1,720,997 research outputs found
Targeting glial B2-adrenoceptors for immunododulation & neuoprotection in a rat model of Parkinson\u27s disease
No full textNeuro-inflammation is a key contributor to the pathogenesis of Parkinson?s disease (PD). Brain-resident microglia are dynamic cellular effectors of inflammation-mediated neurodegeneration in the Parkinsonian brain. Here we have established & characterised an inflammation-mediated preclinical animal model of experimental PD by direct infusion of the bacterial endotoxin, and TLR4 agonist, lipopolysaccharide (LPS) directly into the SNpc of adult male Wistar rats. Unilateral intra-nigral injection of LPS (10?g/2?l) induced robust Iba1 + microglial activation, tyrosine hydroxylase-positive (TH + ) dopamine cell loss in the substantia nigra pars compacta (SNpc), TH + striatal denervation and nigrostriatal dopamine depletion as verified by high performance liquid chromatography with electrochemical detection (HPLC-ECD), findings which were accompanied by deficits in skilled motor function in the staircase test, forelimb use asymmetry in the cylinder test and bidirectional forelimb akinesia in the stepping test.
Moreover, we simultaneously co-administered the astroglial-selective toxin L-alphaaminoadipic acid to investigate whether a more populous, yet majorly overlooked glial subtype known as astrocytes contribute towards, or protect against an intra-nigral LPSinduced Parkinsonian state. Here we show that transient GFAP + astrocytic dysfunction limits the severity & delays the progression of intra-nigral LPS-induced Iba1 + microgliosis, TH + dopaminergic neurodegeneration, nigrostriatal dopamine loss and ensuing motor dysfunction. Our data demonstrates a role for reactive astrocytes in actively sustaining LPS-induced midbrain microglial activation and contributing towards dopaminergic neuronal loss and experimental Parkinsonism, at least in part via the release of soluble factors such as S100?. Here we propose an indelible neurotoxic role for astrocytic crosstalk with midbrain microglia at the interface of intra-nigral LPS-mediated dopaminergic neuropathology, thus spotlighting astrocytes as dark horses of inflammation-mediated neurodegeneration in the Parkinsonian brain.
To this end we sought to investigate whether targeting the noradrenergic system for anti-inflammatory & neuroprotective effects via glial cell immunomodulation and neurotrophic factor production could protect against LPS-mediated neurotoxicity of the nigrostriatal dopaminergic tract. Twice daily treatment with the noradrenaline reuptake inhibitor atomoxetine (3 mg/kg i.p.) alone or in combination with the ?2-adrenoceptor antagonist idazoxan (1 mg/kg i.p.) for 7 days commencing 4 hours post lesioning, attenuates intra-nigral LPS-mediated Iba1 + microglial activation & TH + dopaminergic neuronal loss, ameliorates nigrostriatal dopamine depletion and provides partial protection against associated motor deficits. These findings demonstrate that pharmacologically enhancing noradrenergic tone exerts anti-inflammatory effects in the inflamed midbrain, and protects against LPS-mediated neurotoxicity of the nigrostriatal dopaminergic tract, thus facilitating motor improvements at least in part via immunomodulation of nigral microglia. Akin to the greater susceptibility of the elderly population to the detrimental effects of a bacterial infection, we further examined the impact of superimposing an exposure to a peripheral immune stressor on pre-existing intra-nigral LPS-mediated microglial activation, dopaminergic neurodegeneration & motor dysfunction. Here we show that a sub-toxic, low dose of systemic LPS (250 ?g/kg i.p.) exacerbates ongoing TH + dopamine cell loss in the SNpc, augmented nerve terminal degeneration in the striatum and exaggerated ensuing motor deficits, findings which were underpinned by an expansion in nigral Iba1 + microgliosis, increases in CD68 expression and elevations in nigral IL-1? production. Moreover treatment with formoterol, a long acting, lipophilic and highly selective ? 2 -adrenoceptor agonist curtailed microglial activation in the SN and prevented exacerbations in the degeneration of the nigrostriatal dopaminergic tract, thus attenuating the exaggerated deficits in motor function. These findings indicate that an acute episode of a systemic bacterial infection can accelerate neurodegenerative disease progression, whereas pharmacologically targeting ? 2 -AR?s directly could slow/halt the progression of Parkinsonian neuropathology & symptomology in instances where inflammation contributes to disease pathogenesis.
Taken together, the data gathered herein highlights midbrain glia (both microglia & astrocytes) as crucial cellular effectors of immune-mediated dopaminergic neurodegeneration in the Parkinsonian brain, and promotes pharmacologically targeting the CNS noradrenergic system for anti-inflammatory and neurotrophic effects to provide neuroprotection against inflammation-mediated neurotoxicity, nigrostriatal dopamine loss and motor dysfunction
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Targeting the NMDA receptor/NO signalling pathway following L-? aminoadipic acid-induced astrocytic impairment and associated changes in the structural plasticity of neurons
No full textThis investigation firstly aims to characterise the impact of astrocytic dysfunction on neurons in vitro, specifically the effects of L-? amino adipic acid (L-AAA)-induced astrocytic dysfunction on neurite outgrowth and synapse number in primary cortical neurons. Treatment with conditioned media (CM) derived from healthy astrocytes increased neurite outgrowth in immature neurons and synapse number in mature neurons. In contrast, CM derived from L-AAA-treated astrocytes impaired neurite outgrowth in immature neurons and reduced spine density and synapse formation in mature neurons. In addition, L-AAA provoked a reduction in the astrocytic markers glial fibrillary acid protein (GFAP) and the glutamate aspartate transporter (GLAST) and resulted in altered mitochondrial respiration in astrocytes. The second part of this project focused on the translation from in vitro experiments to an animal model of L-AAA-induced astrocytic dysfunction. Testing L-AAA-induced astrocytic dysfunction in mice serves to scale this work by assessing the effect of astrocytic dysfunction on behaviour, neuronal complexity and dendritic spine density in the prelimbic cortex (PLC) in vivo. Following L-AAA delivery to the PLC, transient depressive-like behaviour in the forced swim test (FST) and reduced GFAP immunoreactivity in the PLC were evident over a 72h post-administration period leading to a full recovery over 7 days. Moreover, L-AAA decreased dendritic spines of mushroom variety 72h after administration with no effect on the number of primary neurites in the PLC. Finally the effect of targeting the neuronal NMDA-R/NO signalling pathway is assessed as a strategy to prevent neuronal atrophic effects following L-AAA-induced astrocytic dysfunction. Co-treatment of neurons with the NMDA-R antagonist ketamine, as well as the nNOS inhibitor TRIM and the PSD-95/nNOS inhibitors IC87201 and ZL006 partially protected against reduced neurite outgrowth and synapse formation induced by CM from L-AAA treated astrocytes. In mice, results demonstrate that the PSD-95/nNOS inhibitor (ZL006) had no effect on dendritic spine density or the number of primary neurites. In vivo, exposure to the FST reduced spine density. ZL006 was able to attenuate FST-induced decreased spine density 24h after administration. ZL006 and TRIM were also able to block depressive-like behaviour observed in the FST. Interestingly, FST combined with L-AAA drove the changes in the opposite direction and increased dendritic spine density. ZL006 response reduced spine density and produced an antidepressant-related response in the FST following L-AAA administration. The results highlight the importance of astrocytes, in particular the consequences of astrocytic impairment on neuronal complexity and synapse formation, and support the hypothesis that selectively targeting the PSD-95/nNOS interaction downstream of the NMDA-R prevents neuronal atrophic effects and potential synapse loss
Influence of anti-inflammatory interventions in the Kainic acid model of hippocampal excitotoxicity
No full textTHESIS 8906Excitotoxicity is implicated as a mechanism of neuronal cell death in a range of neurodegenerative disorders. Such toxicity can be induced experimentally by systemic administration of the glutamate kainate receptor agonist, kainic acid (KA). Specifically, KA induces seizures, inflammation, apoptosis and neuronal cell loss in the hippocampus, following systemic administration to rats. All changes are evident within 24 hours of KA administration and over this period, the model is representative of acute neurodegeneration. The aims of the work described in this thesis were to (i) characterise the inflammatory and apoptotic changes which occur in tandem with cell loss in a time course fashion, (ii) to determine if the inflammatory changes underlie KA-induced apoptosis and cell loss and (iii) to determine if modulation of central noradrenaline (NA) could influence KA-induced neurodegeneration, (i) Animals receiving KA showed seizures and related stereotyped behaviours within 3 hours. Expression of IL-1?, TNF-? and IFN-? were increased in the hippocampus 4, 12 and 24 hours following KA administration. This was accompanied by an increase in expression of the microglial activation marker CD11b, the apoptotic marker caspase 3 and a reduction in cresyl violet staining of viable hippocampal neurons, 24 hours post challenge, (ii) To determine if KA- induced cell loss may be driven by the induction of inflammatory markers in the hippocampus, animals were pre-treated with the anti-inflammatory glucocorticoid, dexamethasone. Pre-treatment with dexamethasone, 1 hour prior to KA administration significantly attenuated the excitotoxin-induced increase in IFN-?, CD11b and caspase 3 expression, but failed to influence KA-induced seizures or increased DNA fragmentation and hippocampal neuronal cell loss. Thus whilst the inflammatory related changes may contribute to apoptosis, the data suggest that microglial activation and IFN-? expression do not account for KA-induced neuronal loss
Multimodal magnetic resonance imaging in animal models of depression
No full textTHESIS 10890Depression Is a debilitating and potentially fatal disorder for which the pathophysiology underlying the illness is still unknown. Aberrant glutamatergic neurotransmission and altered astrocyte function have recently been implicated as potential physiological markers related to depressive illness. The development of magnetic resonance imaging (MRI) as a clinical tool has allowed for the identification of a series of neuroimaging markers in depressed patients. However the physiological processes which underlie these neuroimaging markers and their role in depressive illness is still poorly understood
An investigation of the impact of experimental colitis and inflammatory bowel disease on behaviour and on systemic and central inflammation
No full textTHESIS 10212Inflammatory bowel diseases (IBD) are chronic conditions characterised by uncontrolled inflanmiation of the intestinal mucosa. Clinical symptoms include weight loss, diarrhoea, rectal bleeding and abdominal pain. In addition to physical symptoms, patients with IBD are at increased risk of depression and anxiety. Whether these psychological disturbances occur due to stress associated with the unpleasant symptoms of IBD, or as a result of biological mediators of inflammation is unknown. It has been suggested that pro-inflammatory cytokines themselves can induce mood changes, or that cytokines (particularly interferon ? (IFN?)) can induce depression and anxiety by degrading tryptophan to kynurenine via induction of indolaniine 2,3 dioxygenase (IDO). In addition, tryptophan can be metabolised to kynurenine via tryptophan 2,3 dioxygenase (TDO). The main aim of this thesis was to investigate the association between colonic inflammation or IBD symptoms and mood/anxiety disturbances in patients, and to examine the implications of colonic inflanunation on central markers of immune activation in animal models of colitis. 18 IBD patients and 19 patient controls were scored using the Hamilton-depression (HAM-D), HAM-anxiety (HAM-A), profile of mood states (POMS), and disease activity scores (Inflammatory bowel disease questionnaire, Mayo index, and Crohn?s disease activity index). Intestinal biopsies were analysed by PCR for interleukin-6 (IL-6), IL-1?, tumor necrosis factor TNF?, inducible nitric oxide synthase (iNOS), IFN?, IDO, and matrix metalloproteases 9 (MMP9). Whole blood PAXgene analysis of IFN?, IDO, MMP9, and iNOS was examined by PCR. Circulating concentrations of IL-6, IFN?, and C-reactive protein (CRP) w\u27ere analysed by ELISA, and kynurenine and tryptophan concentrations were examined by High performance liquid chromatography (HPLC). A significant increase in HAM-D scores was found, which was independent of the psychological impact of acute symptoms, but was associated with increased colonic and circulating cytokine expression and kynurenine:tryptophan ratio
Investigation of cerebral perfusion changes following MDMA Ecstasy administration in an animal model using bolus-tracking arterial spin labelling MRI
No full textTHESIS 9787The recreational drug of abuse 3,4 methylenedioxymethamphetamine (MDMA; Ecstasy) carries a risk of cerebrovascular accidents (CVA) that may relate to the role of serotonin (5- HT) and/or dopamine in the regulation of cerebrovascular tone. Recent advances in magnetic resonance imaging (MRI) have enabled measurement of cerebral blood perfusion using contrast agent-free approaches such as bolus-tracking arterial spin labeling (btASL). This investigation assessed changes in cerebral perfusion following systemic MDMA administration to rats using btASL MRI. Adult male Wistar rats were administered MDMA (5 or 20 mg/kg; i.p.) or saline, anaesthetised 1, 3 or 24 hours later and a high resolution anatomical scan followed by a continuous ASL (cASL) sequence was conducted using a 7 Tesla MRI scanner. Perfusion-weighted images were generated by subtraction of labelled from control images and experimental data was fitted to a quantitative model of cerebral perfusion to generate mean transit time (MTT), capillary transit time (CTT) and signal amplitude. MTT and CTT are inversely proportional to cerebral blood flow (CBF) and CBF squared respectively, and signal amplitude is proportional to cerebral blood volume (CBV). MDMA induced a reduction in MTT and CTT and an increase in signal amplitude in primary motor, secondary motor and somatosensory cortex I and 3 hours following administration. Such effects were not obtained in sub-cortical regions. The acute effects of MDMA on cerebral perfusion may go some way towards providing a mechanism to explain the occurrence of CVA in vulnerable recreational ecstasy users
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