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The structure of minor alkaloids of the Amaryllidaceae family as inspiration for the synthesis of compounds with biological activity targeting Alzheimer's disease
Pidaný, Filip ; Cahlíková, Lucie (advisor) ; Drašar, Pavel (referee) ; Strnad, Miroslav (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacognosy and Pharmaceutical Botany Candidate: Mgr. Filip Pidaný Supervisor: Prof. Ing. Lucie Cahlíková, Ph.D. Consultant: Assoc. Prof. Jan Korábečný, Ph.D. Title of Doctoral Thesis: The structure of minor alkaloids of the Amaryllidaceae family as inspiration for the synthesis of compounds with biological activity targeting Alzheimer's disease The theoretical part of this dissertation provides a basic overview of the Amaryllidaceae family known for its rich occurrence of structurally diverse alkaloids. These substances exhibit a wide range of pharmacological effects, with our studies focusing on their potential therapeutic use in the treatment of Alzheimer's disease (AD). It is the most common form of dementia, which is characterized by progressive neurodegeneration. As the life expectancy of the population increases, the global prevalence of AD is also rising. This trend presents not only economic but also social challenges for healthcare systems, and society as a whole. The thesis provides detailed descriptions of the most well-known hypotheses of AD development and the characteristics of clinically used medications. Attention is given to the decline in levels of acetylcholinesterase, the dominant enzyme in a healthy...
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Evaluation of the pharmacological properties of new potential drugs for Alzheimer's disease
Čechová, Pavlína ; Šorf, Aleš (advisor) ; Urbánková Rathouská, Jana (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Social and Clinical Pharmacy Student: Pavlína Čechová Supervisor: PharmDr. Aleš Šorf, Ph.D. Consultant: mjr. PharmDr. Vendula Hepnarová, Ph.D. Title of diploma thesis: Assessment of pharmacological properties of new potencial drugs for Alzheimer's disease treatment Alzheimer's disease is a neurodegenerative disease with a progressive and irreversible course. The cause of AD is still not exactly known. There are currently four drugs available that have been approved by the State Institute for Drug Control. Three of them act as cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the fourth one as a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine). Unfortunately, these drugs do not affect the course of the disease and provide only temporary symptomatic relief. An important area of current research is MTDLs (Multi-Target Directed Ligands), which act on multiple target structures related to the pathophysiology of the disease. These agents represent a promising therapeutic strategy. The aim of the study was to measure the ability to inhibit human acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) of 58 new potential MTDLs derived from biphenyl and benzhydryl using Ellman's method, as well as...
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Synthesis of novel quinazoline derivatives as a potential multipotent therapeutics against Alzheimer's disease
Tošnerová, Daniela ; Karabanovich, Galina (advisor) ; Matouš, Petr (referee)
1 ABSTRACT Charles University, Faculty of Pharmacy in Hradec Králové Department of: Organic and Bioorganic Chemistry Mentor: Ing. Galina Karabanovich, Ph.D. Consultant: Ing. Barbora Svobodová, Ph.D. Student: Daniela Tošnerová Title of Thesis: Synthesis of novel quinazoline derivatives as a potential multipotent therapeutics against Alzheimer's disease Alzheimer's disease (AD) is a severe neurologic disorder. Current treatments only temporarily delay the progression of disease. The main limiting factor for developing of new therapeutic compounds is the simultaneous presence of multiple pathologies. Thus, a new group of potential drugs called multi-target directed ligands (MTDLs) emerged as an alternative option to combat AD. To this date, dozens of MTDLs have been published. As part of the experimetnal section of this thesis, a series of small molecules based on quinazoline scaffold was rationally designed with the intention to influence the activity of acetylcholinesterase, butyrylcholinesterase, monoamine oxidase A and B (MAO-A/MAO-B), and the GluN1/GluN2B subunit of N-methyl-D-aspartate receptor (NMDAR). Subsequently twenty-four new quinazoline derivatives were synthesized, and biologically evaluated. The overall results highlighted compound II-6h ((5E)-8-chlor-N-cyklohexyl-3-methyl-1-...
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Circadian regulation of the glymphatic system and its connection with the development of neurodegenerative diseases
Kuznetsov, Egor ; Sumová, Alena (advisor) ; Kubištová, Aneta (referee)
Due to the absence of an active lymphatic system of the brain and the responsible nodal system, it has long been unclear how interstitial metabolic waste products, in particular amyloid-β, tau- protein, α-synuclein and other biomarkers associated with the development of neurodegenerative diseases, are eliminated. A key role in this process is played by the glymphatic system, a complex network of tunnel-shaped perivascular spaces (PVSs) that conduct the flow of cerebrospinal fluid. These spaces are surrounded by astrocytes, responsible for the transport of fluids and the removal of metabolites. Studies suggest that the glymphatic system is subject to an endogenous circadian clock, and there is an established correlation between the volume of perivascular spaces and, with it, the rate of cerebrospinal fluid flow and sleep. Factors affecting the function of the glymphatic system include pulsation of blood vessels, spatial orientation of the body and functionality of aquaporin-4 (AQP4). Dysfunction of the glymphatic system plays a key role in the aging of the brain and the development of various neurodegenerative diseases. The aim of the work is to summarize the known knowledge about the regulation of the glymphatic system and its influence on the development and prevention of neurodegenerative...
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Behavioral phenotype of APPswe/PSEN1dE9 mice model of Alzheimer's disease and a role of parvalbumin interneurons
Klausová, Tereza ; Svoboda, Jan (advisor) ; Telenský, Petr (referee)
Alzheimer's disease is a notable burden to the contemporary society concerning not only healthcare but also economy. Its aetiology remains unknown, but we know the mechanisms of pathogenesis, which allow us to create animal models (especially mice). In this thesis, we investigate the behavioral phenotype of the frequently used APPswe/PSEN1 murine model. We find that neither six-month-old nor ten-month-old animals show impairment in anxiety (open field test and elevated plus maze) or social behavior tests (three chambre test and social interaction test) compared to controls. However, the prepulse inhibition test revealed that PPI completely disappear in Alzheimer mice, indicating a significant aberration in sensorimotoric gating. The second part of this thesis focuses on a chemogenetic study of the role of parvalbumin interneurons in Alzheimer's disease and the effect of their excitation on sociability, social memory and sensorimotor gating. Here we use the aforementioned model crossed with Pv-Cre mice, which allowed us to introduce Cre-dependent DREADDs and in this group of animals we investigated social behaviour and the presence of disturbances in sensorimotor gating. However, the results obtained so far do not provide any evidence for an effect of parvalbumin interneuron excitation on animal...
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Intergenerational Solidarity in the Care of People with Alzheimer´s Disease
DUŠKOVÁ, Miluše
This bachelor thesis deals with intergenerational solidarity in the context of Alzheimer's care. It includes an introduction to the disease itself and the concept of intergenerational solidarity. The main aim is to explore perceptions of this solidarity among the different groups involved in care - carers, family members and young adults. The thesis is structured in four parts: theoretical introduction, research methodology, presentation of results and final discussion. It focuses on new insights into intergenerational solidarity in the context of Alzheimer's disease and contributes to the further development of discussion and research in this area.
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Social work with people with Alzheimer's disease
ŠTĚPÁNKOVÁ, Jitka
The thesis concerns mapping and analysing the home-based health care for people affected by Alzheimer's disease and focuses especially on coping with the role of a caregiver. Alzheimer's disease is a serious social and medical topical issue as the number of people suffering from this disease is constantly increasing and our society is yet unable to clearly identify its cause. The thesis is dived into two parts. The theoretical part describes the disease itself, the care about people with Alzheimer's disease, and social work with people suffering from Alzheimer's disease and their families. For the practical part I chose to carry out a research survey conducted through interviews with home carers.
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Mechanisms of comorbidity of metabolic and neurodegenerative diseases
Tauchman, Martin ; Telenský, Petr (advisor) ; Brožka, Hana (referee)
In Czechia, number of people with neurodegenerative diseases is in the hundreds of thousands, and the lifetime health care costs and social impact of each patient's disease reach hundreds of thousands of euros, but these costs could be reduced by early and effective intervention. Its correct implementation could be helped by knowledge of causal links between neurodegenerative and metabolic diseases, whose prevalence is correlated in the population. One of the important factors is an increased pro-inflammatory immune response. In people with obesity and type 2 diabetes mellitus, systemic inflammation evolves into neuroinflammation, which subsequently leads to neurodegeneration. Another mechanism is hyperglycaemia, which is a consequence of insulin resistance. Hyperinsulinaemia and hyperglycaemia lead to impaired expression of glucose transporters and insulin-degrading enzyme, resulting in reduced clearance of amyloid beta. Genetic background is also recognized as a highly influential factor, affecting various mechanisms in both beneficial and harmful ways. Lifestyle is also an important factor. In general, smoking and alcohol consumption are harmful to health. Both increased consumption of alcoholic beverages and smoking tobacco products can lead to metabolic disorders as well as neurodegeneration. On the...
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