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The importance of NMDA antagonists in animal models of ischemic injury and major depressive disease
Kletečková, Lenka ; Valeš, Karel (advisor) ; Zach, Petr (referee) ; Ježek, Karel (referee)
Glutamatergic system is the main excitatory system and glutamatergic receptors are the most abundantly expressed in whole central nervous system. The most widespread type of glutamatergic receptors are N-methyl-D-aspartate (NMDA) receptors which are essential for physiological development of nervous tissue, synaptic plasticity and cognitive processes. On the other hand, over-activation of these receptors leads to excitotoxic damage of nervous tissue and serious neurological consequences for future quality of life. Disruption of glutamatergic system is common feature for hypoxic-ischemic damage, traumatic brain injury, neurodegenerative and neuropsychiatric diseases. Therefore glutamatergic system and specifically NMDA receptors are an attractive target for neuropharmacological research. Presented thesis explores the effect of several molecules with modulating inhibiting effect on NMDA receptor. Work is preferentially focused on application research; the main aim is evaluated therapeutic potential of studied compounds. First group of compounds is represented by neuroactive steroids pregnanolone glutamate and pregnanolone hemipimelate, which are allosteric inhibitors of NMDA receptor. Here, their neuroprotective effect is demonstrated in hypoxic-ischemic and excitotoxic damage of nervous tissue....
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Regulation of NMDA receptor trafficking in mammalian cells
Hemelíková, Katarína ; Horák, Martin (advisor) ; Novotný, Jiří (referee) ; Valeš, Karel (referee)
N-methyl-D-aspartate (NMDA) receptors are a subclass of glutamate receptors that play an essential role in mediating excitatory neurotransmission and synaptic plasticity in the mammalian central nervous system (CNS). The activation of NMDA receptors plays a key role in brain development and memory formation. Abnormal regulation of NMDA receptors plays a critical role in the etiology of many neuropsychiatric disorders. NMDA receptors form a heterotetrameric complex composed of GluN1, GluN2(A-D) and GluN3(A, B) subunits. The NMDA receptors surface expression is regulated at multiple levels including early processing (synthesis, subunit assembly, endoplasmic reticulum (ER) processing, intracellular trafficking to the cell surface), internalization, recycling and degradation. NMDA receptors are regulated by the availability of GluN subunits within the ER, the presence of ER retention and export signals, and posttranslational modifications including phosphorylation and palmitoylation. However, the role of N-glycosylation in regulating of NMDA receptor processing has not been studied in detail. The aim of this study was to clarify the mechanisms of regulation of surface expression and functional properties of NMDA receptors. We used a combination of molecular biology, microscopy, biochemistry and...
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Molecular mechanisms of action of antidepressants.
Brenišin, Martin ; Hejnová, Lucie (advisor) ; Valeš, Karel (referee)
Depression is a widely spread medical illness which affects people's thoughts, moods, physical health and general quality of their lives. Typical symptoms of this disorder are bad mood, lack of energy, sadness, insomnia or disability to feel happiness and enjoy life. Most people have encountered depression either directly or indirectly, through their family members or close friends. Number of patients with major depressive disorder grows globally every year. As much as half of the patients have got suicidal thoughts during their depressive episode while a quarter of them have tried to commit suicide. Therefore, the treatment of depression is very important. Antidepressants represent a large group of drugs focused on that treatment. Nowadays, there is a lot of antidepressants with different mechanism of action, their main effect being the increase in levels of monoamine neurotransmitters in brain. Selective reuptake inhibitors achieve this by blocking transporters of said neurotransmitters. Another type of antidepressants inhibits the activity of monoamine oxidase, which degrades serotonin, noradrenaline and dopamine. This paper reviews basic knowledge about main types of antidepressants and their mechanism of action. Key words: antidepressants, serotonin, depression, noradrenaline, monoamine...
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The role of aging and stress in autophagy
Čechová, Kateřina ; Vrajová, Monika (advisor) ; Valeš, Karel (referee)
Autophagy is a nonspecific catabolic mechanism, important for maintaining the cellular homeostasis. Stress condition can increase the activity and support the cell survival. It is well known that normal and pathological aging are associated with a reduced autophagic potential and that experimental induction of autophagy leads to higher longevity of certain model organisms. This decreasing may be facilitated by other factors, such as chronic stress. Higher age and chronic stress are two factors contributing to the development of neurodegenerative diseases, in this context the mechanism of autophagy is now actively studied. We wanted to know if and how the combination of these two factors may influence the activity of autophagy. In our study, we investigated the role of aging and chronic stress, induced by social isolation in Wistar rats at the age of 6 (N= 16) and 12 (N= 16) months. The animals in experimental groups were separated in the individual cages for 4 weeks. Control groups animals were housed in the pair. We measured the markers of autophagy expression (Beclin-1, LC3-II, mTOR) in the hippocampus and striatum of socially isolated and control groups animals. We measured the expression of NMDA receptor subunits (NR1, NR2A, NR2B) in the hippocampus of the same animals. Our results showed that older...
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Determination of critical developmental periods for effects of methamphetamine on rat behavior in adulthood
Hrebíčková, Ivana ; Šlamberová, Romana (advisor) ; Cendelín, Jan (referee) ; Valeš, Karel (referee)
Aim: The aim of the Ph.D. thesis was to find out which of the neuro-ontogenetic stages of laboratory rat is more significant for the methamphetamine (MA) exposure on the behavior in adulthood and to determine a critical developmental period for the effects of this drug. In the experimental part of the study was to test the influence of prenatal and neonatal MA exposure on behavior, social interaction, cognition and drug-seeking behavior in adulthood. Methods: Adult female rats were exposed to MA (5 mg/ml/kg) or saline (S) (1 mg/kg) during different stages of gestation and lactation. The tested substances were administered subcutaneously during the first half of gestation (ED 1-11), the second half of gestation (ED 12-22) or during early lactation (PD 1-11). The effect of prenatal MA exposure was transmitted to pups via placental barrier; the effect of MA exposure during early lactation was transmitted via the breast milk. In order to compare the rate of drug transmission by indirect MA exposure via the breast milk, we chose another group of offspring that we administered the tested substances directly subcutaneously during the same application period (PD 1-11). In this way we obtained 8 groups of exposed pups: ED 1-11 MA, S; ED 12-22 MA, S; PD 1-11 indirectly MA, S; PD 1-11 directly MA, S. These...
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Motor development after repeated dosing of AMPA receptors antagonist in laboratory rats
Hanzalová, Jitka ; Mareš, Pavel (advisor) ; Valeš, Karel (referee)
Substance IEM 1460 is an antagonist of AMPA receptors in the brain. It is a derivative of adamantine, which has already been tested in several studies as a potential age-related anticonvulsant. In the research part of the thesis there is a summary of the knowledge about receptors, focusing on AMPA receptors, IEM 1460, epilepsy and ontogenetic development of laboratory rat. The research section evaluates the effect of IEM 1460 on motor skills of a rat in a few postnatal days of its life. To evaluate spontaneous animal motor skills, Open-Field tracking was used, and several specific tests were used to evaluate provoked motor skills. A total of 30 animals were included in the research. Substances (IEM 1460 at 3 mg / kg, IEM 1460 at 10 mg / kg or 2 ml / kg saline) were infused intraperitoneally on five consecutive days (ages P7-P11) and the animals were repeatedly tested at age 12, 15, 18, 21, 25, 31 and 60 days. In this study, IEM 1460 has not been shown to have significant effect on the gross rat motor skills and therefore the substance remains as a serious candidate for age-specific antiepileptic drugs.
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Assessment of the impact of phenytoin on motor activity development of laboratory rats by motor activity testing and swimming analysis
Matoušková, Kateřina ; Mareš, Pavel (advisor) ; Valeš, Karel (referee)
Phenytoin is well-known antiepileptic drug with high anticonvulsant effect but also with proven side effects on motor activities associated with its long-term use. This thesis summarizes side effects of phenytoin on motor skills and coordination of rats after acute phenytoin treatment. Theoretical part includes proven effects of phenytoin on human and animal model. Knowledge about motor skills development of rats and comparison with human motor skills development is also included in the thesis. Apart from locomotion development, swimming development is also described. We compared three groups of rats in the experiment. Each group consisted of ten rats. We compared group with dosage 60 mg/kg, 30 mg/kg, control group and vehicle group. Each group was tested before application for control. We tested animals on postnatal day 12, 18 and 25. Effects of phenytoin were evaluated by motor skills testing and swimming analyses. The results of this thesis have proved impaired motor skills and coordination after phenytoin treatment of 12 and 25 days old rats.
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Animal model of schizophrenia and time-space integration in the role of AAPA
Janďourková, Pavla ; Nekovářová, Tereza (advisor) ; Valeš, Karel (referee)
Temporal and spatial cognition constitute basic elements of the cognitive function. Both of these competences are important for the individual's orientation and survival and there are likely to be different interactions between them. Perception of time, unlike spatial navigation and memory, is less explored. Impairments of interval timing occur in many neurodegenera- tive and neuropsychiatric disorders. According to current studies it is evident that timing is impaired even in patients with schizophrenia, but the results are still ambiguous. The aim of our work was to test the AAPA task in the time-place integration in the ani- mal model of schizophrenia. In the future, it could help to clarify the impairments of the time perception in patients with schizophrenia. In contrast to the classic AAPA task, our version included alternating of phases of light and darkness. The assumption of the experiment was that the solution of the task by rats in the dark is more dependent on the timing strategy than the solution of the task during the light, which is dependent on the spatial orientation. In the first phase of the experiment, the rats adopted both strategies - spatial (during the light phase of the session) and timing (during the dark phase). In the next phase of the experiment, we tested the animal...
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