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Beneficial Effects of 11β-HSD1 Inhibition on Cognitive Performance in a Mouse Model of Alzheimer's Disease
Červinková, Tereza ; Červený, Lukáš (advisor) ; Musílek, Kamil (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Candidate: Tereza Červinková Supervisor: PharmDr. Lukáš Červený, Ph.D. Title: Beneficial Effects of 11β-HSD1 Inhibition on Cognitive Performance in a Mouse Model of Alzheimer's Disease The increased life expectancy goes hand in hand with ageing-related cognitive impairments. Alzheimer's disease (AD) is the most common type of dementia being an irreversible and progressive brain disorder with loss of cognitive functions. Recent studies suggest that excess of glucocorticoid (GC) action exerts deleterious effects on the hippocampus and causes impaired spatialmemory. In addition, it has been demonstrated that aged mice with cognitive deficits show increased gene expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in the hippocampus and parietal cortex. The Senescence-Accelerated Mouse Prone 8 (SAMP8) strain is a spontaneous animal model of accelerated ageing. Many studies indicate that SAMP8 harbour the behavioural and histopathological signatures of AD. In the present study, we evaluated the neuroprotective effects of 11β-HSD1 inhibition by a potent pyrrolidine-based compound RL-118 and/or effects of diet on cognitive performance in different groups of SAMP8 by conducting behavioural and...
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Beneficial Effects of 11β-HSD1 Inhibition on Cognitive Performance in a Mouse Model of Alzheimer's Disease
Červinková, Tereza ; Červený, Lukáš (advisor) ; Musílek, Kamil (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Candidate: Tereza Červinková Supervisor: PharmDr. Lukáš Červený, Ph.D. Title: Beneficial Effects of 11β-HSD1 Inhibition on Cognitive Performance in a Mouse Model of Alzheimer's Disease The increased life expectancy goes hand in hand with ageing-related cognitive impairments. Alzheimer's disease (AD) is the most common type of dementia being an irreversible and progressive brain disorder with loss of cognitive functions. Recent studies suggest that excess of glucocorticoid (GC) action exerts deleterious effects on the hippocampus and causes impaired spatialmemory. In addition, it has been demonstrated that aged mice with cognitive deficits show increased gene expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in the hippocampus and parietal cortex. The Senescence-Accelerated Mouse Prone 8 (SAMP8) strain is a spontaneous animal model of accelerated ageing. Many studies indicate that SAMP8 harbour the behavioural and histopathological signatures of AD. In the present study, we evaluated the neuroprotective effects of 11β-HSD1 inhibition by a potent pyrrolidine-based compound RL-118 and/or effects of diet on cognitive performance in different groups of SAMP8 by conducting behavioural and...
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Lochman, Lukáš ; Nováková, Veronika (advisor) ; Musílek, Kamil (referee) ; Kubát, Pavel (referee)
Charles University, Faculty of Pharmacy in Hradec Kralove Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Mgr. Lukas Lochman Supervisor: Doc. PharmDr. Veronika Novakova, Ph.D. Advisor: Doc. PharmDr. Petr Zimcik, Ph.D. Doctoral Thesis: Study of recognition moieties of sensoric azaphthalocyanines Azaphthalocyanines (AzaPcs) are planar macrocyclic compounds with unique photophysical properties like absorption and emission over 650 nm and high quantum yields of fluorescence. Alkylamine substituted AzaPcs have been shown to undergo an ultrafast intramolecular charge transfer (ICT) which is responsible for efficient quenching of excited states (nonfluorescent OFF state). ICT occurs between donor (peripheral amine) and acceptor (macrocyclic core). Blocking of ICT leads to restoration of high fluorescence emission (fluorescent ON state) which is the competitive relaxation pathway. There are two known possible ways how to block ICT in AzaPcs sofar: By protonation of donor in pH sensitive AzaPc sensors or by coordination of metal cation into the recognition moiety resulting in cation sensitive AzaPc sensors. Above-mentioned properties predestinate AzaPcs to become new fluorescent sensors with good brightness and advantageous absorption and emission of red light deep...
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Study of recognition moieties of sensoric azaphthalocyanines
Lochman, Lukáš ; Nováková, Veronika (advisor) ; Musílek, Kamil (referee) ; Kubát, Pavel (referee)
Charles University, Faculty of Pharmacy in Hradec Kralove Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Mgr. Lukas Lochman Supervisor: Doc. PharmDr. Veronika Novakova, Ph.D. Advisor: Doc. PharmDr. Petr Zimcik, Ph.D. Doctoral Thesis: Study of recognition moieties of sensoric azaphthalocyanines Azaphthalocyanines (AzaPcs) are planar macrocyclic compounds with unique photophysical properties like absorption and emission over 650 nm and high quantum yields of fluorescence. Alkylamine substituted AzaPcs have been shown to undergo an ultrafast intramolecular charge transfer (ICT) which is responsible for efficient quenching of excited states (nonfluorescent OFF state). ICT occurs between donor (peripheral amine) and acceptor (macrocyclic core). Blocking of ICT leads to restoration of high fluorescence emission (fluorescent ON state) which is the competitive relaxation pathway. There are two known possible ways how to block ICT in AzaPcs sofar: By protonation of donor in pH sensitive AzaPc sensors or by coordination of metal cation into the recognition moiety resulting in cation sensitive AzaPc sensors. Above-mentioned properties predestinate AzaPcs to become new fluorescent sensors with good brightness and advantageous absorption and emission of red light deep...
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Inhibitors of mitochondrial enzymes as potential therapeutics for Alzheimer's disease
Hroch, Lukáš ; Musílek, Kamil (advisor) ; Farsa, Oldřich (referee) ; Zimčík, Petr (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Lukáš Hroch Supervisor assoc. prof. PharmDr. Kamil Musílek, Ph.D. Title of Doctoral Thesis Inhibitors of mitochondrial enzymes as potential therapeutics for Alzheimer's disease There were about 50 million people living with dementia in 2015. It is expected that number of people living with dementia will reach 130 million by the year of 2050. Alzheimer's disease (AD) is one of the most common causes of dementia and it is estimated to account for about 60 80% of overall cases. Current symptomatic treatment only alleviates symptoms and delays progression of the disease. However, there is no effective treatment, which would address the underlying cause of AD. The extracellular depositions of insoluble amyloid beta peptide (Aβ) were thought to be a causative factor and main target for a long time. Yet, targeted treatment towards the reduction of extracellular Aβ depositions failed to show expected therapeutic merit. Later on, it has been shown that development of AD starts much earlier than any Aβ plaques or symptoms could be observed. With growing evidence of soluble Aβ in intracellular regions, main attention moved to investigations of Aβ within the cells. Aβ...
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Influence of structural aspects on photophysical properties at phthalocyanines
Cidlina, Antonín ; Zimčík, Petr (advisor) ; Musílek, Kamil (referee) ; Lang, Kamil (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Drug Control Candidate: Mgr. Antonín Cidlina Supervisor: doc. PharmDr. Petr Zimčík, Ph.D. Consultant: doc. PharmDr. Veronika Nováková, Ph.D. Title of the Thesis: Influence of structural aspects on photophysical properties at phthalocyanines Phthalocynines (Pc) and their aza-analoues tetrapyrazinoporphyrazines (TPyzPz) are macrocyclic compounds with 18 delocalized π-electrons. The large conjugated system of double bonds imparts them unique spectral, photophysical and electronic properties which can be tuned by peripheral substitution or/and central metal cation. They found their use in several areas such as photodynamic therapy, catalyst, liquid crystals and solar cells. The first part of this doctoral thesis describes the influence of structural aspects on effectiveness of intramolecular charge transfer (ICT) at TPyzPz. ICT is responsible for considerable decrease of photophysical parameters of TPyzPz - quantum yields of singlet oxygen () and fluorescence (F). At first, we focused on the effect of the electronic properties of peripheral substituents attached on macrocycle core on ICT efficiency in TPyzPz. The series of TPyzPz with various peripheral substituents was designed and...
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Inhibitors of mitochondrial enzymes as potential therapeutics for Alzheimer's disease
Hroch, Lukáš ; Musílek, Kamil (advisor) ; Farsa, Oldřich (referee) ; Zimčík, Petr (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Lukáš Hroch Supervisor assoc. prof. PharmDr. Kamil Musílek, Ph.D. Title of Doctoral Thesis Inhibitors of mitochondrial enzymes as potential therapeutics for Alzheimer's disease There were about 50 million people living with dementia in 2015. It is expected that number of people living with dementia will reach 130 million by the year of 2050. Alzheimer's disease (AD) is one of the most common causes of dementia and it is estimated to account for about 60 80% of overall cases. Current symptomatic treatment only alleviates symptoms and delays progression of the disease. However, there is no effective treatment, which would address the underlying cause of AD. The extracellular depositions of insoluble amyloid beta peptide (Aβ) were thought to be a causative factor and main target for a long time. Yet, targeted treatment towards the reduction of extracellular Aβ depositions failed to show expected therapeutic merit. Later on, it has been shown that development of AD starts much earlier than any Aβ plaques or symptoms could be observed. With growing evidence of soluble Aβ in intracellular regions, main attention moved to investigations of Aβ within the cells. Aβ...
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Derivatives of pyrazine as potential antituberculars (preparation and study of biological properties)
Janďourek, Ondřej ; Doležal, Martin (advisor) ; Farsa, Oldřich (referee) ; Musílek, Kamil (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical chemistry and Pharmaceutical analysis Candidate Mgr. Ondřej Janďourek Supervisor Prof. PharmDr. Martin Doležal, Ph.D. Consultant PharmDr. Jan Zitko, Ph.D. Title of Doctoral Thesis Derivatives of pyrazine as potential antituberculars (preparation and study of biological properties) This work is focused on pyrazine derivatives with the structural relationship to pyrazinamide (PZA) and with the potential antitubercular effect. In the introduction, there are summarized theoretical findings about tuberculosis (TBC), its epidemiology and primarily the development of resistance to current pharmacotherapy. Brief overview of known antituberculars, novel compounds and auspicious molecules in clinical trials is outlined. PZA, which is counted among the first line antitubercular agents, is widely described due to its cardinal role in this thesis. PZA possible mechanisms of action are described together with its pharmacological profile. Finally, brief summary of already prepared derivatives of PZA is stated. Practical part of this thesis is focused on synthesis of three starting compounds (5-chloro-6-methylpyrazine-2,3-dicarbonitrile; 3-chloropyrazine-2-carboxamide; N-benzyl-3-chloropyrazine-2-carboxamide) that were...
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Alkylamino- Derivatives of Pyrazinamide as Potential Antituberculotic Drugs
Mlčoch, Michal ; Zitko, Jan (advisor) ; Musílek, Kamil (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Drug Control Candidate: Mgr. Michal Mlčoch Supervisor: Mgr. Jan Zitko, Ph.D. Title of candidate thesis: Alkylamino- derivatives of pyrazinamide as potential antituberculotic drugs This thesis is a result of intention to prepare potential effective derivatives from pyrazinamide (PZA) structure. These results contribute to enrichment of the research of new antituberculars (antiTBC) which has been carried out at the Dpt. of Pharmaceutical Chemistry and Drug Control at the Faculty of Pharmacy in Hradec Králové. The aim of the research to produce the new effective antituberculars is supported by the contemporary state of tuberculosis in the world. This state is closely described in this thesis. Despite of decreasing number of new cases in all six WHO regions, spreading of this infectious disease is not under the control. The main reason is a resistance formation of new mycobacterial strains which can cause hardly treatable cases. The prepared substances are PZA derivatives which represent one of the most important first line drugs for tuberculosis treatment. The latest research focused on mechanism of PZA showed new information which was included in this thesis. Furthermore, some...
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Design and synthesis of tacrine-quinone hybrids as multitarget ligands against Alzheimer's disease
Nepovimová, Eugenie ; Opletalová, Veronika (advisor) ; Musílek, Kamil (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Eugenie Nepovimová Supervisor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of Thesis: Design and synthesis of tacrine-quinone hybrids as multi-target ligands against Alzheimer's disease Alzheimer's disease (AD) is a multifactorial progressive neurodegenerative disorder that manifests as memory loss, personality changes, global cognitive dysfunction, and functional impairment. It is the leading cause of dementia in aged humans. Nowadays, there are no effective preventative measures, definitive diagnostic guidlines, or curative therapy for AD, its precise ethiology, too, remains unknown. To date, the pharmacotherapy of AD has relied on acetylcholinesterase (AChE) inhibitors - donepezil, rivastigmine and galantamine - and, more recently, on an N-methyl-D- aspartate (NMDA) receptor antagonist - memantine. Cholinesterase inhibitors enhance cholinergic transmission directly by inhibiting AChE which hydrolyses acetylcholine. Furthermore, it has been demonstrated that AChE plays an important role in Aβ-aggregation during the early stages of senile plaque formation, one of the hallmarks of AD. Therefore, AChE inhibition represents a critical target for the effective...
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