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Microglia control adenosine A2A-receptor mediated astrogliosis
Svobodová, Magdaléna ; Mladěnka, Přemysl (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Magdaléna Svobodová Supervisor: Assoc. Prof. Přemysl Mladěnka, Ph.D. Assoc. Prof. Maria da Glória Correia da Silva Queiroz, Ph.D. Title of diploma thesis: Microglia control adenosine A2A-receptor mediated astrogliosis In the central nervous system, astrocytes and microglia are the main cells coordinating the inflammatory response. During inflammation, dying or temporarily damaged cells release ATP, as a danger-associated signal molecule, that contributes to the induction of astrogliosis and promotes clearance of the debris by immune cells such as microglia. Adenosine that results from ATP metabolism also stimulates astrogliosis. However, the effects of adenosine on astrogliosis may be more complex, since it also modulates microglia phenotype and microglia have been shown to prevent excessive astroglial proliferation mediated by nucleotides. In this context, ATP and adenosine are assumed as relevant signalling molecules in the control of astrogliosis and its modulation by microglia. However, it is still unknown whether and how microglia modulate adenosine-mediated astrogliosis. The present study aims to clarify the impact of microglia in the control of adenosine-induced astrogliosis. Two...
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Ultrastructural interactions of larval bird schistosome Trichobilharzia regenti and immune cells of hosts nervous system
Krčmářová, Veronika ; Bulantová, Jana (advisor) ; Hodová, Iveta (referee)
Trichobilharzia regenti is a neurotropic fluke belonging to family Schistosomatidae. Larvae called schistosomula migrate in the definitive hosts (anseriform birds) throuth the central nervous system (CNS) to their final location in nasal mucosa, where they mature and lay eggs. In contrast with that, the infection of accidental mammalian hosts (including human), is often stopped already in the skin immediately after entering the host. However, some schistosomula are able to reach CNS of experimentally infected mice, and survive there temporarily. Reaction to the CNS infection of mice is usually provided by microglia, astrocytes or the other immune cells infiltrated from the hosts blood. Parasite protects itself against the host reaction with its tegument. It does not serve only as mechanical barrier, but also as main secretoric organ that is capable of active immune evasion. Changes within CNS of the vertebrate hosts, caused by migrating schistosomula of T. regenti, were already described by routine histological and immunohistochemical methods. Till now, there was a lack of informations about interactions of immune cells of the host and the tegument of the parasite on ultrastructural level. To fill this gap in knowledge, two different methods were used: (1) imunohistochemistry in light and electron...
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Molecular mechanisms of the glycinergic signalization in the central nervous system
Melichar, Adolf ; Králíková, Michaela (advisor) ; Ladislav, Marek (referee)
The amino acid neurotransmitter glycine, which mediates the inhibitory transmission and regulates the excitatory signalization, is found in many regions of the central nervous system. It is produced especially the spinal cord and the brainstem, where glycine activates the presynaptic and postsynaptic Gly receptors (GlyR). In other regions of the brain, glycine is released in the area of occurrence of NMDA receptors (NMDAR), which it activates together with the excitatory neurotransmitter glutamate. The binding of the glycine leads to the opening of the channel of these ionotropic receptors and thus also to a change in the electrochemical properties of the membrane, such as permeability for Ca2+ ions, membrane potential and shunting. The expression of different subunits of NMDAR and GlyR is specific in terms of location and time, which enables various responses to the presence of glycine in the synaptic cleft and its surroundings. The concentration of glycine in synaptic cleft and glycinergic terminals is controlled especially by glycine transporters (GLYT), that are found in two functionally different types. The destabilisation of the equilibrium and signal mechanisms of glycine may lead to serious diseases such as hyperekplexia that can be caused by mutations in the glycine receptors and...
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Murine cerebral toxocariasis
Bernardová, Nicol ; Chanová, Marta (advisor) ; Panská, Lucie (referee)
Toxocara canis is endoparasitic geohelminth of canids. In its life cycle it uses paratenic host (even humans) and can cause severe problems called cerebral toxocariasis when attacks central nervous system. The exact mechanism of pathogenicity in nervous system is unknown and experimental studies examines rather the acute phase of toxocariasis, therefore we characterized the course of cerebral toxocarosis in mice from acute to chronic phase in this master thesis. We found larvae of the parasite in the brains of mice. The larvae in the tissues occurred both, individually and in clusters. The presence of larvae was observed in regions that affect both movement and memory. We did not find any visible injury nor inflammation surrounding the larvae in the tissue. However, histological examination showed brain tissue pathologies in all mice, namely local necrosis, hemorrhages, thickened vessel walls, cell infiltrates in tissue and around vessels and abnormal angiogenesis. The mice showed neurological symptoms with increasing frequency from the 9th week post infection. Production of specific antibodies was also monitored. The level of antibodies in reinfected mice was higher compared to antibody levels of mice with a single infection. No correlation with the presence of neurological symptoms was shown. Key...
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The role of D-amino acids in central nervous system
Pangrácová, Marie ; Konvalinka, Jan (advisor) ; Balík, Aleš (referee)
Only recently, the presence of D-amino acids in the mammalian central nervous system has been confirmed and their biological functions revealed. D-serine and D-aspartate, the best described D-amino acids, have been found to be the co-agonists activating NMDA receptors. In this way D-serine and D-aspartate, among other functions, affect synaptic plasticity which is the basic cellular mechanism for learning and memory. Pathological changes in the levels of these D-amino acids and their metabolical enzymes can lead to the development of epilepsy, schizophrenia, and neurodegenerative diseases such as amyotrophic lateral sclerosis, Huntington disease or Alzheimer disease. The main role in the D-serine synthesis is played by serin racemase while D-aspartate is synthetised with the help of aspartate racemase. The key enzymes for the degradation of D-amino acids are DAAO (D-amino acid oxidase) and DAspO (D-aspartate oxidase). This thesis presents an overview of available knowledge on the individual amino acids and their respective metabolical enzymes in the mammalian central nervous system, i.e. their distribution, cell localizations, metabolism and functions. Furthermore, the emphasis is put on the possibilities of inhibition and activation of the metabolical enzymes and their importance with respect to...
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Characterization of the effect of pregnanolone sulfate and its derivatives on NMDA receptors.
Švehla, Pavel ; Vyklický, Ladislav (advisor) ; Blahoš, Jaroslav (referee)
N-methyl-D-aspartate (NMDA) receptors are a subtype of receptors for major excitatory neurotransmitter glutamate in the central nervous system. Their activity is regulated by variety of allosteric modulators, including endogenous neurosteroids and their synthetic analogues. NMDAreceptor dysfunction is implicated in various forms of neurodegeneration and inhibitory neurosteroids have unique therapeutic potential to act as neuroprotective agens. The aim of this work is to investigate relationship between structure and function of neurosteroids with modifications in the D-ring region, using whole-cell patch clamp recording at recombinant GluN1/GluN2B receptors. In this work, we characterised inhibition effect of 19 neurosteroid analogues on NMDA receptor activity and found several of them to be potent NMDA receptor inhibitors. According to our results, there is a linear relationship of IC50 and lipophilicity of a neurosteroid compound, suggesting the plasma membrane plays an important role in neurosteroid access to NMDA receptor. Indeed, using capacitance recording configuration in combination with amphipathic molecule gamma-cyclodextrin, we were able to separate the kinetic of neurosteroid membrane binding from receptor binding. Moreover, these experiments showed that neurosteroid accumulation in the...
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Impairment of cellular metabolism as common pathophzsiological mechanism of CNS diseases
Hasala, Ondřej ; Otáhal, Jakub (advisor) ; Konopková, Renata (referee)
Name of thesis: Impairment of cellular metabolism as common pathophysiological mechanism of CNS diseases Problem definition: Every human cell needs energy for living. If the prodcution of ATP (as an universal energy carrier) is broken, cell restricts its activity first and during longterm depletion of ATP, dies. It was found, that cellular metabolism is broken in most pathologies in CNS. Disorder of respiratory chain by free radicals is the best known at Parkinson's disease, epilepsy, brain ischemia etc. Mitochondria, where respiratory chain is situated, is not only the aim of free radicals, but it is their major producer. The activity of respiratory chain decreases during the life and this phenomenan is called aging. Aim of thesis: To determine whether there is increased production of free radicals in mitochondria of rat (LE Wistar) hippocampus during the epileptic seizure. Method: Thesis involves experiment which was done with acute rat hippocampal slices. To induce epileptic seizure it was used 4-aminopyridine model. It was used fluorescence imaging as imaging method. Changes of superoxide production was detected with MitoSOX. Electrophysiological record was taken by programme Spike 2 with stimulation and recording electrode inside the slice. Results: There was no significant difference between...
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Localization of individual opioid receptor subtypes in CNS
Lišháková, Michaela ; Hejnová, Lucie (advisor) ; Bendová, Zdeňka (referee)
In last decades, the research focused on opioid receptors has been intensively conducted in order to determine their role in various homeostatic functions, control of movement, neurotransmission and drug addiction. An important factor determining the pharmacologic role of opioid receptors is their distribution within the brain regions as well as at the cellular level. Over the past 40 years, a great deal of information concerning their distribution in the central nervous system has been collected, allowing us to determine their localization and mechanisms of their action. In general, results obtained from previous studies are in agreement. However, there are some inconsistencies that impede the accurate determination of receptor distribution and need to be clarified. This paper aims to summarize results of the previously published studies observing the localization of opioid receptors in the rat CNS. Emphasis is placed on the comparison of results obtained by all available methods.
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