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Neuroprotective effects of novel anorexigenic analogs of prolactin-releasing peptide (PrRP) in models of neurodegeneration in vitro and in vivo
Mengr, Anna ; Maletínská, Lenka (advisor) ; Sumová, Alena (referee) ; Hampl, Aleš (referee)
Alzheimer's disease (AD) is a progressive brain disorder characterized by extracellular beta amyloid (Aβ) plaques, intracellular neurofibrillary tangles formed by hyperphosphorylated Tau protein and neuroinflammation. Since obesity and type 2 diabetes mellitus (T2DM) have been established as risk factors for the development of neurological disorders, anorexigenic and antidiabetic peptides, such as prolactin-releasing peptide (PrRP) seem to be potential neuroprotective agents. In the first part of the study, the molecular mechanisms of action of natural PrRP31 and its lipidized analog palm11 -PrRP31 was studied in the human neuroblastoma cell line SH-SY5Y. Both compounds significantly activated the signaling pathways typical for insulin promoting cell survival and growth. Moreover, PrRP31 and palm11 -PrRP31 increased cell viability and suppressed apoptosis in methylglyoxal-stressed SH-SY5Y cells. The second part of the thesis was focused on the neuroprotective and anti-inflammatory effects of 2-month-long subcutaneous administration of palm11 -PrRP31 in the brains of APP/PS1 mice, model of Aβ pathology. Palm11 -PrRP31 significantly reduced the Aβ plaque load and microgliosis in the hippocampi, cortices, and cerebella. Furthermore, palm11 -PrRP31 increased the synaptogenesis and attenuated...
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Effects of stable analogs of anorexigenic neuropeptides in models of metabolic syndrome
Mráziková, Lucia ; Maletínská, Lenka (advisor) ; Kříž, Jan (referee) ; Bardová, Kristina (referee)
Obesity is a worldwide health problem and an effective treatment is still scarce. Anorexigenic neuropeptides, such as prolactin-releasing peptide (PrRP), have a potential for the treatment of obesity and its complications, but in their natural form they have several limitations such as poor bioavailability, low stability and inability to cross the blood-brain barrier after peripheral administration. Recently we have designed lipidized analogs of PrRP. Lipidization makes this peptide more stable and able to act centrally after peripheral administration. The aim of this study was to investigate the chronic effect of PrRP palmitoylated at position 11 (palm11 -PrRP31) on obesity and obesity-related metabolic parameters and to clarify mechanisms of its action. We used three rodent models of obesity: Wistar Kyoto (WKY) rats with high-fat diet-induced obesity (DIO) having intact leptin and leptin receptor as well as rodents with disrupted leptin function: leptin deficient ob/ob mice and fa/fa rats with a disturbed leptin signaling. Consumption of a high-fat diet in DIO WKY rats increased their body weight, caused strong glucose intolerance and increased liver mRNA expression of enzymes of de novo lipogenesis. Palm11 -PrRP31 treatment significantly decreased cumulative food intake, body weight, plasma...
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New pharmacological interventions influencing food intake focused on effects of CART (cocaine- and amphetamine-regulated transcript) peptide and prolactin-releasing peptide
Maixnerová, Jana ; Maletínská, Lenka (advisor) ; Zorad, Štefan (referee) ; Skálová, Lenka (referee)
The thesis was focused on characterization of biological activities of two recently discovered anorexigenic neuropeptides: CART (cocaine- and amphetamine-regulated transcript) peptide and prolactin-releasing peptide (PrRP). In order to find a pharmacophore of CART peptide, shorter fragments of CART(61- 102) peptide were tested for binding to PC12 cells and inhibition of food intake in fasted mice. The results showed that a compact structure of CART peptide containing three disulphide bridges is necessary for preservation of its full biological activity. In the second part of the thesis, synergistic and long-lasting effect of centrally administered peptide CART and peripherally administered cholecystokinin (CCK) is described. In fasted C57BL/6 mice, the anorexigenic effect of CART was enhanced by a subthreshold dose of CCK, while CCK1 receptor antagonist devazepide blocked the effect of CART peptide on food intake. In the third part of the thesis, food intake in fed lean and MSG (monosodiumglutamate treated) obese male mice with lesions in nucleus arcuatus (ARC) was followed. Anorexigenic action of CART peptide was preserved but satiety effect of CCK was completely lost in MSG obese mice and therefore, effective leptin signaling in ARC is necessary for satiety effect of CCK. Finally, the PrRP...
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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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Peptide hormones affecting the food intake and their analogs as potential drugs for treatment of obesity
Nagelová, Veronika ; Maletínská, Lenka (advisor) ; Vybíral, Stanislav (referee)
Obesity is nowadays a major global health problem. Every year amount of obese (BMI > 30 kg . m-2 ) and overweight (BMI > 25 kg . m-2 ) people increases. Obesity is not just a cosmetic problem, but it leads to many serious health complications, particularly cardiovascular diseases, metabolic diseases etc. We can define obesity as an excessive amount of body fat. The development of obesity is often influenced by energy intake, which overrides the energy expenditure. Many studies are currently describe the influence of various substances that could potentially act as antiobesity drugs. Peptide hormones, which are engaged in this work, can be divided to the long-term (leptin, insulin, ghrelin) and short-term (e.g. cholecystokinin, glucagon like peptide 1, peptide YY, CART peptides, melanocortin system, neuropeptide Y and melanin concentrating hormone) acting. Peptides can be also divided according to their effect on food intake to the anorexigenic and orexigenic. Anorexigenic peptides reduce food intake, orexigenic do the reverse.
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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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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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