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Effects of sulfated neurosteroids on proteins involved in excitatory synaptic transmission
Naimová, Žaneta ; Smejkalová, Terézia (advisor) ; Mrózková, Petra (referee)
The discovery of steroid compounds capable of synthesize or accumulation in CNS and PNS led to a question about their function. Neurosteroid compounds are capable of modulating synaptic transmission. Effect is direct and fast mediated through nongenomic mechanisms. They are known to affect wide array of channels and receptors - both excitatory and inhibitory. This thesis summarizes findings about effect of sulfated neurosteroid on proteins involved in excitatory synaptic transmission. Thesis covers findings about ionotropic glutamate receptors, TRP channels, metabotropic receptors, sodium and potassium channels. Excessive or insufficient activity of these proteins involved in synaptic transmission can lead to a pathological condition. The purpose of this thesis is to summarize findings about effect of these compounds, point out structural and function characteristic probably responsible for their action and to outline possible pharmacological usage.
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Effects of NMDA receptor modulators on cell death in models of excitotoxicity in vitro.
Strnadová, Lenka ; Smejkalová, Tereza (advisor) ; Skřenková, Kristýna (referee)
NMDA receptors are ionotropic glutamate receptors (iGluR) activated by the amino acid glutamate and mediating signal transmission in the central nervous system. Their proper activity is essential for synaptogenesis, neuronal plasticity and synaptic transmission. However, excessive activation of NMDAR causes strong influx of calcium ions into neurons which triggers several destructive effects, eventually ending with cell death. This so-called excitotoxicity is present not only in many neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease, but also in acute pathophysiological conditions, such as stroke or traumatic brain injury. General NMDAR inhibitors that could potentially prevent neuronal excitotoxicity have shown severe negative side effects in models in vivo. On the other hand, selective inhibitors of NMDA receptors with the ability to block the unwanted excessive activity while preserving NMDAR physiological function have shown to be therapeutically useful. This work is going to briefly summarize the knowledge of structure, activation and localization of NMDA receptors, then it is going to describe their rule in mediating neuronal toxicity and a few methods we can use to study excitotoxicity in vitro. Finally, this work will compare the effects of several known NMDAR...
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Effects of sulfated neurosteroids on proteins involved in excitatory synaptic transmission
Naimová, Žaneta ; Smejkalová, Terézia (advisor) ; Mrózková, Petra (referee)
The discovery of steroid compounds capable of synthesize or accumulation in CNS and PNS led to a question about their function. Neurosteroid compounds are capable of modulating synaptic transmission. Effect is direct and fast mediated through nongenomic mechanisms. They are known to affect wide array of channels and receptors - both excitatory and inhibitory. This thesis summarizes findings about effect of sulfated neurosteroid on proteins involved in excitatory synaptic transmission. Thesis covers findings about ionotropic glutamate receptors, TRP channels, metabotropic receptors, sodium and potassium channels. Excessive or insufficient activity of these proteins involved in synaptic transmission can lead to a pathological condition. The purpose of this thesis is to summarize findings about effect of these compounds, point out structural and function characteristic probably responsible for their action and to outline possible pharmacological usage.
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Simulation of the interaction of steroid allosteric modulators of NMDA receptors with membrane
Riedlová, Kamila ; Konopásek, Ivo (advisor) ; Novák, Josef (referee)
Molecular dynamics (MD) method allows the real-time monitoring of the system composed of molecules and atoms, such as phospholipid bilayer or biomolecule. Applications of MD are very common in drug design where the real experimental procedures could be much more financially- and time-consuming or even impossible. The aim of this project is to explain the applications and advantages of MD method in case of studies of lipid membranes, with a special emphasis on a study od neurosteriod behaviour in lipid bilayer. Properly designed and synthesized neurosteroids could be used for the treatment of the serious neurological diseases. This work also included the experimental data obtained by MD simulations for two neurosteroids - pregnanolone glutamate and pregnanolone sulphate. Behaviour of this molecules in model membranes was observed and analyzed by MD simulations. Key words: molecular dynamics simulation, model membrane, lipid bilayer, NMDA receptor, neurosteroids, pregnanolone glutamate, pregnanolone sulfate
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