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Steroid metabolome and multiple pregnancy
Černý, Andrej ; Pařízek, Antonín (advisor) ; Hubka, Petr (referee) ; Kiss, Imrich (referee)
Steroid hormones can be divided into 2 groups - intracellular and extracellular, depending on location of their activity. Intracellular ones influence expression of genes while acting as transcription factors. This so-called genomic effect is very slow. Extracellular (non-genomic) steroids bind to neurotransmitter receptors located on the cytoplasmic cell membrane and thus affect ionic channels permeability. Their effect is faster. We refer to them as neuroactive steroids (produced in different body tissues or administered externally) or neurosteroids (synthetized in nervous system cells). Some neuroactive steroids and their metabolites (e.g. progesterone) are crucial in stabilizing the pregnancy. Other steroid disorders play their role in wide spectre of pregnancy complications, such as preterm labor, preeclampsia, intrahepatic cholestasis in pregnancy etc. Our scientific interest in collaboration with the Department of Steroids and Proteofactors of the Institute of Endocrinology in Prague is focused on investigation of multiple pregnancies in term of steroid metabolome. Studies conducted so far have not provided a comprehensive analysis of steroidome within mothers and fetuses of multiple pregnancies. The aim of our research is to clarify the relationship between fetuses and mother from the point...
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The study of functional and pharmacological properties of glutamate receptors
Kysilov, Bohdan ; Vyklický, Ladislav (advisor) ; Valeš, Karel (referee) ; Novotný, Jiří (referee)
N-methyl-D-Aspartate receptors (NMDAR) are ionotropic glutamate receptors that are involved in the regulation of nearly every process in the brain. Therefore, even a subtle disturbance in NMDAR function may result in severe pathological consequences. Loss-of- function mutations in the NMDAR-encoding genes have been implicated in numerous neuropsychiatric disorders, including intellectual disability, developmental delay, schizophrenia, autism spectrum disorders, epilepsy, and movement disorders. Insufficient NMDAR function can be rectified by positive allosteric modulators, including neurosteroids; however, the mechanism underlying the potentiating effect of steroids is not well understood. By employing patch-clamp electrophysiology we assessed the effect of newly synthesized neurosteroid-like pregnane analogues on recombinant GluN1/GluN2B receptors. We demonstrated that compounds with short C3 residues, such as pregnanolone acetate (PA- Ace) and pregnanolone carboxylate (PA-Car), are negative modulators of NMDAR, whereas compounds with longer C3 residues, such as pregnanolone butyrate (PA-But) and epipregnanolone butyrate (EPA-But), are positive modulators of NMDARs. Furthermore, we revealed that EPA-But has a disuse-dependent positive allosteric effect, being similar in that regard to endogenous...
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Effects of allopregnanolon on motor functions of young laboratory rat.
Krejčí, Lukáš ; Mareš, Pavel (advisor) ; Valeš, Karel (referee)
Allopregnanolone is a typical representative of neurosteroids. It can be formed by de novo synthesis directly in the CNS or as a metabolite of progesterone. It is an allosteric modulator of GABAA receptors, due to which it has anxiolytic, sedative and anticonvulsant effects. This work investigates the effect of allopregnanolone (ALLO) on the locomotor skills of laboratory rat pups. The results will serve as a reference study for the work of Tereza Košťálová (2020), who investigated the newly discovered neuroactive steroid pregnanolone pyroglutamate (PPG). This exogenous steroid, synthesized at the Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic (IOCB PRAGUE), offers potential use in the treatment of epilepsy. Our goal was to perform the same battery of motor tests after the application of allopregnanolone as a comparison, to what extent and in what way these two substances acutely affect the motor performance of the rat pup. The theoretical part of the thesis describes the physiological mechanisms of neurosteroids in the human body and their potential in the treatment of serious diseases, especially epilepsy. Next, the ontogenetic development of the rat's motor skills is described and compared to humans. The methodology describes the selection and...
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Neuroactive steroids and addictions
Jandíková, Hana ; Vondra, Karel (advisor) ; Miovský, Michal (referee) ; Kršek, Michal (referee)
Neuroactive steroids are a group of steroid hormones which act non-genomically to influence the neuron excitability of neuronal synapses. Addictive substances can interfere with the synthesis of neuroactive steroids through many mechanisms, affecting their levels and changing their functionality. At the same time, neuroactive steroids play a role in the development of addiction, since their levels change during attempts to quit and therefore affect the success of treatments for addiction. This study focuses on the relationships between individual addictive substances and neuroactive steroids, the individual functional mechanisms and how they influence each other. It is generally known that addictive substances result in the release of anxiolytics that act on neuroactive steroids. This plays a role in the development of addiction. We also describe in detail the effect of smoking on steroid hormones and the endocrine system in general. Using tobacco addition as a model, we studied the relationship between addiction and neuroactive steroids. As part of my doctoral studies we performed a prospective study that followed changes in the steroid spectra induced by smoking as well as when quitting smoking. We also developed a predictive model to predict the likelihood of success in treating tobacco...
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