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The role of cholesterol in the pathogenesis of Alzheimer's disease
Tax, Martin ; Rudajev, Vladimír (advisor) ; Randáková, Alena (referee)
Alzheimer's disease is a neurodegenerative disorder and the most common form of dementia affecting a significant part of the aging population. It seems that the main cause of this disease is the accumulation of amyloid β (Aβ). Cholesterol is an important component of plasma membranes where it is essential for proper synapse function. Changes in its concentration are considered to be a risk factor for the onset and development of Alzheimer's disease. Data show that this lipid has an effect on Aβ synthesis and also has a role in Aβ cytotoxicity where it may promote the negative properties of Aβ or on the contrary can be protective against them.
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Physiological principles of current therapeutic approaches in the treatment of Alzheimer's disease
Denisova, Elizaveta ; Rudajev, Vladimír (advisor) ; Veverová, Kateřina (referee)
Alzheimer's disease is a progressive neurodegenerative disease that affects millions of people worldwide. The pathology of Alzheimer's disease includes amyloid and tau hypothesis, mitochondrial dysfunction and neurodegeneration. Classical treatments for Alzheimer's disease include drugs targeting the cholinergic and glutamatergic systems, such as donepezil, galantamine, rivastigmine, and memantine. Diagnostic tools and techniques are constantly evolving to better identify and monitor the course of the disease. New approaches to the treatment of Alzheimer's disease include beta-amyloid-targeted therapies that seek to reduce the production or facilitate the clearance of these pathological peptides. Nutritional and lifestyle interventions, such as the potential effects of antioxidants on reducing oxidative stress, the neuroprotective effects of statins, and the potential benefits of a ketogenic diet for Alzheimer's patients, have become a key part of a multidisciplinary approach to treatment and are being explored as part of a comprehensive strategy to improve patients' quality of life. Key words: Alzheimer's disease, amyloid hypothesis, tau hypothesis, mitochondrial dysfunction, neurodegeneration, cholinergic system, glutamatergic system, new therapeutic approaches, nutrition, lifestyle.
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Potential role of opioids in neuroprotection
Gebauer, Martin ; Novotný, Jiří (advisor) ; Rudajev, Vladimír (referee)
The opioids have been used by mankind for more than two millennia, but effect and mechanism of their action on the cells has been unveiling in the last few decades. The mechanism itself is often still unknown, but its effect is observed only. There are several groups of opioid receptors which are able to bind opioids. These groups are characterized by their differe nt affinity to opioids, in some cases by their different effects on cells and by their representation in the various areas in the CNS. Thus, the effects induces by these opioid are very different in many cases. This thesis summarizes the current knowledge about coronary heart disease and the potential of opioids for the prevention and their effect during ischemia, also summarizes the effects of morphine on the CNS. During ischemia δ-opioid receptors play a major role, because they inhibit or block the proapoptotic effects of ischemia on many levels. These receptors are also involved in inducing and maintaining the animal hibernation and protect animal's body against very harmful effects of hibernation, e.g lack of oxygen and nutrients. Morphine is opioid which has been used as anesthetic for longest time. It is well-known opioid and it has the most known derivates. This thesis also summarizes most significant effects of morphine on...
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Effect of chronic morphine treatment of rats on myocardial signaling systems regulated by trimeric G-proteins
Škrabalová, Jitka ; Novotný, Jiří (advisor) ; Rudajev, Vladimír (referee)
It has recently been discovered that the effect of morphine can significantly reduce the tissue damage that occurs during myocardial ischemia. The molecular mechanisms by which morphine acts on the heart are still little understood. The aim of this thesis was to monitor the effect of chronic 27-day and 10-day administration of low (1 mg/kg/day) and high (10 mg/kg/ day) doses of morphine on the expression of selected G-protein-coupled receptors (GPCR) and on the expression and activity of adenylyl cyclase (AC). Chronic (27 days) morphine treatment reduced the expression of к-opioids receptors, but 10-day morphine exposure did not influence the expression of these receptors. Assessment of β1- and β2-AR by immunoblot technique did not show any significant change in the expression, but the more accurate determination of β-AR expression using the saturation binding studies revealed that 27-day treatment with high doses of morphine appreciable increased the total number of these receptors. Administration of high doses of morphine led to marked up-regulation of adenylyl cyclase (AC) isoforms V/VI, and the amount of AC decreased proportionally with the time of discontinuation of morphine administration. Low doses of morphine up- regulated AC only during 27-day administration. Chronic morphine exposure did...
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Endogenous opioids and their physiological significance
Jandová, Gabriela ; Novotný, Jiří (advisor) ; Rudajev, Vladimír (referee)
This study examines the influence of endogenous opioid system on physiological processes. Opioid substances and their receptors are located not only in central but also in peripheral nervous systems, as well as in other tissues. Endogenous opioids are produced in the body and influence a wide-range of physiological functions. They are regulators of pain, emotions, breathing, memory, homeostatic functions, etc. Due to their diversity and variety of effects, they may have many possible medical uses, whether in the field of cardiology, anesthesiology or psychiatry. Since the opioid system influences many physiological processes, the understanding of its properties and functioning is prerequisite for deeper study of those processes. Therefore, the study of opioid system and new discoveries in this field receive a great deal of attention nowadays. Key words: Opioid system, endogenous opioids, receptors, nervous system, physiological functions, pain, emotions, breathing, memory, homeostasis
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Biocompatibility of porous NCD layers with neurons
Freislebenová, Hana ; Benson, Veronika (advisor) ; Rudajev, Vladimír (referee)
Nanodiamond is currently one of the most researched materials in the field of regenerative medicine in the study of treatment of neurodegenerative diseases. Due to direct interaction of this material with nerve tissue, it needs to be biocompatible with primary neurons. Furthemore, it is desirable for the used material to induce cell adhesion and stimulate the adherent cells to regeneration. This work evaluates the biocompatibility of porous boron-doped diamond layers with the culture of primary neurons. We compared the effect of diamond surface treatment by poly- D-lysine (PDL) coating on the adhesion and prosperity of the primary neuronal culture. We found that the tested nanodiamond layers are biocompatible with the primary neuronal culture. We further conclude that the PDL coating slightly increases the rate of cell adhesion to the surface but on the other hand induces greater adhesion of glial cells than the surface without PDL coating. Key words: nanodiamond, biocompatibility, adhesion, neurons
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A study of molecular interactions of the μ-opioid receptor: the effect of biased ligands
Marková, Vendula ; Novotný, Jiří (advisor) ; Rudajev, Vladimír (referee)
G protein-coupled receptors (GPCRs) are the largest group of membrane-bound receptors. Transmission of signals into the cell interior is mediated through the interactions of these receptors with other signaling molecules. Nowadays, a great attention is devoted to biased ligands which are able to alter the conformation of the receptor in a specific way and thus distinctly affect its function. This diploma thesis was focused on a study of µ-opioid receptor (MOR), which is important in nociception. The aim of this study was to find out, how the activation of MOR by specific biased ligands (morphine, endomorphin-2 and DAMGO) affects the function and the interactions of MOR with potential molecular partners (for example G proteins or β-arrestin) A method of siRNA interference was used to knock down the following selected signaling molecules: Gαi1, Gαi2, Gαi3, Gαz and β-arrestin2. The effect of biased ligands on lateral mobility of MOR in the plasma membrane and on activity of adenylyl cyclase (AC) was examined under these conditions. We observed a possible involvement of Gαz subunit in the lateral mobility of MOR after the effect of morphine and endomorphin-2. The lateral mobility of MOR was significantly increased in cells lacking Gαi2 or Gαi3 or β-arrestin2. In this case the MOR was in inactive state....
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The role of G protein-coupled receptor signaling systems in neuroprotection
Hofmannová, Adéla ; Novotný, Jiří (advisor) ; Rudajev, Vladimír (referee)
Nervous tissue, especially the brain, is very sensitive to the lack of oxygen and nutrients. Without supply of these components, the tissue endures only a few minutes and then, after the depletion of all ATP, permanent damage or even cell death occurs in neurons and glial cells. During ischemia or hypoxia, an excessive amount of the excitant neurotransmitter glutamate is released, which is neurotoxic. It causes ion imbalance and also apoptotic signaling pathways may be triggered because of the high level of intracellular calcium. Signaling through G protein-coupled receptors (GPCRs) can be involved in the establishment of increased cell resilience to hypoxic injury. Stimulation of some GPCRs, e.g. adenosine, opioid, cannabinoid and melatonin receptors, can afford neuroprotection. Activation of their cognate G proteins may lead to blockade of ion channels or affect the effector proteins, thus helping the stabilization of ion homeostasis and the inhibition of glutamate release. Moreover, some of the receptor agonists have antioxidant character, whereby they prevent the harmful action of free radicals. Neuroprotective mechanisms promote neuronal survival during harmful conditions and are also able to slow down the processes responsible for the development of neurodegenerative diseases. Key words: G...
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