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The role of SGIP1 protein interaction with cannabinoid receptor 1 in nociception under pathological conditions.
Dresslerová, Denisa ; Špicarová, Diana (advisor) ; Zímová, Lucie (referee)
The cannabinoid receptor type 1 (CB1) is a component of the endocannabinoid system and is abundantly expressed in the central nervous system. CB1 receptor has been extensively studied primarily due to its inhibitory role in neurotransmitter release from presynaptic terminals, and this process subsequently modulates postsynaptic currents and postsynaptic neuron excitation. Its interaction with the Src homology domain 3 growth factor 2 receptor binding protein (SGIP1) has recently been investigated in the context of nociception modulation (Hájková et al., 2016b). However, the role of this CB1 regulatory protein, SGIP1, in pathological pain conditions has not yet been described. Clarification of the role of SGIP1 interaction with CB1 receptor may help future research based on the use of cannabinoids as potential therapeutics. The thesis is structured into two parts, theoretical and practical. In the theoretical part of the thesis, knowledge of the given topic is summarized. First, pain is described from an anatomical-physiological perspective, followed by a description of the endocannabinoid system, where a part is dedicated to the CB1 cannabinoid receptor itself, and then another part is dedicated to the SGIP1 protein and its interaction with the CB1 receptor. In the practical part, the role of SGIP1...
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Molecular mechanism of Cannabinoid receptor 1 regulation by SGIP1
Dvořáková, Michaela ; Blahoš, Jaroslav (advisor) ; Konvalinka, Jan (referee) ; Stuchlík, Aleš (referee)
Molecular mechanism of Cannabinoid receptor 1 regulation by SGIP1 Abstract Src homology 3-domain growth factor receptor-bound 2-like endophilin interacting protein 1 (SGIP1) has been identified as an interacting partner of cannabinoid receptor 1 (CB1R). Their protein-protein interaction was confirmed by co-immunoprecipitation. SGIP1 hinders the internalization of activated CB1R and modulates its signaling in HEK293 cells. Employing whole-cell patch-clamp electrophysiology, we have shown that SGIP1 affects CB1R signaling in autaptic hippocampal neurons. Using a battery of behavioral tests in SGIP1 constitutive knock-out (SGIP1-/- ) and WT mice, we investigated the consequences of SGIP1 deletion on behavior regulated by the endocannabinoid system. In SGIP1-/- mice, exploratory levels, working memory and sensorimotor gating were unaltered. SGIP1-/- mice showed decreased anxiety-like and depressive-like behaviors. Fear extinction to tone was enhanced in SGIP1-/- females. Several cannabinoid tetrad behaviors were altered in the absence of SGIP1. SGIP1-/- males exhibited abnormal THC withdrawal behaviors. SGIP1 deletion also reduced acute nociception, and SGIP1-/- mice were more sensitive to antinociceptive effects of CB1R agonists and morphine. CB1R-SGIP1 interaction results in profound modification of CB1R...
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The effect of endocannabinoid system on light entrainment of rat circadian system
Filipovská, Eva ; Bendová, Zdeňka (advisor) ; Balík, Aleš (referee)
Circadian system of mammals is generated in suprachiasmatic nuclei of hypothalamus. This system is synchronized with light conditions through phase shifts that occur after light exposition during the subjective night. Recent studies have shown that activation of endocannabinoid receptors attenuates the light-induced phase shifts and influences the ability of circadian system to light entrainment. The aim of this work is to examine this influence on behavioral level and on light-reactive cellular processes within the suprachiasmatic nuclei. Our results show that the activation of endocannabinoid system via CB1 receptor agonist modulates the light-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and the expression of c-Fos protein in neurons of suprachiasmatic nuclei in the rat's brain; these cellular processes correlate with the attenuation of light entrainment. Keywords: circadian system, suprachiasmatic nuclei, light entrainment, endocannabinoid system, CB1 receptors, extracellular signal-regulated kinase 1/2, ERK1/2, c-Fos
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Dysregulation of the endocannabinoid system in obesity and its modulation by dietary omega-3 fatty acids
Kalendová, Veronika ; Rossmeisl, Martin (advisor) ; Hlaváčková, Markéta (referee)
Obesity is associated with metabolic complications including insulin resistance, dyslipidemia and hypertension (metabolic syndrome). The endocannabinoid system (ECS) activity is elevated in obesity, which can further potentiate metabolic impairments. Pharmacological treatment based on the cannabinoid receptor CB1 blockade led to a decrease in body weight and significant improvements of metabolic parameters in obese individuals. However, parallel effects on the central nervous system resulted in unwanted side-effects including anxiety and depressive moods. Recent experimental studies suggested that dietary interventions with omega-3 polyunsaturated fatty acids of marine origin (EPA, DHA) can decrease the ECS activity in peripheral tissues (adipose, liver, pancreas), and thus partially protect against metabolic disturbances in obesity. One of the underlying mechanisms behind the effects of EPA and DHA could be a replacement of arachidonic acid from the sn-2 position of membrane phospholipids, thereby reducing the substrate availability for the synthesis of endocannabinoid molecules. Key words: omega-3 fatty acids, obesity, endocannabinoid system, 2-arachidonoylglycerol, anandamide
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The role of cannabinoid system in neurobiology and therapy of psychotic disorders - an experimental study in animal models of psychosis
Nováková, Pavlína ; Páleníček, Tomáš (advisor) ; Šustková, Magdaléna (referee)
Throughout the scientific world the topic of cannabis usage and its link with psychosis seems to be discussed intensively. Considering the fact that the Czech Republic is a country with one of the highest prevalence of cannabis usage in the world it becomes a sensitive issue even in our circumstances. In the theoretical part of the work we attempted to review current knowledge of a link between cannabinoid system, canabis usage and psychosis and to point out possible future therapeutic potential of cannabinoids in the treatment of psychotic diseases. In the practical part of the work we focused on verification of propsychotic features of THC in animal model with particular attention to validation of acute subcutaneous admonistration of this drug as a novel cannabinoid model of psychosis. At the same time we tried to elucidate antipsychotic effect of CBD in this model. We tested these hypotheses in two behavioral tests (open field test, PPI ASR) and electrophysiologically (quantitative EEG). The whole analysis is enriched with pharmacokinetic data from subcutanneous and oral administration of cannabinoids. Powered by TCPDF (www.tcpdf.org)
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Cannabinoid signalling and its physiological significance
Pavluch, Vojtěch ; Novotný, Jiří (advisor) ; Moravcová, Simona (referee)
Lidská společnost je ve styku s kanabinoidními látkami již od starověku. Ať už lidé využívali rostlinnou biomasu nebo bylinné léčitelství, bylo konopí vždy předmětem diskuzí. Poznatky objasňující molekulární principy účinku látek obsažených přírodně jen v konopí jsou však známy jen několik málo desítek let. Cílem této práce je charakterizovat subtypy receptorů, na které se kanabinoidy vážou, molekulární mechanismy jejich působení, následné konsekvence ve fyziologii a také poukázat na potenciální uplatnění jak rostlinných, tak syntetických kanabinoidů v lékařství. Kanabinoidní receptory jsou hojně se vyskytující podskupinou integrálních membránových receptorů, spadající do velké rodiny receptorů spřažených s G-proteiny. Vzhledem k ubikviternímu výskytu v organismu tyto receptory po aktivaci příslušnými lipofilními ligandy ovlivňují celou škálu fyziologických pochodů. Vazba kanabinoidních látek na daný subtyp těchto receptorů spouští specifickou signální kaskádu v buňce a ovlivňuje tak určitým způsobem buněčný metabolismus. Studium kanabinoidních receptorů a jejich ligandů přispívá k porozumění procesům zahrnujícím tvorbu paměti a učení, ale také mechanismům zapojeným v analgézii, imunomodulaci a buněčné proliferaci. Tyto receptory však ovlivňují také fyziologii kardiovaskulárního systému nebo...
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