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Exploring the role of opioid signaling in modulation of microglial function
Mali, Akash Shivling ; Novotný, Jiří (advisor) ; Svoboda, Petr (referee) ; Machová Urdzíková, Lucia (referee)
Microglial activation is the most important component of neuroinflammation. It appears that opioids may affect microglial M1/M2 polarization in different ways depending on the type of receptor employed. In addition to opioid receptors, Toll-like receptor 4 (TLR4) of the innate immune system can also be activated by some opioid ligands and thus elicit specific cellular responses. Although opioid receptors (ORs) are known to regulate neurotransmission in various peptidergic neurons, their potential role in modulation of microglial function remains largely unknown. In this study, we investigated the effects of OR agonists, namely DAMGO, DADLE, and U-50488, on polarization and metabolic modulation of C8-B4 microglial cells. Our findings have revealed that opioids effectively suppress lipopolysaccharide (LPS)-triggered M1 polarization and promote the M2 polarization state. This was evidenced by decreased phagocytic activity, decreased production of nitric oxide (NO), diminished expression of proinflammatory cytokines such as TNF-α, IL-1β, IL-6, IL-86, and IL-12 beta p40, along with an increased migration rate and elevated expression of anti-inflammatory markers such as IL-4, IL-10, IL-13 arginase 1, and CD206 in microglia compared to cells influenced by LPS. Furthermore, we have demonstrated that...
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The effect of methamphetamine on the neuroimmune system
Petrášová, Blanka ; Hejnová, Lucie (advisor) ; Lapka, Marek (referee)
Metamphetamine is worldwide problem and in the Czech republic is 2-3 % of people older than 15 years exposed to it. There are 34,7 thousand long-term users in Czech republic and 19 methamphetamine-related deaths in 2022. The impact on the neuroimmune system has only started to be studied in recent years. Understanding its effect on the neuroimmune system may outline new treatment options, as there is no cure for methamphetamine addiction to date. This paper summarizes its effects on the different components of the neuroimmune system and outlines some substances that could be used in treatment. Key words: methamphetamine, neuroimmune system, inflammation, microglia, astrocytes
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Circadian system as a modulator of neuroinflammation
Kotková, Eliška ; Spišská, Veronika (advisor) ; Dočkal, Tereza (referee)
The circadian system is involved in the regulation of biological rhythms in physiological, behavioural and immune processes. These rhythms can be found in the central nervous system, including the blood-brain barrier, astrocytes, microglia, and the pineal gland, which produces the hormone melatonin. Neuroinflammation is a complex response of the central nervous system to inflammatory stimuli by rhythmic expression of pro-inflammatory and anti-inflammatory mediators or by rhythmic regulation of immune system cells. Studies have examined the influence of genes and proteins of the circadian system, suprachiasmatic nuclei, melatonin, and glial cell rhythms on neuroinflammation. Lipopolysaccharide was used to induce neuroinflammation in these studies. Based on these studies, the effect of melatonin on mikroglia and endothelial cells, and the responses of suprachiasmatic nuclei was evaluted as the most important circadian modulator of neuroinflammation. This thesis describes the basic principles of the circadian system and neuroinflammation, with the last section presenting the modulation of neuroinflammation by the circadian system. Keywords: astrocytes, blood-brain barrier, circadian system, cytokines, immune system, melatonin, microglia, neuroinflammation, suprachiasmatic nuclei
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The role of microglia and astrocytes in Alzheimer's disease
Pospíšilová, Eva ; Telenský, Petr (advisor) ; Svoboda, Jan (referee)
Alzheimer's disease is a neurodegenerative disease that affects the central nervous system and is characterized mainly by problems with memory abilities. With the more aging population, the number of patients with this disease is gradually increasing, so Alzheimer's disease research is becoming one of the main priorities of today's health care. Although the research has been going on for more than a century, the exact causes of the Alzheimer's disease are still unclear. For a long time, the main role was attributed to the pathology of amyloid β and tau protein, the basic pathophysiological features of this disease, but in recent years, it has become clear that microglia and astrocytes also play an important role. These glial cells affect the amount of amyloid β and the hyperphosphorylated tau protein, but they are also crucial for maintaining homeostasis of the central nervous system. Activation of microglia and astrocytes in Alzheimer's disease can lead to disruption of the physiological functions of these neuroglia, and thus to problems with the removal of amyloid and tau protein, but also to the induction of chronic neuroinflammation. This work aims to summarize and organize the basic knowledge about the role of microglia and astrocytes in Alzheimer's disease, while focusing mainly on their role...
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Molecular mechanisms of morphine action on the immune system
Zeťková, Anna ; Hejnová, Lucie (advisor) ; Vašek, Daniel (referee)
This paper focuses on the molecular effect of morphine, which is widely used for its analgesic and sedative properties. This makes it an important drug for the treatment of chronic and severe pain. In addition to its positive effects, the long-term administration of morphine in particular has its drawbacks, such as the rapid development of tolerance and dependence on it. Other negative effects include constipation, respiratory stagnation or vomiting. These effects are caused not only by the influence of morphine on nerve cells, but also on other cells of the body. This thesis is primarily concerned with the effect of morphine on microglia, which are not only involved in the immune response in the central nervous system, but also have an effect on pain perception or the development of tolerance. This is one of the main areas of research in the field of opioids, therefore, the aim of this thesis is to summarize the findings on the effect of morphine on microglia, which happens mainly through opioid receptors, toll-like receptors and purinoceptors.
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The role of neuroinflammation in neurodegenerative CNS disease processes
Červenák, Karol ; Novotný, Jiří (advisor) ; Spišská, Veronika (referee)
Inflammatory processes in the CNS are an important element in neuroimmunity. They may be beneficial and have a neuroprotective effect but depending on the extent and duration of their activation they may also have a negative effect on the function of the CNS. Neuroinflammation is characterized by the activation of resident immune cells, microglia and astrocytes, activation of inflammatory signal pathways, recruitment of immune cells from the blood and their penetration through the blood-brain barrier. Chronic neuroinflammation may cause neurodegeneration and is key in the pathogenesis of neurodegenerative diseases. Neurodegeneration is irreversible but it can be mitigated. Therapeutic methods aimed at the modulation of neuroinflammation present a promising option for slowing down or stopping neurodegeneration for people with diseases such as Alzheimer's, Parkinson's, or Huntington's disease. The aim of this thesis is to sum up information about inflammatory processes in the brain and our current knowledge about their role in the pathogenesis of some neurodegenerative diseases. Key words: Inflammation, microglia, neurodegeneration, Alzheimer's disease, Parkinson's disease, Huntington's disease, CNS
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Calcium signalling in glial cells in progress of Alzheimer disease
Waloschková, Eliška ; Anděrová, Miroslava (advisor) ; Maršáková, Lenka (referee)
Alzheimer's disease (AD) is a neurodegenerative disorder affecting the entire central nervous system including glial cells. The mechanisms of this disease are not yet entirely clear, although recent studies suggest that among the known hallmarks of AD, such as accumulation of amyloid β and hyperphosphorylated tau, dysregulation of intracellular calcium homeostasis is proposed to be a significant feature both in neurons and glial cells, namely astrocytes and microglia. Glial cells play an important role both in healthy brain and during AD progression. Their major functions, such as supporting neurons or maintaining synapses, are impaired during this disease. Recent findings suggest that aberrant glial calcium signaling activated during AD, could possibly promote the malfunction of these cells and increase their inflammatory response, thus affecting neurons and causing brain damage. It is likely, that the ongoing inflammation and the impaired calcium signaling affect one another, consequently enhancing the progression of AD.
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Nervous tissue regeneration following ischemic injury in adulthood - the role of glial cells
Kamenická, Monika ; Anděrová, Miroslava (advisor) ; Kletečková, Lenka (referee)
Ischemic stroke (ischemia) is one of the most common causes of death in the world. The consequences of this disease are enormous and markedly affect the lives of patients who often are unable to live a full quality of life as before. Therefore, the current research is focused on elucidating new mechanisms that could mitigate the effects of ischemia and better regeneration of nerve tissue. This theses aims to summarize the current knowledge about neurogenesis/gliogenesis in the nerve tissue under physiological conditions, after ischemic injury and subsequent regeneration. The first chapter is focused on neurogenesis in the nervous tissue of adults. The two main neurogenic regions are described, such as subventricular zone and the gyrus dentatus in hippocampus. The following is a brief description of cells that are located in neurogenic regions and their function under physiological conditions. The second chapter focuses on gliogenesis in adult nervous tissue and describes the glial cells responsible for numerous functions in CNS. Furthermore, the functions of individual types of glial cells are listed. The third chapter gives the overview about pathophysiology of ischemia. The author tries to explain what is happening in the brain tissue during and following ischemia, what types of ischemia are...
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The immune response of naïve mice infected with the neuropathogenic schistosome Trichobilharzia regenti
Macháček, Tomáš
Helminth neuroinfections represent a serious health issue, but the mechanisms of the host immune response often remain neglected despite the fact they might contribute to pathogenesis. This is partly due to the unavailability of clinical samples and the lack of suitable laboratory models. Herein, I focused on the characterization of several aspects of the immune response of mice infected with the neuropathogenic avian schistosome Trichobilharzia regenti. After the percutaneous infection of mice (accidental hosts), most T. regenti schistosomula are entrapped and eliminated in the skin, but the parasite antigens initiating the protective immune reaction are not known. Our in vitro experiments revealed that T. regenti cathepsin B2, a cysteine peptidase used for the skin penetration, activates bone marrow-derived dendritic cells much stronger than the parasite homogenate, suggesting its role in initiating the mixed type1/2 host immune response. However, some schistosomula manage to escape from the skin and continue their migration to the spinal cord. Here they crawl preferentially within the white matter which we demonstrated by the robust 3D imaging techniques, ultramicroscopy and micro-CT. The invasion of the spinal cord is accompanied by striking hypertrophy of astrocytes and microglia. We showed...
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The immune response of naïve mice infected with the neuropathogenic schistosome Trichobilharzia regenti
Macháček, Tomáš
Helminth neuroinfections represent a serious health issue, but the mechanisms of the host immune response often remain neglected despite the fact they might contribute to pathogenesis. This is partly due to the unavailability of clinical samples and the lack of suitable laboratory models. Herein, I focused on the characterization of several aspects of the immune response of mice infected with the neuropathogenic avian schistosome Trichobilharzia regenti. After the percutaneous infection of mice (accidental hosts), most T. regenti schistosomula are entrapped and eliminated in the skin, but the parasite antigens initiating the protective immune reaction are not known. Our in vitro experiments revealed that T. regenti cathepsin B2, a cysteine peptidase used for the skin penetration, activates bone marrow-derived dendritic cells much stronger than the parasite homogenate, suggesting its role in initiating the mixed type1/2 host immune response. However, some schistosomula manage to escape from the skin and continue their migration to the spinal cord. Here they crawl preferentially within the white matter which we demonstrated by the robust 3D imaging techniques, ultramicroscopy and micro-CT. The invasion of the spinal cord is accompanied by striking hypertrophy of astrocytes and microglia. We showed...
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