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The role of stable analogs of prolactin-releasing peptide in obesity and hypertension.
Neprašová, Barbora ; Maletínská, Lenka (advisor) ; Poledne, Rudolf (referee) ; Rossmeisl, Martin (referee)
Anorexigenic neuropeptides have the potential to decrease food intake and ameliorate obesity and its complications such as high blood glucose or high blood pressure. However, they are not able to cross the blood-brain barrier after peripheral application. Recently, we have designed and synthesized lipidized analogs of prolactin-releasing peptide (PrRP), which resulted in stabilization of the molecule and allowed us to apply the peptide to the periphery to achieve its central biological effect, as it was demonstrated by increased neuronal activity shown by c-Fos in particular hypothalamus nuclei. The aim of this study was to choose the effective dose in acute food intake experiments and then to characterize the subchronic effect of palmitoylated PrRP analogs in mouse and rat models of obesity and diabetes. Several animal models were used: diet-induced obese (DIO) mice (C57Bl/6J), DIO Sprague-Dawley rats, and two rat models with leptin receptor-deficiency: Zucker diabetic (ZDF) rats and spontaneously hypertensive (SHROB) rats. Consumption of a high-fat diet in DIO mice and rats increased their body weight and blood pressure. Two-week intraperitoneal treatment with palmitoylated PrRP31 lowered the food intake, body weight, and returned the blood pressure to normal levels. This treatment also improved...
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Effect of stable prolactin-releasing peptide analog in rat model of obesity
Pospíšilová, Kateřina ; Maletínská, Lenka (advisor) ; Bardová, Kristina (referee)
Obesity is a serious worldwide problem of modern society. Current state is at epidemic level not just in the developed world. It is no more "western disease" or "disease of affluence" as obesity used to be called. Determination of mechanisms that regulate energy balance in the human organism is necessary for further development of obesity drugs. Prolactin-releasing peptide (PrRP) is anorexigenic (food intake lowering) neuropeptide, which acts centrally in hypothalamus. Lipidized analogs of PrRP are promising tools in obesity and type-two diabetes mellitus treatment. This work is focused on impact of palmitoylated analog of prolactin-releasing peptide (palm11 -PrRP31) in a diet induced rat model of obesity after chronical administration. Body weight and cumulative food intake was monitored during the experiment. Administration of palm11 -PrRP31 markedly lowered food intake which caused decrease of body weight compared to obese control group on high-fat diet. This reduction correlated with significantly lower amount of intraperitoneal fat compared to group on high fat-diet. Also, high-fat diet worsened studied metabolic parameters including glucose tolerance. Palm11 -PrRP31 lowered leptin plasma level and improved glucose tolerance both compared to the high-fat fed. Therefore, palm11 -PrRP31 is...
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Peptides regulating food intake and their lipidized analogs for possible treatment of obesity and cachexia
Buková, Anna-Marie ; Maletínská, Lenka (advisor) ; Janovská, Petra (referee)
In spite of good living conditions, the number of people in the state where the total food intake or individual nutrients is insufficient, unnecessary or unbalanced has increased in recent years. In case of superfluous food intake, amount of fat tissue increases and overweight and obesity appear, which is associated with an increased risk of type 2 of diabetes, cardiovascular disease or certain types of cancer. Insufficient intake of food may, for example, result in the function of the immune system, resulting in an increased risk of infection or poor wound healing. In addition to primary malnutrition, we can see malnutrition as the secondary manifestation of another illness. The state of weight loss and malnutrition caused by another disease is called cachexia. This is a serious complication of primary therapies. At present, in addition to established approaches to the treatment of these diseases, some studies address treatment options using compounds that influence the regulation of food intake. One group of these compounds is peptides able to reduce food intake (anorexigenic peptides) or increase it (orexigenic peptides). To these natural substances in the organism are also sought analogs with properties more favorable for use in practice. One of the possibilities are lipidized analogs, among...
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Neuroprotective effects of food intake regulating peptides in vitro and in vivo
Kasperová, Barbora Judita ; Maletínská, Lenka (advisor) ; Vaněk, Ondřej (referee)
Nowadays, Alzheimer's disease (AD) is one of the most serious health problems among elder. To this day, pathogenesis of AD is still unknown and therefore no effective treatment has been found. AD is characterized by neuropathological features, the formation of extracellular senile plaques of amyloid β and intracellular neurofibrillary tangles of Tau protein. Numerous experimental studies have confirmed that metabolic disorders such as type 2 diabetes mellitus or obesity contribute significantly to the development of cognitive impairment and therefore the development of AD. In this diploma thesis, the potential neuroprotective effect of peptides regulating food intake was investigated in in vitro and in vivo experiments. The potential neuroprotective effect of liraglutide, a glucagon-like peptide-1 analog used as a type 2 diabetes mellitus treatment, a prolactin-releasing peptide (PrRP) and its palmitoylated analog, palm11 -PrRP31, was investigated on SH-SY5Y cell line. The peptides were used as a pretreatment on SH-SY5Y cells in methylglyoxal-induced cytotoxicity. It has been proven that the peptides themselves are not toxic and do not significantly reduce the viability of SH-SY5Y cells. The tested peptides showed prophylactic effects against cytotoxicity and apoptosis induced by toxic...
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The in vitro study of the new lipidized analogs of prolactin-releasing peptide
Šatrová, Lucie ; Maletínská, Lenka (advisor) ; Tichá, Anežka (referee)
Bakalářská práce se zabývá neuropeptidy ovlivňujícími příjem potravy anorexigenním účinkem (snižujícím příjem potravy), které jsou potenciálními Mezi tyto neuropeptidy se řadí peptid uvolňující prolaktin (PrRP), který se váže s itou ke svému receptoru GPR10, a také k afinitou jen o řád nižší než laboratoři RNDr. Lenky Maletínské, CSc. byly navrženy a syntetizovány nové lipidované analogy PrRP, které mají podobnou afini receptorům GPR10 i NPFF2 přirozený PrRP a snižují příjem potravy po periferním podání. Na základě skutečnosti, že GPR10 má vysoko jedním receptorem označovaným jako Y1 a receptor Y1 je homologický s dalšími íněných peptidů Y2 a Y5, byla této bakalářské práci stanovena afinita přirozeného a jeho dvou palmitovaných analogů k receptorům Na buňkách U2OS s transfekovanými pomocí saturačních vazeb . Ty sloužily k výpočtu kompetitivních vazebných experimentech, kde přirozený a jeho dva palmitoylované měly velmi nízkou buňkám U2OS s transfekovanými receptory Y1 nebo Y2. Na druhé straně přirozený PrRP vázal buňkám transfekovaným receptorem řádu 10 a jeho palmitoylované analogy s až stokrát nižší Součástí bakalářské práce byla i optimaliz a přítomnosti inhibitorů proteáz stanovení K buněčn sfekovaným NPFF2 Stanovená K řádu 10 mol/l podobná hodnotám pro přirozené ligandy receptorů Zkoumání vazby...
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Characterization of molecular components in cannabinoid signaling pathways.
Hájková, Alena ; Blahoš, Jaroslav (advisor) ; Vyklický, Ladislav (referee) ; Maletínská, Lenka (referee)
The cannabinoid receptor 1 (CB1R), a member of the G-protein coupled receptors superfamily, is a key player in endocannabinoid signalling. The CB1R is found presynaptically in neurones where it modulates synaptic plasticity. Precise description of the molecular mechanisms of synaptic neurotransmission is crucial for understanding of brain diseases and development of new therapeutic aproaches. Possible pharmacological targets of CB1R signalling include the treatment of various ailments such as energy imbalance disorders (anorexia, obesity), drug addiction, pain, insomnia, and some psychiatric conditions. This study reveals the "Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1" (SGIP1) as a novel interacting partner of the CB1R. The SGIP1 is an intracellular neuronal protein localized predominantly in axon terminals and is involved in clathrin mediated endocytosis. The overexpression of SGIP1 imbalance energy homeostasis and leads to obesity. We show that SGIP1 affects CB1R signalling via ERK1/2 whereas G-protein signallization remains unaltered. The SGIP1 also hinders CB1R internalization from the cell surface and supports its interaction with β-arrestin2. Also, we demonstrated heterodimerization of the main splice variants of metabotropic glutamate...
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New analogs of anorexigenic neuropeptides involved in food intake regulation
Pražienková, Veronika ; Maletínská, Lenka (advisor) ; Novotný, Jiří (referee) ; Skálová, Lenka (referee)
This work focuses on anorexigenic neuropeptides, cocaine- and amphetamine-regulated transcript (CART) and prolactin-releasing peptide (PrRP), which decrease food intake and body weight. CART peptide is an anorexigenic neuropeptide and, despite many efforts, its receptor has not yet been identified. We found CART peptide specific binding sites in pheochromocytoma PC12 cells. Cells differentiated to neurons increased significantly the number of binding sites. On the other hand, after differentiation to chromaffin cells the number of binding sites was so low that it was impossible to determine their density. To clarify the importance of each of the three disulfide bridges in the CART molecule, analogs with one or two disulfide bridges were synthetized. The biological activity was maintained in analog with two disulfide bridges in positions 74-94 and 88-101. Moreover, we demonstrated the stimulation of JNK and subsequently c-Jun activation in PC12 cells. Neuropeptide PrRP belongs to the RF-amide peptide family and has anorexigenic properties. PrPR has a high affinity to GPR10 and neuropeptide FF (NPFF2) receptor. In our laboratory lipidized analogs of PrRP were synthesized, which are able to decrease food intake after peripheral administration and may cross the blood-brain barrier. We tested biological...
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Impact of different types of antidiabetic interventions on the development of neurodegenerative changes in brains of diabetic mice and rats
Popelová, Andrea ; Maletínská, Lenka (advisor) ; Mareš, Pavel (referee) ; Hölscher, Christian (referee)
Alzheimer's disease (AD) is neurological disorder characterized by extracellular beta amyloid plaques and intracellular neurofibrillary tangles formed by hyper-phosphorylated Tau protein. Since type 2 diabetes mellitus (T2DM) is a risk factor of AD development, in the first part of the thesis, a potential relationship between hyper-phosphorylation of Tau protein and central insulin resistance was followed in hippocampi of two models of obesity-induced pre-diabetes, fa/fa rats, and mice with monosodium glutamate (MSG) induced obesity. In both 8-month-old fa/fa rats and 6-month- old MSG mice a decreased phosphorylation of insulin signaling cascade resulted in an increased activation of main Tau kinase glycogen-synthase kinase-3Beta (GSK-3β) and an increased Tau phosphorylation at epitopes Ser396 and Thr231. This phenomenon was less developed in 2-month-old animals. The second part of the thesis was focused on a potential neuroprotective anorexigenic neuropeptide, prolactin-releasing peptide (PrRP), designed at our Institute. Palmitoylation enabled PrRP to cross the blood-brain barrier and employ its central anorexigenic activity. In the third part of the thesis, an effect of 14-day-long SC administration of liraglutide, the most used anti-T2DM drug with central anorexigenic effect, and palmitoylated...
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