred at an acrylamide dose level insufficient to cause clinical signs of neuropathy. Investigations into the mechanisms underlying these observations yielded the following observations. Analysis of miniature endplate potentials at this dose level indicated prolongation of the life of acetylcholine in the synaptic cleft but the implied decrease in cholinesterase activity could not be demonstrated biochemically or histologically. The electrical excitability of the nerve terminal region of phrenic motor nerves was reduced following acrylamide although a possible compromise of antidromic action potential conduction could not be confirmed. There was no histopathological evidence of neuropathy at this dose level. Further exploration of this phenomenon is desirable in order to ascertain whether the effect is specific to acrylamide and/or ecothiopate and to elucidate the mechanisms behind these novel observations.
4
Kern, Cynthia H. "Neurotoxicity of neonatal manganese exposure /." Diss., Digital Dissertations Database. Restricted to UC campuses, 2009. http://uclibs.org/PID/11984.
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Menton, Kevin. "Intracellular mechanisms of manganese neurotoxicity." Thesis, University of Sunderland, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311078.
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Dick, Finlay D. "The neurotoxicity of paint solvents." Thesis, University of Aberdeen, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288257.
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<i>Objectives</i>- To investigate the relationship between neuropsychological symptoms, as measured by questionnaire, and formal measurements of neurological and psychological function. To investigate the relationship between neuropsychological symptoms and solvent exposure estimates. To test the hypothesis that neuropsychological disorder in solvent exposed workers is more likely to those with genetic predisposition. <i>Methods </i>- A nested case-control study was carried out in a cohort of former dockyard painters and community controls. The 78 painters and 42 community controls had previously participated in a postal study that had shown an excess of neuropsychological symptoms amongst painters. The 120 participants in the nested - case control study underwent detailed neuropsychological testing, colour vision testing, estimation of solvent exposure indices and genetic testing for GSTM1, GSTT1, NAT1 and NAT2 enzyme polymorphisms. <i>Results </i>- A case-control analysis of 68 patients failed to demonstrate significant differences in neuropsychological function between symptomatic and asymptomatic painters as measured by the Q16. Subsequent regression analyses of all 120 subjects showed a range of neuropsychological deficits with an exposure response relationship. There was no convincing evidence of risk modification by any of the enzyme polymorphisms studied. During the study a pattern of deficits was recognised, sufficient to constitute a syndrome of impaired colour vision, cognitive impairment impaired vibration perception and resting tremor. <i>Conclusions </i>- Exposure to mixed solvents is associated with neuropsychological impairment, the risk increasing with increasing intensity of exposure. The risk of impairment was not altered in this study by the presence of different enzyme polymorphisms.
7
Abdulla, Elizabeth McFarlane. "In vitro studies of neurotoxicity." Thesis, King's College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248040.
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Alm, Henrik. "Proteomic Characterization of Induced Developmental Neurotoxicity." Doctoral thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-99652.
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The developing brain goes through a number of developmental periods during which it displays an increased sensitivity to exogenous disturbances. On such period is the so called “Brain growth spurt” (BGS) which in humans takes place starting from the third trimester of pregnancy and throughout the first few years of life. The corresponding period in rats and mice is the first postnatal weeks. Exposure to relatively modest concentrations of the brominated flame retardant PBDE-99 during the second week of life in mice causes a more or less permanent impairment in the ability of the animals to adjust properly to environmental changes at adulthood. This “late response on early exposure” reflects the long-term consequences of disrupting the developing brain during a sensitive time period. The cellular mechanisms underlying the behavioral effects are far from clear. To address the initial damage occurring around the time of exposure, the approach used in this thesis is to use proteomics to analyze the effects of PBDE-99 on protein expression soon (24 hours) after exposure of the neonatal mouse on postnatal day (PND) 10.The thesis comprises the effects on the proteome in three distinct brain parts: cerebral cortex, striatum and the hippocampus. In addition, an in vitro model was developed and used to evaluate the PBDE-99 effects on cultured cerebral cortex cells from embryonic rat brains. Gel-based proteomics (2D-DIGE) coupled to MALDI- or ESI-MS has been used throughout for the proteomics experiments, but other techniques aimed at analyzing both proteins and mRNA have also been used to better characterize the effects. Even if the protein complements expressed by the different brain parts and separated with 2D-DIGE are seemingly similar, the effects are apparently specific for the different brain regions. In hippocampus, PBDE induces effects on proteins involved in metabolism and energy production, while the effects in striatum point towards effects on neuroplasticity. PBDE-99 changes the expression of cytoskeletal proteins in the cerebral cortex 24 hours after exposure. Interestingly, in vitro exposure of cerebral cortex cells to a PBDE-99 concentration in the same order of magnitude as in the in vivo neonatal brain also induces cytoskeletal effects, in the absence of cytotoxicity. This may suggest effects on regulatory aspects of cytoskeletal dynamics such as those involved in neurite sprouting. This thesis also addresses the problems involved in presenting proteomics data. Many of the available methods and approaches for presenting transcriptomics data are not suitable for isoform rich protein data. Modifications of existing methods and the development of a new approach (DEPPS) is also presented. Most importantly, the thesis presents the application and usefulness of proteomics as hypothesis generating techniques in neurotoxicology.
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Campbell, Sonja Gray. "Methylmercury Neurotoxicity and Interactions with Selenium." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/33173.
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Methylmercury (MeHg) is a ubiquitous contaminant and potent neurotoxicant with no completely effective therapy, although selenium antagonises MeHg toxicity. Furthermore, nanoparticles are promising as a novel drug delivery system. We researched the potential of selenium nanoparticles (SeNPs) in antagonising MeHg neurotoxicity compared to selenomethionine (SeMet) using primary astrocyte cell cultures and examining outcomes related to oxidative stress. We found that SeNPs were more toxic than SeMet. Increasing SeNPs significantly decreased MeHg cellular uptake and MeHg significantly decreased uptake of SeNPs at the highest concentration. Finally, SeNPs alone produced significantly higher reactive oxidative species and altered the ratio of reduced-to-oxidised glutathione, but MeHg, SeMet, and co-exposures did not. There were no significant effects on glutathione peroxidase or reductase activity. This suggests that SeNPs are more toxic than MeHg in cerebellar astrocytes and that they may not be suitable as a therapy at the doses and formulation used in this research.
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Axelrad, Janie Clodah. "Neurotoxicity of organophosphates : synergy and interactions." Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250224.
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Lau, Karen Y. T. "Developmental neurotoxicity of food additive interactions." Thesis, University of Liverpool, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.431726.
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Garcia, Reitböck Pablo. "Mechanisms of α-synuclein induced neurotoxicity". Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612371.
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Hawkins, Simon James. "Nanoparticle induced neurotoxicity across placental barriers." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.683558.
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Humans are increasingly being exposed to nanoparticles from sources such as CoCr nanoparticles in metal on metal bearing orthopaedic implants, and also due to the increasing use of nanotechnology. The potential for nanoparticle exposures during pregnancy to cause developmental toxicity has been shown in vivo, and most commonly affects fetal neural development. This has generally been presumed to be due to the passage of nanoparticles to the fetus. It has however been shown that nanoparticles can cause DNA damage across placental barriers without crossing them. This 'indirect toxicity' is due to nanoparticles being internalised within the barrier and initiating a signalling cascade that is believed to transverse the barrier via connexin 43 gap junctions. In this thesis BeWo trophoblast cells were used to make in vitro models of the placenta to determine whether indirect nanoparticle toxicity could alter neurodevelopment. BeWo barriers were exposed to CoCr nanoparticles and media was harvested from beneath the barrier. This was applied to human neural progenitor cells that were differentiating into neurons and astrocytes. The viability of these cells was.unaffected although a shift to an astrocytic phenotype did occur. The resultant astrocytes had enlarged nuclear and cytoplasmic areas on immunostaining and were believed to be reactive astrocytes. These astrocytes also exhibited high levels of yH2AX foci on immunostaining, representing increased levels of DNA damage. The developing human cortical neurons, in culture with the astrocytes, were also found to have increased levels of yH2AX foci but to a lesser level than found in astrocytes. Near pure neuronal cultures did not however develop increased levels of yH2AX foci, therefore it was believed that the reactive astrocytes were initiating the DNA damage in the developing neurons. Exposures to differentiating embryoid bodies derived from human embryonic stem cells also found that differentiation into neuroectoderm was not affected. These results indicate that nanoparticies may alter neurodevelopment due to triggering signalling within the placenta, and that this is dependent on the presence of astrocytes, with earlier developmental events not being equally affected. Finally further investigations were performed to delineate the initiation and methods of transfer of this DNA damaging signalling in the BeWo barrier. These found that when nanoparticles come into contact with the barriers, impairment of autophagic flux occurs in the upper layers. Successful knockdown of Cx43 in the BeWo barriers was performed using shRNA lentiviral vectors to investigate the transfer of DNA damaging signalling. This however did not prevent morphological changes from developing in astrocytes, suggesting that Cx43 gap junctions may not be the only method of signalling transport involved in indirect nanoparticle toxicity. These results are discussed in relation to our current knowledge of neurodevelopment and the effects that astrocytes have in health and disease. Based on the results in this thesis I believe that limiting exposure to nanoparticles is important in women of childbearing age.
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Bhide, Nirmal S. "Tolerance to MDMA-induced serotonergic neurotoxicity." University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1267719790.
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Bastos, Maria de Fátima Camões Sobral de. "Aluminium neurotoxicity and neuronal phosphorylation systems." Doctoral thesis, Universidade de Aveiro, 2007. http://hdl.handle.net/10773/938.
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Doutoramento em Biologia<br>O alumínio é o terceiro elemento mais abundante na Terra. Uma vez que se
encontra distribuído ubiquamente pelo meio ambiente e é utilizado em vários
produtos e processos, a população humana está inevitavelmente exposta
diariamente a este metal. De facto, o alumínio tem sido relacionado com
diversas doenças neurodegenerativas como: a esclerose lateral amiotrófica, a
demência de Parkinson (DP), a doença de Alzheimer (DA) e a encefalopatia
relacionada com a diálise.
A fosforilação de proteínas é um dos principais mecanismos reguladores
intracelulares da maior parte das vias de sinalização nas células eucarióticas.
Este processo dinâmico regula o estado de fosforilação e/ou a actividade das
proteínas através de um balanço entre as proteínas cinases, que fosforilam, e
as proteínas fosfatases (PP) que desfosforilam as proteínas.
A proteína fosfatase 1 (PP1) é uma fosfatase específica para serina/treonina
que está envolvida em importantes mecanismos celulares tais como o ciclo
celular, contracção muscular e apoptose, entre outros. A PP1 tem três
isoformas conhecidas, denominadas PP1α, PP1β e PP1γ,. O gene que
codifica para a isoforma gama pode sofrer splicing alternativo originando a
isoforma ubíqua PP1γ1 e a isoforma enriquecida no testículo PP1γ2.
A fosforilação anormal de proteínas tem sido associada a várias patologias,
incluindo cancro, diabetes e várias doenças neurodegenerativas (DP, doença
de Huntington e DA). Uma das proteínas que se encontram anormalmente
fosforiladas na DA são, por exemplo, os neurofilamentos (NF).
Neste contexto, avaliou-se o efeito do alumínio na expressão de proteínas
(PP1, NF) e realizou-se um estudo comparativo entre duas linhas celulares
com características diferentes, as células PC12 e COS-1. Observou-se que o
alumínio induziu um decréscimo na viabilidade celular, assim como na
expressão e actividade de ambas as isoformas da PP1 em ambas as linhas
celulares. Verificou-se que este efeito podia ser revertido retirando-se o
alumínio. Um estudo semelhante foi ainda realizado num sistema neuronal
utilizando culturas primárias de neurónios corticais. A expressão de ambas as
isoformas da PP1 permaneceu inalterada após a exposição ao alumínio. No
entanto, o alumínio induziu um decréscimo da expressão dos NF e da
sinaptofisina, uma proteína que marca os terminais sinápticos. Por fim,
estudou-se o efeito do alumínio na expressão de outras proteínas em sistemas
in vitro e in vivo utilizando a tecnologia SELDI-TOF MS. Esta tecnologia
permitiu detectar várias proteínas cuja expressão foi alterada devido ao
alumínio. Com este trabalho pretendeu-se contribuir para um melhor
conhecimento da neurotoxicidade do alumínio.<br>Aluminium is the third most abundant element on Earth. Aluminium is
ubiquitous in the environment and is used in a variety of products and
processes, thus, daily exposure of the general population to this metal is
unavoidable. Indeed, aluminium has been implicated with various
neurodegenerative disorders like: amyotrophic lateral sclerosis
(ALS)/Parkinson’s dementia (PD) complex of Guam, Alzheimer’s disease (AD)
and dialysis encephalopathy. Aluminium is known to interfere with several
mechanisms of the nervous system, including alteration of cytoskeletal
proteins, behavioural abnormalities, neurotransmission systems, oxidative
damage, energy metabolism, second messengers, and also to induce neuronal
apoptosis.
Protein phosphorylation is a major intracellular regulatory mechanism of all
signalling pathways in the eukaryotic cell. This dynamic process regulates the
net phosphorylation state and the activity of proteins by a balance between
protein kinases, which phosphorylate, and protein phosphatases (PP), which
dephosphorylate proteins. Protein phosphatase 1 (PP1) is a serine/threonine
specific phosphatase which is involved in the control of important cellular
mechanisms such as the cell cycle, muscle contraction and apoptosis, among
others. PP1 has three known isoforms termed PP1α, PP1β and PP1γ. The
gene for PP1γ produces by alternative splicing a ubiquitously expressed PP1γ1
and a testis-specific PP1γ2 isoform.
Abnormal protein phosphorylation has been associated with various disorders,
including cancer, diabetes, and several neurodegenerative disorders (PD,
Huntington’s disease and AD). Besides tau other proteins that are abnormally
phosphorylated in AD are the neurofilaments (NF).
In this context, the aluminium effect on the expression of proteins (PP1, NF)
was evaluated. A comparative study was performed using two cell lines with
different characteristics, PC12 and COS-1 cells. It was observed that
aluminium induced a decrease in the cellular viability, as well as in the
expression and activity of both PP1 isoforms in both cell lines. This effect was
reverted following aluminium withdrawal. A similar study was also performed in
a neuronal system, primary cortical neuron culture. The expression of both
PP1 isoforms remained unchanged after aluminium exposure. However,
aluminium induced a decrease in the expression of NF and of synaptophysin, a
protein marker for synaptic terminals.
Finally, the effect of aluminium on the expression of other proteins in in vitro
and in vivo systems was evaluated using SELDI-TOF MS technology. In this
study, several proteins with altered expression due to aluminium were
detected. This work aimed to contribute to the better understanding of
aluminium neurotoxicity.
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Robinson, Emily. "Mediators of inflammation in acute neurotoxicity." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/mediators-of-inflammation-in-acute-neurotoxicity(a657668f-f6de-4fb6-878d-65846fc18e66).html.
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Neuroinflammation is a major feature of most neurodegenerative conditions, and can leadto the exacerbation of neuronal injury. Inflammatory challenges in the central nervoussystem (CNS) have been shown to activate peripheral immune cells, which subsequentlyinfiltrate into the brain. Concurrently, resident inflammatory cells in the CNS, such asmicroglia, become activated and release inflammatory mediators, including cytokines.The pro-inflammatory cytokine interleukin-1 (IL-1) is a key mediator of neuronal injury.Although two IL-1 agonists exist, IL-1α and IL-1β, the majority of research has focussedon the contribution of IL-1β to neuronal injury. Excitotoxic cell death in the rat brain,induced by striatal injection of the glutamate agonist AMPA, is exacerbated by coadministrationof recombinant IL-1β. To identify possible mediators which facilitate theexacerbation of neuronal injury by IL-1 this study investigated the early peripheral andcentral mediators of inflammation in response to AMPA + IL-1β.Neutrophil infiltration and increased neuronal activity were found to be present at 4h post-AMPA + IL-1β injection, which lead to the induction of microglial IL-1α in the ipsilateralcortex, in the absence of any IL-1β expression. To target the peripheral neutrophil responsean intervention study was performed to inhibit peripheral TNFα, which is thought tomobilise neutrophils. No significant effect of pre-treatment with etanercept, a TNFαinhibitor, was observed on neuronal injury produced in response to AMPA + IL-1β, thougha slight trend for protection was seen. To target the central IL-1α response after AMPA +IL-1β treatment an anti-IL-1α antibody was injected directly into the cerebral cortex, butthis had no effect on AMPA + IL-1β induced cell death. Therefore, using a reductionist invitro approach in organotypic slice cultures haemin, an inducer of endogenous IL-1α, wasused to investigate IL-1α mediated cell death. Haemin induced cell death was shown to beIL-1 dependent and preliminary studies using IL-1αKO mice indicated that IL-1α maypartially mediate this effect. This suggests that in the AMPA + IL-1β paradigm IL-1α is thedominant IL-1 isoform early after AMPA + IL-1β treatment, which can trigger subsequentneuronal cell death, as a result of the additive effects of neutrophil infiltration and highneuronal activity in the cortex. This study highlights the potential therapeutic value ofinhibiting IL-1α expression early following acute neuronal injury.
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Starling, Isabella. "Mechanisms and specificity of lentivirus neurotoxicity." Thesis, University of Edinburgh, 1998. http://webex.lib.ed.ac.uk/abstracts/starli01.pdf.
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Lehtinen, S. (Satu). "Neurotoxicity in children after treatment for acute lymphoblastic leukaemia and methotrexate neurotoxicity in a controlled animal model." Doctoral thesis, University of Oulu, 2003. http://urn.fi/urn:isbn:9514270339.
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Abstract
In the Nordic countries, event-free survival (EFS) exceeds 80% in certain groups of children treated for acute lymphoblastic leukaemia (ALL). With the improved cure rates, however, there are more children suffering from neurological late effects, especially due to therapy directed at the central nervous system (CNS). The aim of this study is to examine the changes taking place in the nervous system after leukemia treatment and to evaluate the role of treatment in these changes in patients and in an animal model.
Twenty-seven ALL survivors and healthy controls were examined by means of motor evoked potentials (MEPs). ALL survivors were also examined clinically. The children with ALL continued to show decreased motor nerve conduction in the peripheral nerves, but not within the CNS, five years after the cessation of treatment. Clinical neurological findings were obtained in 33% of the cases. The MEP results indicated reversibility of the motor injury due to CNS effects.
Nineteen patients underwent perfusion magnetic resonance imaging (MRI) at the cessation of treatment or 4-8 years after the treatment. Seventeen of them also underwent single-photon emission computed tomography (SPECT). The studies showed small perfusion defects in SPECT, which were not visible by perfusion MRI.
Methotrexate (Mtx) neurotoxicity was studied in a swine model using functional MRI, brain perfusion SPECT, iodine-123 labelled 2β-carbomethoxy-3β-(4-iodophenyl) tropane ([123I]β-CIT) SPECT and whole-hemisphere autoradiography with [125I]β-CIT in ten Mtx-treated animals and five control animals. Mtx-related changes in the brain could be detected as reduced or negative blood-oxygen-level-dependent (BOLD) responses to somatosensory activation in BOLD contrast MRI, which indicates changes in flow metabolism coupling. Perfusion defects in brain SPECT were seen in the Mtx group and the control group, which suggests that the perfusion defects seen in brain SPECT are probably multifactorial. The change in dopamine transporter (DAT) density in the Mtx group was not different from that in the controls.
The abnormalities in nerve conduction after treatment in survivors of ALL were partly reversible years after the treatment. The patients had perfusion defects in SPECT imaging which were not seen in perfusion MRI. The clinical significance of these defects remains obscure. The animal model suggested perfusion defects to be multifactorial.
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Högberg, Helena. "Developmental Neurotoxicity Testing Using In vitro Approaches." Doctoral thesis, Stockholms universitet, Wenner-Grens institut, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-30056.
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There is a great concern about children’s health as the developing brain in foetuses and children is much more vulnerable to injury caused by different classes of chemicals than the adult brain. This vulnerability is partly due to the fact that the adult brain is well protected against chemicals by the blood brain barrier (BBB) and children have increased absorption rates and diminished ability to detoxify many exogenous compounds, in comparison to that of adults. Moreover, the development of the central nervous system (CNS) is a very complex process involving several different important events, e.g. proliferation, migration and differentiation of cells. These events are occurring within a strictly controlled time frame and therefore create different windows of vulnerability. Furthermore, the brain consists of numerous different cell types (neuronal, glial and endothelial cells) that have specific functions. The development of each cell type occurs within a specific time window and is therefore susceptible to environmental disturbances at different time periods. Evidence indicates that exposure to industrial chemicals, pesticides or drugs, contributes to the increasing incidence of neurodevelopment disorders. However, due to lack of studies only a few industrial chemicals have been identified as developmental neurotoxicants so far. The current developmental neurotoxicity (DNT) guidelines (OECD TG 426 and US EPA 712-C-98-239) are based entirely on in vivo studies that are time consuming, complex, costly and not suitable for the testing of a high number of chemicals. Applying alternative approaches such as in silico, in vitro and non-mammalian models as a part of an integrated test strategy, could speed up the process of DNT evaluation and reduce and refine animal usage. Both in vitro and non-mammalian test systems offer the possibility of providing an early screening for a large number of chemicals, and could be particularly useful in characterising the compound-induced mechanism of toxicity of various developmental processes. This thesis has characterised two primary neuronal cultures (cerebellar granule cells (CGCs) and cortical neuronal cultures) and identified them as relevant models for DNT testing, since the key processes of brain development are present, such as cell proliferation, migration and neuronal/glial differentiation. Furthermore, two emerging technologies (gene expression and electrical activity) have been evaluated and were identified as promising tools for in vitro DNT assessment. In combination with other assays they could be included into a DNT intelligent testing strategy to speed up the process of DNT evaluation mainly by prioritising chemicals with DNT potential for further testing.<br>The work of this thesis was performed at ECVAM, European Commission, Italy.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: In press. Paper 3: In progress. Paper 4: In progress.
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Bhatia, Inderjeet. "An in vivo model of bilirubin neurotoxicity." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B31222213.
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Halpin, Laura E. "The Contribution of Ammonia to Methamphetamine Neurotoxicity." University of Toledo Health Science Campus / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=mco1370868834.
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Högberg, Helena. "Developmental Neurotoxicity Testing Using In vitro Approaches." Stockholm : The Wenner-Gren Institute, Stockholm University, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-30056.
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Diss. (sammanfattning) Stockholm : Stockholms universitet, 2009.<br>The work of this thesis was performed at ECVAM, European Commission, Italy. At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: In press. Paper 3: In progress. Paper 4: In progress. Härtill 4 uppsatser.
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Williams, Rebecca Elizabeth. "Biochemical and neurotoxicological effects of L-2-chloropropionic acid on the brain : an MRS and MRI study." Thesis, University of Nottingham, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243458.
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Kaur, Parvinder. "Cellular and Molecular Mechanisms Behind Methylmercury-Induced Neurotoxicity." Doctoral thesis, Norwegian University of Science and Technology, Department of Neuroscience, 2008. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-2225.
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Peaire, Amy. "Neurotoxicity and neuroinflammation in the enteric nervous system." Thesis, University of Ottawa (Canada), 2002. http://hdl.handle.net/10393/6331.
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The enteric nervous system (ENS) is the intrinsic nervous system of the gastrointestinal (GI) tract. Damage and degeneration of the ENS is a feature of some GI diseases, such as inflammatory bowel disease (IBD), and is associated with several other diseases including diabetes mellitis and Parkinson's disease. The overall goal of this thesis research was to identify specific classes of compounds capable of inducing ENS degeneration. These studies are intended to form a knowledge base upon which further studies can build towards the goal of preventing or attenuating clinical ENS damage. Reactive oxygen species (ROS), proinflammatory cytokines, and the process of anoxia-reoxygenation have been identified as inducers of CNS neurodegeneration and mediators in the neuropathogenesis of inflammatory diseases. As the ENS bears a considerable functional resemblance to the CNS, these compounds and processes are likely to have similar actions in this nervous system. Many of these mediators have been implicated in the pathogenesis of inflammatory diseases of the bowel, whereas initial studies of some of these mediators suggest their involvement in ENS neuropathogenesis. Thus, the general hypothesis of this thesis is that anoxia-reoxygenation, ROS, and the proinflammatory cytokine tumor necrosis factor-alpha (TNF) act on the ENS to induce neurodegeneration. In summary, the findings of this thesis are consistent with the hypothesis that inflammatory mediators can induce enteric neurodegeneration. This study identified specific inflammatory mediators as inducers of enteric neurodegeneration, characterized their neurodegenerative properties, and identified GDNF as a neuroprotective agent. Subsequent investigations further defined the respective roles of inflammatory immunocytes and the pro-inflammatory cytokine TNF in enteric neuronal cell death relevant to IBD pathogenesis. These findings are intended to form a basis for further studies into the mechanisms underlying clinical enteric neurodegeneration in disease pathogenesis. (Abstract shortened by UMI.)
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Miranda, Jamilette. "Neurotoxicity after poisonings with organophosphate pesticides in Nicaragua /." Stockholm : Arbetslivsinstitutet, 2003. http://diss.kib.ki.se/2003/91-7045-668-2/.
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Ma, Thong Chi. "The molecular mechanisms of free 3-nitrotyrosine neurotoxicity." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1189707727.
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Messmer, Kirsten. "Studies relating to inflammatory neurotoxicity in neurodegenerative diseases." Thesis, University of Sheffield, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340182.
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Kou, Jinghong. "The Neurotoxicity of Insecticides to Striatal Dopaminergic Pathway." Diss., Virginia Tech, 2005. http://hdl.handle.net/10919/77991.
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Parkinson's disease (PD) is an age-related neurodegenerative disease, which is characterized by severe loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and consequent dopamine depletion in its projecting area. In this dissertation, I evaluated the neurotoxicity of several classes of insecticides/drugs/neurotoxins to the striatal dopaminergic pathway and their potential relationship to Parkinsonism in the C57BL/6 mouse model, using biochemical and molecular biology methods.
In the first objective, I investigated the neurotoxicity in striatal dopaminergic pathways following co-application of permethrin (PM), chlorpyrifos (CPF) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The study was done because pyrethroid and organophosphorus compounds are widely used insecticides and they have been implicated in Gulf War Syndrome. We found that short-term, high-dose exposure to PM or CPF had no significant effects on the expression of dopamine transporter (DAT), tyrosine hydroxylase (TH), or α-synuclein protein in striatal nerve terminals, but the insecticides slightly enhanced the neurotoxicity of MPTP in C57BL/6 mice at 28 days post-treatment. This finding indicates a slowly developing neurotoxicity may occur after termination of high-dose exposure. Long-term, low-dose exposure to PM did not show significant neurotoxicity to striatal dopaminergic pathways when given alone, nor did this injection of PM enhance the neutotoxicity of MPTP in C57BL/6 mice. In addition, experiments with pure cis or trans isomers of permethrin showed that both cis and trans isomers contributed equally to the neurotoxicity of PM in the short-term high dose study.
Previous studies demonstrated a deficiency in mitochondrial function in PD, and a high density of K⁺ATP channels are present in substantia nigra, which play an important role in the maintenance of the membrane potential under metabolic stress. Therefore, in the second objective, I investigated the effect of K⁺ATP channel blockage on the neurotoxicity of mitochondrial-directed neurotoxins to striatal dopaminergic pathways. I found that mitochondrial inhibitors are potent releasers of preloaded dopamine from striatal nerve terminals, with the most potent compounds active in the nanomolar range. Co-application of the K⁺ATP channel blocker glibenclamide selectively increased the dopamine-releasing effect by complex I inhibitors in vitro, and potentiated the neurotoxicity of MPTP (a complex I inhibitor) on DAT and TH expression, in vivo. Mechanistic studies demonstrated that mitochondrial inhibitor-induced dopamine release is Ca²⁺-dependent. In addition, the selectivity of glibenclamide is not correlated to ATP depletion, but associated with the generation of excessive reactive oxygen species at the site of complex I.
In the third objective, I conducted comparative studies on the mode of action of rotenone-/reserpine-/tetrabenzaine (TBZ)-induced depletion, in vitro, as these three compounds share some similarities in their chemical structures. I found that rotenone, reserpine and TBZ selectively released preloaded dopamine and serotonin (5-HT), with the rank order as rotenone>reserpine>TBZ. Mechanistic studies demonstrated more than one mechanism was involved in both rotenone- and reserpine-induced neurotransmitter release. Ca²⁺-stimulated vesicular release and neurotransmitter transporter-mediated release are the common mechanisms involved in rotenone- and reserpine-induced dopamine release.
Overall, the insecticides/drugs/neurotoxins tested in the above experiments all exhibited some effect on the nigrastrital dopaminergic pathway, either alone or by enhancing the toxicity of other chemicals in combination treatment.<br>Ph. D.
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Huff, Courtney L. M. S. "MDMA and Glutamate: Implications for Hippocampal GABAergic Neurotoxicity." University of Cincinnati / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1460444662.
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Karuppagounder, Senthilkumar S. Dhanasekaran Muralikrishnan Suppiramaniam Vishnu. "Environmental toxins and dopaminergic neurotoxicity novel neuroprotective strategies /." Auburn, Ala, 2009. http://hdl.handle.net/10415/1883.
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Blair, Laura J. "Age-associated increases in FKBP51 facilitate tau neurotoxicity." Scholar Commons, 2014. https://scholarcommons.usf.edu/etd/5185.
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Tau is a protein which regulates microtubule stability and is heavily involved in axonal transport. This stability is dynamically controlled in part by over 40 phosphorylation sites across the tau protein which allows for binding and release from the microtubules. However, if abnormal hyperphosphorylation occurs, tau dissociates from the microtubules. Once released, the microtubules become unstable and the aberrant tau mislocalizes from the axon to the somatodendric compartment, where it aggregates. These aggregates are made of many pathological forms of tau including oligomeric species, paired helical filaments, and neurofibrillary tangles, all of which have associated toxicities. Tau pathology is a hallmark of Alzheimer's disease, one of over 15 diseases known as tauopathies which present with tau pathology, all of which lack effective treatments. Heat shock protein 90 kDa (Hsp90) is a major adenosine triphosphate (ATP)-dependent regulator of non-native proteins, like misfolded tau. Although Hsp90 is able to effectively refold and degrade many aberrant proteins, it has been associated with preserving aberrant tau. In fact, inhibiting the Hsp90 ATPase activity leads to the degradation of tau, which has been demonstrated in a number of models with the use of various Hsp90 inhibitors. However, there are many side-effects associated with the use of these inhibitors including toxicity and heat shock factor 1 (HSF1) activation. Although improvements on Hsp90 inhibitors are still in progress, this study explores targeting Hsp90 through a slightly different mechanism, by targeting Hsp90 co-chaperones. Hsp90 is involved in almost every pathway in each cell throughout the body. Co-chaperone proteins assist Hsp90 in these various processes, but are each only involved in a subset of the total Hsp90 interactome. Therefore, targeting Hsp90 co-chaperones could lead to improved efficacy, potency, and safety of drugs designed toward Hsp90 for the treatment of tauopathies. We previously showed one of these co-chaperones, FK506 binding protein 51 kDa (FKBP51), a tetratricopeptide repeat (TPR) domain containing immunophilin, coordinates with Hsp90 to regulate tau metabolism. More specifically, we found that increases and decreases in FKBP51 levels correlated with increases and decreases in tau levels, respectively.
FKBP51 knockout mice have been extensively studied and have shown no negative phenotypes in these characterizations. In this study, we found that this mouse model has decreased endogenous tau levels. Furthermore, this study demonstrates that FKPB51 colocalizes with pathological tau in the AD brain, and synergizes with Hsp90 to preserve tau from proteasomal degradation. Additionally, FKBP51 overexpression in mouse model of tau pathology leads to the preservation of tau. We went on to characterize this accumulated tau as being neurotoxic and oligomeric in nature, while being low in silver positive, β-sheet structure. In the human brain, we found that FKBP51 is strikingly increased with aging and even further in the AD brain. In support of these findings, we also found age-associated decreased methylation in the FKBP5 gene, which encodes FKBP51. Moreover, we found that increasing levels of FKBP51 caused other co-chaperone to have reduced Hsp90 binding and led to tau preservation. This supports a model where age-related increases in FKBP51 lead to the preservation of misfolded tau species and ultimately disease.
In order to model the high FKBP51 expression found in the aging brain, we generated the first FKBP5 overexpressing mouse model, which is tet-regulatable. This mouse, rTgFKBP5, was made by targeted, single insertion of the human FKBP5 gene into the HIP11 locus of the mouse genome crossed with CamKIIα tTa mice. We have now confirmed high FKBP51 levels in the forebrain and hippocampus of this mouse, which will serve as a testing platform for FKBP51 regulating drugs.
Overall, this work exemplifies FKBP51 as an important regulator of tau metabolism through Hsp90. With the absence of a negative phenotype in mice ablated of FKBP51 and the development of this novel, FKBP51 overexpressing mouse model, strategies designed to decrease FKPB51 levels or to disrupt the FKBP51/Hsp90 complex could be relevant for the treatment of tauopathies, like AD.
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Soussain, Carole. "Etude du rôle des péricytes dans le développement des lésions du système nerveux central induites par la radiothérapie. Développement d'un modèle animal de lymphome cérébral appliqué aux essais thérapeutiques précliniques." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T003.
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L’irradiation cérébrale thérapeutique comporte un risque de neurotoxicité tardive irréversible en partie lié à l’effet de l’irradiation sur le compartiment vasculaire cérébrale. Les péricytes et les communications entre les péricytes et les cellules endothéliales jouent un rôle majeur dans la stabilisation des vaisseaux, dans la formation et la régulation de la barrière hématoencéphalique et dans le contrôle du flux sanguin cérébral. Nous montrons, dans un modèle murin d’irradiation cérébrale, que les péricytes sont une cible précoce de l’irradiation cérébrale. Après irradiation, la morphologie des péricytes est modifiée et des marqueurs d’activations du péricytes sont surexprimés. En conséquence, la communication entre péricyte et cellule endothéliale est rompue, ce qui se traduit par une diminution de la capacité du péricyte à induire une constriction vasculaire après stimulation électrique. De façon concomitante, la perméabilité de la barrière hémato-encéphalique est anormalement augmentée après irradiation. Un traitement par thalidomide, administré dans la semaine précédant et suivant l’irradiation, prévient les conséquences de l’irradiation sur les péricytes. Les communications entre péricytes et cellules endothéliales sont maintenues ainsi que les fonctions contractiles des péricytes. L’imperméabilité de la barrière hématoencéphalique est également préservée. La voie de signalisation PDGF-β/PDGFR-β essentielle au recrutement des péricytes par les cellules endothéliales, est, au moins partiellement, impliquée dans l’effet protecteur de la thalidomide. Des études supplémentaires sont nécessaires pour définir les mécanismes sous tendant l’effet de l’irradiation sur les péricytes ainsi que l’effet protecteur de la thalidomide. Nous avons en parallèle mis au point un modèle murin de lymphome cérébral luciférase positif pour vérifier, dans un premier temps, l’innocuité de l’association de la radiothérapie et de la thalidomide et de ses dérivés de la classe des immunomodulateurs (iMids), le lénalidomide et le pomalidomide. Ces trois molécules ne diminuent pas l’effet antitumoral de la radiothérapie, mais l’association de radiothérapie et de pomalidomide est synergique sur la décroissance tumorale mesurée par l’évolution des courbes de bioluminescence. Le concept de normalisation de la vascularisation tumorale fait référence aux molécules capables, non pas de faire régresser les vaisseaux tumoraux anormaux, mais de les « normaliser » pour améliorer, d’une part, la disponibilité des chimiothérapies au sein de la tumeur, et d’autre part, l’oxygénation tumorale pour accroitre l’efficacité de la radiothérapie. Nos résultats sont en faveur d’un tel effet exercé par le pomalidomide dans notre modèle murin de lymphome cérébral, caractérisé par une infiltration tumorale périvasculaire, une fuite capillaire mais sans néo angiogenèse. Nos travaux fournissent un rationnel biologique à de futurs essais cliniques avec les iMids dans le traitement des lymphomes cérébraux primitifs voire des tumeurs malignes cérébrales<br>Therapeutic brain irradiation carries a risk of irreversible delayed neurotoxicity partly due to the effect of irradiation on the cerebral vascular compartment. Pericytes and communication between pericytes and endothelial cells play a major role in vessel stabilization in the formation and regulation of the blood-brain barrier and in the control of cerebral blood flow. We show in a murine model of brain irradiation, that pericytes are a target of early brain irradiation. After irradiation, the morphology of pericytes is altered and markers of activation of pericytes are overexpressed. Consequently, communication between the endothelial cell and pericyte is disrupted , which results in a decreased capacity of pericytes for inducing a vascular constriction after electrical stimulation. Concomitantly, the permeability of the blood - brain barrier is abnormally increased after irradiation. Treatment with thalidomide administered in the week before and after irradiation, prevents the effects of irradiation on pericytes . Communication between pericytes and endothelial cells are maintained as well as the contractile properties of pericytes. The impermeability of the blood brain barrier is also preserved. The PDGF-β/PDGFR-β signaling pathway, which is essential for the recruitment of pericytes by endothelial cells, is at least partially involved in the protective effect of thalidomide. Further studies are needed to define the mechanisms underlying the effect of irradiation on the pericytes and the protective effect of thalidomide. We have, in parallel, developed a model of murine luciferase positive CNS lymphoma to verify first, the safety of the combination of radiotherapy and thalidomide and its derivatives of the class of immunomodulators ( IMiDs ), lenalidomide and pomalidomide. These three molecules do not decrease the antitumor effect of radiotherapy, but the antitumoral effect of the association of radiotherapy and pomalidomide is synergistic. The concept of the normalization of the tumor vascularization refers to molecules capable not to induce regression of the abnormal tumor vessels but to "normalize" the tumoral vasculature in order to improve, on one hand , the availability of chemotherapy in the tumor , and on the other hand, the tumor oxygenation to increase the effectiveness of radiotherapy. Our results are in favor of such an effect exerted by pomalidomide in our murine model of cerebral lymphoma, characterized by perivascular tumor infiltration and capillary leak .Our work provide a biological rational for future clinical trials with IMiDs in the treatment of brain lymphomas or malignant brain tumors
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McGregor, Ailsa L. "Evaluation of a novel non-competitive antagonist as a radioligand for the N-methyl-D-aspartate receptor-channel complex in vivo." Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244363.
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Mead, Carole. "Studies of toxic responses in cultured astrocytes." Thesis, University of Salford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244928.
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Fletcher, Lynda. "A study of differentiation and proliferation in cultured neuroblastoma cells : the effects of bFGF and acrylamide." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267718.
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Freeborn, Ethan Ray. "The Murine Brain Slice as a Model for Investigation of Environmental Toxin Involvement in the Etiology of Parkinson's Disease." Thesis, Virginia Tech, 1999. http://hdl.handle.net/10919/9769.
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Epidemiological and analytical studies have suggested that environmental exposure to neurotoxic insecticides may exist as a factor in the etiology of Parkinson's Disease (PD). This study has focused on two insecticides, dieldrin and heptachlor epoxide, members of the cyclodiene class of insecticides. The cyclodienes are environmentally persistent, and brain residues of these compounds are correlated with the occurrence of PD. Cyclodiene mode of action has been attributed to two mechanisms: 1) facilitation of neurotransmitter release (with specificity for release of dopamine) and 2) antagonism of the inhibitory neurotransmitter, GABA. In order to assess the relative contributions of these two mechanisms leading to toxicity, eletrophysiological studies were undertaken in murine striatal slices. Extracellular recordings of spontaneous nerve discharge were used to compare the effects of the cyclodienes and the prototypical GABA antagonist, picrotoxinin, upon striatal neurons. At low micromolar concentrations of cyclodiene, depression of firing, consistent with dopamine release and not GABA antagonism, was seen. Alternatively, application of the prototypical GABA antagonist, picrotoxinin, produced excitation in slices. Additionally, the inhibitory action of dieldrin was blocked by a dopamine receptor (D1) antagonist, fluphenazine, verifying that cyclodiene-released dopamine was responsible for the observed depression of striatal neurons. These results suggest that the ability of these cyclodienes to evoke neurotransmitter release may significantly contribute to the neurotoxicity of these cyclodienes in vivo. In light of this data, the neurotoxic potential of the cyclodiene insecticides must be reassessed, particularly within the scope of PD.<br>Master of Science
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Wang, Weijun. "Speciation analysis of aluminum complexes with neurotransmitters in biological media." Thesis, Glasgow Caledonian University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.481190.
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Easton, Neil. "3,4-Methylenedioxymethamphetamine (MDMA, Ecstacy) neurotoxicity : role of thioether adducts." Thesis, Nottingham Trent University, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272853.
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Gartlon, Joanne. "Detection of neurotoxicity using in vitro neuronal cell systems." Thesis, University of Nottingham, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417115.
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Klima, Stefanie [Verfasser]. "Developmental neurotoxicity in a human model system / Stefanie Klima." Konstanz : KOPS Universität Konstanz, 2021. http://d-nb.info/1232176516/34.
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Terrasso, Ana Paula Barreto. "Development of novel human cellular models for neurotoxicity studies." Master's thesis, Faculdade de Ciências e Tecnologia, 2012. http://hdl.handle.net/10362/8488.
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Dissertation to obtain master degree in
Genética Molecular e Biomedicina<br>Information currently available on neurotoxicity of chemicals is scarce and there are a growing number of new compounds to be tested. Therefore, new strategies are necessary to identify neurotoxic agents with speed, reliability and respect for animal welfare.
The limited availability of primary human brain cells means that there is a need for human cell lines that reliably model human neurons and astrocytes. Despite the advances in stem cell research, numerous challenges must be overcome before this technology can be widespread used, such as low differentiation efficiency.
Human pluripotent embryocarcinoma NTera2/cloneD1 (NT2) cell line is an alternative cell source from which neurons and astrocytes can be derived in vitro.
The aim of this work was to develop scalable and reproducible novel human cellular models using NT2 cells as source of differentiated neural phenotypes.
A 2D culture system for astrocytic differentiation was implemented. After 4 weeks of differentiation with retinoic acid followed by 5 weeks maturation with mitotic inhibitors, astrocytes obtained expressed vimentin, GFAP, S100- and GLT-1 as characterized by immunodetection and qRT-PCR.
Then, a 3D culture approach was adopted, using stirred suspension culture systems, in which cell-cell and cell-extracellular matrix interactions occur, mimicking better the in vivo situation. NT2 cells, inoculated as single cells, spontaneously aggregated without compromising their pluripotency. Optimization of stirring rate allowed control of aggregate size along time. After 3 weeks of RA treatment and 2 weeks of maturation, neurons expressing βIII-tubulin, MAPs and synaptophysin and astrocytes expressing vimentin, GFAP, S100- and GLT-1 were detected, as characterized by immunodetection and qRT-PCR. Furthermore, astrocytes presented a 2.5-fold higher yield than that observed in 2D culture systems.
Results showed that NT2 differentiated cells are promising models for neurotoxicity testing. Furthermore, the 3D culture systems developed herein can contribute to increase the relevance of these studies, recapitulating human neuron-astrocyte interactions in a 3D cellular context.<br>Fundação para a Ciência e Tecnologia - PTDC/EEB-BIO/112786/2009
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Kim, Seol-Hee. "Acetaminophen Associated Neurotoxicity and its Relevance to Neurodevelopmental Disorders." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6717.
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Autism is a lifelong neurodevelopmental disorder. The etiology of autism still remains unclear due to the heterogeneous and complex nature of the disorder, however synergistic actions between genetic components and environmental factors have been suggested. Acetaminophen (APAP) is one of the most popular over-the-counter drugs that possess antipyretic and analgesic effects. It is considered a relatively safe and effective within therapeutic doses. Recently, early exposure to APAP has been suggested to be one of the underlying cause of autism. Children are often prescribed APAP to lessen fever or irritability after vaccination during the first year, and APAP may adversely affect the normal brain development. In order to better understand the association with APAP and autism, we used an inbred mouse strain BTBR T+tf/J (BTBR). BTBR exhibits behavioral deficits that mimic the core behavioral deficits of human autism. In the study, investigated 1) if BTBR mice showed differences in thiol biochemistry and EAAT3 levels in brain compared with C57BL/6J (C57) mice, 2) if early exposure to APAP induced behavioral changes worsening the autistic phenotypes of BTBR in adolescence, and 3) if APAP exposure in neonatal mice induced possible toxicity at various doses. As a result, we observed that BTBR mice have significantly lower plasma sulfate levels and EAAT expression levels in the frontal cortex compared to C57 mice. Surprisingly, neonatal therapeutic dose of APAP administration did not induce behavioral changes in both C57 and BTBR in adolescence. However, we showed that a supratheraputic dose of APAP significantly elevated levels of oxidative stress marker in the brain. Overall, the results suggested that BTBR mice would be a useful mouse model to investigate effects of various environmental factors that have been associated with autism. In addition, early exposure to APAP at supratherapeutic doses may negatively affect normal brain development.
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Murakami, Kazuma. "Mechanism of neurotoxicity of Aβ42 peptide in Alzheimer's disease". Kyoto University, 2007. http://hdl.handle.net/2433/136527.
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Kyoto University (京都大学)<br>0048<br>新制・課程博士<br>博士(農学)<br>甲第13108号<br>農博第1613号<br>新制||農||940(附属図書館)<br>学位論文||H19||N4234(農学部図書室)<br>UT51-2007-H381<br>京都大学大学院農学研究科食品生物科学専攻<br>(主査)教授 大東 肇, 教授 吉川 正明, 教授 永尾 雅哉<br>学位規則第4条第1項該当
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Tam, Stephen Jed. "Eukaryotic chaperonin-mediated modulation of polyglutamine aggregation and neurotoxicity /." May be available electronically:, 2007. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
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Thrash, Bessy Suppiramaniam Vishnu Dhanasekaran Muralikrishnan. "Neuroprotection against methamphetamine induced neurotoxicity applications for Parkinson's disease /." Auburn, Ala, 2009. http://hdl.handle.net/10415/1718.
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Erives, Quezada Gladys Vanessa. "The Role of Metabolism in Ecstasy-Mediated Serotonergic Neurotoxicity." Diss., The University of Arizona, 2009. http://hdl.handle.net/10150/195730.
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3,4-(±)-Methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine derivative commonly used as a recreational drug. Although the selectivity of MDMA for the serotonergic system in rat and humans is well established, the specific mechanism associated with MDMA-induced neurotoxicity is not fully understood. The long-term neurotoxicity of MDMA appears to be dependent upon systemic metabolism since direct administration of MDMA into the brain fails to reproduce the neurotoxic effects seen following peripheral administration, indicating that the parent compound alone is unlikely to be responsible for the neurotoxicity. MDMA is O-demethylenated to the catechol metabolite N-methyl-α-methyldopamine (N-Me-α-MeDA) and N-demethylated to MDA by cytochrome (s) P450 (CYP450). Thioether (glutathione and N-acetylcysteine) metabolites of N-Me-α-MeDA and α-MeDA are neurotoxic and can be found in rat brain following s.c. injection of MDMA. Because multidose administration of MDMA is typical of drug intake during rave parties, we investigated the effects of multiple doses of MDMA on the concentration of neurotoxic thioether metabolites in rat brain. Administration of MDMA at 12-h intervals for a total of four injections led to a significant accumulation of the N-Me-α-MeDA thioether metabolites in striatal dialysate. In contrast, acute release of 5-HT concentrations was decreased. Since isoenzymes of the CYP2D subfamily (30% metabolism), and the CYP2B or CYP3A1 isoforms, catalyze the low and high KM O-demethylenation reactions, respectively, we subsequently examined the potential role of CYP2D1 in both a genetic and pharmacological model. The data is consistent with the hypothesis that systemic metabolism of MDMA contributes to MDMA-induced serotonergic neurotoxicity via the 20) generation of reactive metabolites. In both the genetic and pharmacological models of CYP2D1 deficiency, attenuation of MDMA-mediated decreases in brain 5-HT concentrations were in the same range (30-40%). Finally, we examined the contribution of various transporters using genetic and pharmacological models to investigate the mechanisms regulating the concentration of thioether metabolites in MDMA neurotoxicity. The data suggest that by regulating various transporters and brain concentrations of the neurotoxic thioether metabolites of MDMA, may subsequently modulate the degree of neurotoxicity. However, further studies are necessary to understand the precise mechanism by which Mrp’s and Oat1 transporters modulate MDMA-neurotoxicity. Taken together, these studies are consistent with the view that neurotoxicity of MDMA requires systemic metabolism to form α-MeDA and N-Me-α- MeDA by CYP2D6. Therefore, It is likely that neurotoxicity is mediated by the formation of systemic neurotoxic metabolites.
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Giraudi, Pablo Jose'. "Mechanism involved in the UCB neurotoxicity on cellular models." Doctoral thesis, Università degli studi di Trieste, 2009. http://hdl.handle.net/10077/3048.
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2007/2008<br>Summary
This doctoral thesis covers three years period (2006-2008) during which I have investigated the bilirubin neurotoxicity in the neuroblastoma SH-SY5Y cell line, a neuronal cell model widely used in the study of the pathogenesis and in the development of new therapeutic compounds for neurodegenerative diseases.
In the first chapter is summarized the current knowledge about bilirubin chemistry and metabolism including disorders of bilirubin metabolism and the neuronal disturbances associated. In addition, the main discoveries in bilirubin toxicity mechanisms are described.
Chapter two describes how we have chosen the cellular model to study the unconjugated bilirubin (UCB) damage. We first compared the bilirubin accumulation and cell viability in two neuronal cell lines (2a1 mouse neuronal progenitor cell line and SH-SY5Y cell line) and one non neuronal cell line (HeLa cells). In addition, we performed studies on cellular localization of Mrp1 (involved in UCB extrusion) and mRNA expression. We observed that SH-SY5Y cells show higher accumulation of bilirubin and lower survival than 2a1 and HeLa cells. SH-SY5Y cells shows a clear localization of Mrp1 at membrane level. Based on these observations we selected the SH-SY5Y cell line as our experimental model, and we characterized this cell line for molecular events linked with bilirubin neurotoxicity.
Chapter three revises original data published by mainly our group, about “the free bilirubin hypothesis”. It has been suggested that cell injury correlates better with free unconjugated bilirubin (Bf) than total unconjugated bilirubin (BT). To directly test this hypothesis we evaluated cell viability in four cell lines (SH-SY5Y, MEF, HeLa and 2a1 cell lines) after incubation with different Bf/BT ratios, obtained by mixing varied UCB concentrations and albumins with different binding affinities (bovine, fetal calf and human); Bf was measured in each solution by the peroxidase method. Our data show that the loss of viability is dependent on the Bf but not on BT although bilirubin sensitivity varied with the different cell line tested. This in vitro study reinforces the proposal that Bf or Bf combined with total serum bilirubin should improve risk assessment for neurotoxicity in both term and premature infants.
Chapter four describes our studies about the biochemical and molecular changes in SH-SY5Y cells exposed to a rather high Bf (140 nM) for 24 hours. Biochemical changes (cell viability, proliferation, cellular redox environment -ROS and GSH content) and gene expression profile were evaluated in the cells which survived after the treatment. Results suggest that the surviving cells become more resistant to a second oxidative exposition (Bf or H2O2) and this was associated with an increases expression of various genes involved both in ER stress response and in the transport system Xc- (cystine-glutamate exchanger). This transport system is of great relevance in maintaining the redox homeostasis within the cell, and together with the ER stress genes may contribute to the activation of an adaptative response to bilirubin damage.
Further studies will be necessary to elucidate the molecular mechanisms that confer resistance to bilirubin toxicity; these mechanisms could help understanding the different sensitivity of the cells to bilirubin damage, and why some neuronal cells die (as the Purkinje cells) while others don’t. Furthermore, these studies may achieve to the identification of target proteins useful to develop new drugs: this may be the case of the system Xc-.<br>Riassunto
Questo lavoro di tesi è il frutto delle ricerche svolte nei tre anni del mio dottorato (2006-2008), durante i quali mi sono occupato dello studio della neurotossicità da bilirubina nella linea cellulare di neuroblastoma umano SH-SY5Y; si tratta di un modello cellulare neuronale ampiamente utilizzato nello studio della patogenesi di malattie neurodegenerative, nonché nello sviluppo di composti neuroprotettivi.
Nel primo capitolo si trovano riassunte le conoscenze attuali riguardanti la chimica della bilirubina, il suo metabolismo ed eventuali disordini ed i disturbi neuronali associati ad essa; inoltre, sono descritte le principali scoperte sui suoi meccanismi di tossicità.
Nel secondo capitolo viene descritta come è stata effettuata la scelta di un modello cellulare adeguato allo studio del danno da bilirubina non coniugata (UCB). A questo scopo sono stati confrontati l’accumulo in bilirubina triziata e la vitalità cellulare dopo un trattamento con bilirubina libera, in due linee cellulari neuronali (progenitori neuronali di striato di topo -cellule 2a1- , neuroblastoma umano -cellule SH-SY5Y-) ed in una linea cellulare non neuronale (cellule HeLa). Oltre a ciò, sono stati eseguiti alcuni studi sulla localizzazione del trasportatore Mrp1 (coinvolto nell’estrusione di UCB), e sull’espressione dei geni Mrp1 ed Mdr1 (il cui prodotto proteico è un possibile trasportatore di bilirubina). Abbiamo osservato che le cellule SH-SY5Y presentano un accumulo di bilirubina più elevato ed una più bassa sopravvivenza rispetto alle cellule 2a1 ed HeLa, sebbene nelle cellule SH-SY5Y la localizzazione di Mrp1 risulti essere a livello di membrana plasmatica. Basandoci su queste osservazioni abbiamo scelto di lavorare con il modello cellulare già noto SH-SY5Y, e ci siamo occupati di caratterizzarlo per la neurotossicità da bilirubina.
Nel terzo capitolo vengono presentati dati sperimentali pubblicati dal nostro gruppo a supporto dell’ “ipotesi della bilirubina libera”, la quale postula che il danno cellulare da bilirubina correli in modo migliore con la concentrazione di bilirubina libera (Bf) piuttosto che con quella di bilirubina totale (BT). Al fine di testare quest’ipotesi abbiamo valutato la vitalità in quattro diverse linee cellulari (SH-SY5Y, MEF, HeLa e 2a1) dopo aver incubato le cellule in soluzioni con un diverso rapporto Bf/BT. Tali soluzioni sono state ottenute sciogliendo diverse quantità di UCB in terreno con diversi tipi di albumina (bovina, umana e di siero fetale bovino); questi binders possiedono differenti affinità per la bilirubina. La Bf è stata determinata in ciascuna soluzione utilizzando il metodo della perossidasi. I dati ottenuti suggeriscono che, sebbene la sensibilità alla bilirubina vari nelle diverse linee cellulari, la riduzione in vitalità dipenda dalla Bf e non dalla BT. Quindi, questi studi in vitro costituiscono un’evidenza in più a favore della teoria della bilirubina libera, e sostengono la necessità di valutare il rischio di Kernittero mediante la misura della Bf serica e non solo della bilirubina totale.
Nel quarto capitolo si descrivono le modificazioni a livello biochimico e molecolare nella linea cellulare SH-SY5Y dovute ad un trattamento di 24 ore in presenza di un’elevata concentrazione di bilirubina libera. Nelle cellule sopravvissute al trattamento abbiamo valutato diversi parametri biochimici tra cui vitalità e proliferazione cellulare ed ambiente redox cellulare (contenuto di ROS e GSH), nonché il pattern di espressione genica indotto dalla bilirubina. I risultati ottenuti suggeriscono che le cellule SH-SY5Y sopravvissute siano più resistenti all’esposizione ad un secondo stress ossidativo (Bf o H2O2), inoltre queste cellule mostrano un’aumentata espressione di diversi geni coinvolti nella risposta allo stress di reticolo endoplasmatico e dei geni i cui prodotti proteici fanno parte del sistema di trasporto Xc- (antiporto cistina-glutammato). Questo sistema di trasporto è estremamente importante nel mantenimento dell’omeostasi redox cellulare, ed insieme ai geni dello stress di ER potrebbe contribuire all’attivazione di una risposta adattativa al danno da bilirubina.
Ulteriori studi che ci consentano di comprendere i meccanismi molecolari che conferiscono resistenza alla neurotossicità da bilirubina potrebbero aiutarci a capire la differenza di sensibilità dei diversi tipi di cellule alla bilirubina stessa, ed il motivo per cui alcune cellule neuronali muoiano (come ad esempio le cellule di Purkinje) mentre altre no. Inoltre questi studi possono portarci all’identificazione di target proteici utili allo sviluppo di nuovi farmaci, quale può essere ad esempio il caso del trasportatore Xc-.<br>XXI Ciclo<br>1978
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ATZEI, ALESSANDRO. "Developmental neurotoxicity testing of chemical mixtures in zebrafish embryos." Doctoral thesis, Università degli Studi di Cagliari, 2021. http://hdl.handle.net/11584/312978.
Full textAbstract:
Developmental neurotoxicity (DNT) is an understudied problem. Every day, people are exposed to complex mixtures of several chemical substances via food intake, inhalation and dermal contact. Nevertheless, risk assessment is performed on single compounds only under the assumption that the individual exposure levels (below no observed adverse effect levels, NOAELs) are predictive of the mixture effect. In the EuroMix project, a method has been developed to evaluate the effects of mixtures of substances, even at or below NOAELs. This method follows the strategy proposed by the European Food Safety Authority (EFSA), and further implements the Adverse Outcome Pathway (AOP) concept as a basis. Currently, assessment of the DNT potential of compounds is performed in costly and time-consuming in vivo rodent studies involving a large number of animals studied over more than one generation. Therefore, from a 3Rs (Replacement, Reduction, Refinement) perspective an alternative approach is needed. The zebrafish (Danio rerio) embryo (ZFE) provides an interesting and potentially useful model to study DNT as neurodevelopment occurs fast with a large resemblance to the higher vertebrate including the human system. Also, from a legal perspective, experimental work with zebrafish embryos within 120 hours post-fertilization, is not considered an animal experiment. Combined with the ease of culture and the high reproduction rate this renders the ZFE a suitable model for high throughput DNT testing in vitro. One of the suitable readouts for DNT testing is neurobehavior since it provides integrated information on the functionality/status of the full nervous system of the embryo. Within 120 hpf the embryo develops from a fertilized egg to a fully functional embryo responsive to environmental stimuli such as light and sound (vibration). The present Ph.D. study investigated the potential human health risk caused by the simultaneous exposure of chemical substances and the need to include the mixtures in the risk assessment. To obtain a real-life picture ofenvironmental pollution by chemical mixtures, an UHPLC-MS/MS-MRM method was developed and validated for screeining pesticide residues on raw and processed tomatoes. Then, the attention was focused on the potential use of the zebrafish model for assessing the chemical mixtures effects in DNT. Recognised that pharmaceuticals display a well-known MOA and are known to cause DNT, their use as model compounds instead of pesticides was preferred. Therefore, the combined effect of three psychoactive pharmaceuticals of concern, Carbamazepine (CBZ), Fluoxetine (FLX), Venlafaxine (VNX) and their main metabolites, Carbamazepine 10,11 -epoxide (CBZ 10,11E), Norfluoxetine (norFLX), and Desvenlafaxine (desVNX), was studied using the zebrafish embryos as a study model. At first, single-compound concentration-effect relationships were assessed as input for dose-response modelling following the benchmark approach leading to a classification of compounds based on potency. Subsequently, a binary mixture was composed based on the relative potency of the individual compounds and tested for their effect on neurological development. To support the assessment of developmental neurotoxicity, the gene expression of three specific DNT markers was investigated.
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Bode, Karsten [Verfasser], Gerd [Akademischer Betreuer] Bicker, Stefanie [Gutachter] Becker, and Michael [Gutachter] Stern. "An intact insect embryo as a test system for neurotoxicity and developmental neurotoxicity / Karsten Bode ; Gutachter: Stefanie Becker, Michael Stern ; Betreuer: Gerd Bicker." Hannover : Stiftung Tierärztliche Hochschule Hannover, 2020. http://d-nb.info/1224232984/34.
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