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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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Circadian changes of the cholinergic system in various areas of the central nervous system
Křížová, Monika ; Mysliveček, Jaromír (advisor) ; Jakubík, Jan (referee)
Muscarinic acetylcholine receptors type 4 are one of the five subtypes of metabotropic muscarinic receptors whose knockout led to disruption of the biorhythm represented by locomotion in female mice. In this thesis, we attempted to determine the biorhythmic activity of selected components of the cholinergic system in structures of the central nervous system which are suspected to regulate circadian locomotion. These selected structures were the striatum, motor cortex, thalamus, intergeniculate leaflet, subparaventricular zone and posterior hypothalamic area. Changes of muscarinic receptor density in wild type and M4 receptor knockout female mice were measured by using autoradiography throughout the day. In the striatum, motor cortex, and thalamus, the density of muscarinic receptors type 1 and the activity of acetyl- and butyrylcholinesterases were also measured by autoradiography and the Ellman's method. Rhythmic oscillations of muscarinic receptor density were observed in all structures selected in both types of mice. The main brain structure responsible for the differences in the biological rhythm of wild type and M4 receptor knockout mice was identified as the striatum and motor cortex region, where the percentage of M4 receptors was highest. Diurnal oscillations were also exhibited by...
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Evaluation of the kinetics of acetylcholinesterase inhibitors in vitro
Janská, Kateřina ; Herink, Josef (advisor) ; Hrdina, Radomír (referee)
Kateřina Janská Evaluation of the kinetics of acetylcholinesterase inhibitors in vitro Diploma thesis Charles University in Prag, Faculty of Pharmacy in Hradec Králové Pharmacy Department of Biological and Medical Sciences Supervisor: Doc. MUDr. Josef Herink, DrSc. Consultant: PharmDr. Vendula Šepsová The aim of the thesis was to determine the type of an inhibition of newly synthesized AChEI and to find out if AChEI structure changes influence the type of an inhibition. Altogether 12 substances (7 tacrine hybrides and 5 7-methoxy- donepezil hybrids) were investigated. The inhibition potential of the tested substances was studied in vitro on the human recombinant AChE. Spectrophotometric Ellman method was utilized as the measurement tool. The noncompetitive type of an inhibition for substances EN 1-5, PC-25 and PC-33, mixed type of an inhibition for substances PC-48 and PC-49, uncompetitive type of an inhibition for substances EN-6, EN-7 and competitive type of an inhibition for the substance PC-37 was determined. The greatest inhibition potential according to Ki values were found for substances EN-7 and PC-37. Substances PC-37 and PC-48 were determined as substances with the biggest affinity to the AChE. The type of an inhibition has been influenced by a substituent position in PC substances and by...
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Role of M4 muscarinic receptors in the central nervous system
Křížová, Monika ; Mysliveček, Jaromír (advisor) ; Slepička, Jakub (referee)
Muscarinic receptors type 4 are one of the five subtypes of muscarinic receptors, that are members of cholinergic receptors family, together with nicotinic receptors. An acetylcholine binding on the receptor triggers the receptor activation and the signal transmission into the cell by G-proteins located on plasmatic membrane, in the case of muscarinic receptors type 4 by Gi/o proteins. The M4 receptors are, just like other subtypes on muscarinic receptors, located in central and peripheral nervous system. In the central nervous system, they are mostly located in striatum and hippocampus. The M4 receptors have a whole range of regulative functions, the most significant one is most likely the regulation of a locomotion in striatum by the dopaminergic system. The muscarinic receptors type 4 are involved in many behavioural and cognitive processes and are therefore studied as potential drug target for the treatment of mental disorders. Key words: muscarinic receptors, M4 muscarinic receptors, GPCRs, cholinergic system, central nervous system
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Studying the role of striatal cholinergic signaling in control of behaviour and behavioural flexibility
Tyshkevich, Alexandra ; Janíčková, Helena (advisor) ; Levčík, David (referee)
Cognitive flexibility is an important mechanism enabling organisms to adapt to their changing environment. Different brain structures are involved in this complex process. It has been repeatedly shown that the striatum is one of the key structures controlling cognitive flexibility. Striatum receives rich input from different brain regions while its output is rather uniform. Striatal functions and signalling are greatly modulated by dopamine and acetylcholine. A number of studies have shown involvement of striatal acetylcholine and its receptors in the control of cognitive flexibility but very little is known about the role of M4 muscarinic acetylcholine receptors. These receptors are inhibitory, and they have been shown to induce long-term depression in striatal medium spiny neurons, therefore opposing the action of the dopamine D1 receptors. We hypothesize that the inhibitory effect of M4 muscarinic acetylcholine receptors may supress spiny projection neurons coding for outdated and no longer effective behavioural strategy and thus they may be necessary for the flexible change of behaviour. In the present thesis, I investigated the effects of pharmacological antagonism of M4 receptors on cognitive flexibility of mice tested in a simple reversal learning paradigm. Key words: striatum; cholinergic...
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Cholinergic signaling in the striatum and its significance in cognitive flexibility
Smolík, Matyáš ; Janíčková, Helena (advisor) ; Funda, Jiří (referee)
In the striatum, cholinergic interneurons (CINs) contribute to the control of behaviour, motor and cognitive functions. Recently, number of studies have shown a special significance of CINs in the control of cognitive flexibility: the ability to learn new behavioural strategies when requirements of the environment change. Along with working memory, cognitive inhibition, attention control and other cognitive domains, cognitive flexibility belongs to executive functions. Cognitive flexibility impairment is present in a range of neuropsychiatric disorders and thus, understanding its mechanisms is of outstanding importance. The proposed work will first describe anatomy and cellular composition of the striatum and its functions. It will further describe cholinergic system with a special attention to cholinergic signalling in the striatum. The final chapter of the general part of the thesis will focus on cognitive flexibility. After discussing the involved structures and systems separately, the thesis will eventually provide comprehensive review of currently available studies investigating how striatal CINs contribute to brain's ability to replace old concepts with new and more efficient ones.
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Role of M4 muscarinic receptors in the central nervous system
Křížová, Monika ; Mysliveček, Jaromír (advisor) ; Slepička, Jakub (referee)
Muscarinic receptors type 4 are one of the five subtypes of muscarinic receptors, that are members of cholinergic receptors family, together with nicotinic receptors. An acetylcholine binding on the receptor triggers the receptor activation and the signal transmission into the cell by G-proteins located on plasmatic membrane, in the case of muscarinic receptors type 4 by Gi/o proteins. The M4 receptors are, just like other subtypes on muscarinic receptors, located in central and peripheral nervous system. In the central nervous system, they are mostly located in striatum and hippocampus. The M4 receptors have a whole range of regulative functions, the most significant one is most likely the regulation of a locomotion in striatum by the dopaminergic system. The muscarinic receptors type 4 are involved in many behavioural and cognitive processes and are therefore studied as potential drug target for the treatment of mental disorders. Key words: muscarinic receptors, M4 muscarinic receptors, GPCRs, cholinergic system, central nervous system
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Targeting cholinergic system in tretment of Alzheimer's disease.
Golianová, Nikoleta ; Jakubík, Jan (advisor) ; Říčný, Jan (referee)
Alzheimer's disease (AD) is a neurodegenerative disorder of CNS and very serious type of dementia. AD affected 46.8 million people worldwide in 2015, and it is estimated that the number of patients will double every 20 years, reaching over 130 million people in 2050 according to Alzheimer's Disease International. There are two forms of the AD: familial (FAD) and sporadic (SAD) form. FAD is an early-onset disease caused by genetic mutations. SAD is more common, a late-onset disease with the age and ε allele of apolipoprotein E as major risk factors. The most crucial symptom is memory disorder, followed by disorientation, confusion, depression and later on, serious psychical and motor-skill problems. These symptoms are the result of a neuronal loss due to formation of β-amyloid oligomers and neurofibrillary tangles in the central nervous system (CNS). As for now, there are neither efficient diagnostic approaches, nor therapeutic ways to stop the degeneration of the brain. There are some drugs available, such as inhibitors of acetylcholinesterase, that have proven to slow down the progression of the AD. Other cholinergic approaches have been developed, but they have shown a lot of side effects, as they are targeting a large scale of receptors. Additional approaches are focusing on clearance of -...
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Mnemonic and behavioural effects of biperiden, an M1-selective antagonist, in the rat
Popelíková, Anna ; Stuchlík, Aleš (advisor) ; Telenský, Petr (referee)
Due to the persisting lack of reliable animal models of cognitive impairment with good translational validity, researches strive to discover new ways and tools to replicate symptoms of human neurodegenerative diseases in rodents. Recently, biperiden, an M1- selective muscarinic antagonist, has been proposed as a potential tool for generating fast screening models of mnemonic deficits such as seen in patients with Alzheimer's disease. Being highly selective for the M1 receptor, a predominant type of muscarinic acetylcholine receptors in the brain involved in cognitive processes, it has been speculated to possibly only influence cognition without causing sensorimotor side effects. Studies assessing the usability of this drug reported conflicting results. We have decided to expand the experimental data and evaluate biperiden's validity in several variants of the Morris water maze. The results of this study showed no significant effect of biperiden on cognitive flexibility, tested by reversal learning. In delayed-matching-to-position paradigm, which tests assesses working memory, we found a difference in performance between the two experimental groups; however, it cannot be unequivocally attributed to a memory impairment. No effects were observed in visible platform task, confirming a lack of...
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Evaluation of the kinetics of acetylcholinesterase inhibitors in vitro
Janská, Kateřina ; Herink, Josef (advisor) ; Hrdina, Radomír (referee)
Kateřina Janská Evaluation of the kinetics of acetylcholinesterase inhibitors in vitro Diploma thesis Charles University in Prag, Faculty of Pharmacy in Hradec Králové Pharmacy Department of Biological and Medical Sciences Supervisor: Doc. MUDr. Josef Herink, DrSc. Consultant: PharmDr. Vendula Šepsová The aim of the thesis was to determine the type of an inhibition of newly synthesized AChEI and to find out if AChEI structure changes influence the type of an inhibition. Altogether 12 substances (7 tacrine hybrides and 5 7-methoxy- donepezil hybrids) were investigated. The inhibition potential of the tested substances was studied in vitro on the human recombinant AChE. Spectrophotometric Ellman method was utilized as the measurement tool. The noncompetitive type of an inhibition for substances EN 1-5, PC-25 and PC-33, mixed type of an inhibition for substances PC-48 and PC-49, uncompetitive type of an inhibition for substances EN-6, EN-7 and competitive type of an inhibition for the substance PC-37 was determined. The greatest inhibition potential according to Ki values were found for substances EN-7 and PC-37. Substances PC-37 and PC-48 were determined as substances with the biggest affinity to the AChE. The type of an inhibition has been influenced by a substituent position in PC substances and by...
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