Obesity and type 2 diabetes mellitus (T2DM) are preconditions for the development of metabolic syndrome, which is reaching pandemic levels worldwide, but there are still only a few anti-obesity drugs available. One of the promising tools for the treatment of obesity and related metabolic complications is anorexigenic peptides, such as prolactin-releasing peptide (PrRP). PrRP is a centrally acting neuropeptide involved in food intake and body weight (BW) regulation. In its natural form, it has limitations for peripheral administration; thus, we designed analogs of PrRP lipidized at the N-terminal region that showed high binding affinities, increased stability and central anorexigenic effects after peripheral administration. In this review, we summarize the preclinical results of our chronic studies on the pharmacological role of the two most potent palmitoylated PrRP31 analogs in various mouse and rat models of obesity, glucose intolerance, and insulin resistance. We used mice and rats with diet-induced obesity fed a high-fat diet, which is considered to simulate the most common form of human obesity, or rodent models with leptin deficiency or disrupted leptin signaling in which long-term food intake regulation by leptin is distorted. The rodent models described in this review are models of metabolic syndrome with different severities, such as obesity or morbid obesity, prediabetes or diabetes and hypertension. We found that the effects of palmitoylated PrRP31 on food intake and BW but not on glucose intolerance require intact leptin signaling. Thus, palmitoylated PrRP31 analogs have potential as therapeutics for obesity and related metabolic complications.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Prolactin-releasing peptide (PrRP) is a potential drug for the treatment of obesity and associated Type 2 Diabetes Mellitus (T2DM) due to its strong anorexigenic and antidiabetic properties. In our recent study, the lipidized PrRP analog palm11-PrRP31 was proven to exert beneficial effects in APP/PS1 mice, a model of Alzheimer ́s Disease (AD)-like amyloid-β (Aβ) pathology, reducing the Aβ plaque load, microgliosis and astrocytosis in the hippocampus and cortex. OBJECTIVE: In this study, we focused on the neuroprotective and anti-inflammatory effects of palm11-PrRP31 and its possible impact on synaptogenesis in the cerebellum of APP/PS1 mice, because others have suggested that cerebellar Aβ plaques contribute to cognitive deficits in AD. METHODS: APP/PS1 mice were treated subcutaneously with palm11-PrRP31 for 2 months, then immunoblotting and immunohistochemistry were used to quantify pathological markers connected to AD, compared to control mice. RESULTS: In the cerebella of 8 months old APP/PS1 mice, we found widespread Aβ plaques surrounded by activated microglia detected by ionized calcium-binding adapter molecule (Iba1), but no increase in astrocytic marker Glial Fibrillary Acidic Protein (GFAP) compared to controls. Interestingly, no difference in both presynaptic markers syntaxin1A and postsynaptic marker spinophilin was registered between APP/PS1 and control mice. Palm11-PrRP31 treatment significantly reduced the Aβ plaque load and microgliosis in the cerebellum. Furthermore, palm11-PrRP31 increased synaptogenesis and attenuated neuroinflammation and apoptosis in the hippocampus of APP/PS1 mice. CONCLUSION: These results suggest palm11-PrRP31 is a promising agent for the treatment of neurodegenerative disorders.

• MeSH
• Alzheimerova nemoc * metabolismus   MeSH
• amyloidní beta-protein metabolismus   MeSH
• amyloidní plaky patologie   MeSH
• amyloidový prekurzorový protein beta genetika   metabolismus   MeSH
• diabetes mellitus 2. typu * MeSH
• hormon uvolňující prolaktin metabolismus   farmakologie   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• mozeček MeSH
• myši transgenní MeSH
• myši MeSH
• presenilin-1 genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Obesity leads to low-grade inflammation in the adipose tissue and liver and neuroinflammation in the brain. Obesity-induced insulin resistance (IR) and neuroinflammation seem to intensify neurodegeneration including Alzheimer's disease. In this study, the impact of high-fat (HF) diet-induced obesity on potential neuroinflammation and peripheral IR was tested separately in males and females of THY-Tau22 mice, a model of tau pathology expressing mutated human tau protein. METHODS: Three-, 7-, and 11-month-old THY-Tau22 and wild-type males and females were tested for mobility, anxiety-like behavior, and short-term spatial memory in open-field and Y-maze tests. Plasma insulin, free fatty acid, cholesterol, and leptin were evaluated with commercial assays. Liver was stained with hematoxylin and eosin for histology. Brain sections were 3',3'-diaminobenzidine (DAB) and/or fluorescently detected for ionized calcium-binding adapter molecule 1 (Iba1), glial fibrillary acidic protein (GFAP), and tau phosphorylated at T231 (pTau (T231)), and analyzed. Insulin signaling cascade, pTau, extracellular signal-regulated kinase 1/2 (ERK1/2), and protein phosphatase 2A (PP2A) were quantified by western blotting of hippocampi of 11-month-old mice. Data are mean ± SEM and were subjected to Mann-Whitney t test within age and sex and mixed-effects analysis and Bonferroni's post hoc test for age comparison. RESULTS: Increased age most potently decreased mobility and increased anxiety in all mice. THY-Tau22 males showed impaired short-term spatial memory. HF diet increased body, fat, and liver weights and peripheral IR. HF diet-fed THY-Tau22 males showed massive Iba1+ microgliosis and GFAP+ astrocytosis in the hippocampus and amygdala. Activated astrocytes colocalized with pTau (T231) in THY-Tau22, although no significant difference in hippocampal tau phosphorylation was observed between 11-month-old HF and standard diet-fed THY-Tau22 mice. Eleven-month-old THY-Tau22 females, but not males, on both diets showed decreased synaptic and postsynaptic plasticity. CONCLUSIONS: Significant sex differences in neurodegenerative signs were found in THY-Tau22. Impaired short-term spatial memory was observed in 11-month-old THY-tau22 males but not females, which corresponded to increased neuroinflammation colocalized with pTau(T231) in the hippocampi and amygdalae of THY-Tau22 males. A robust decrease in synaptic and postsynaptic plasticity was observed in 11-month-old females but not males. HF diet caused peripheral but not central IR in mice of both sexes.

• MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• fosforylace MeSH
• hipokampus metabolismus   MeSH
• inzulinová rezistence * MeSH
• krátkodobá paměť MeSH
• modely nemocí na zvířatech MeSH
• mozek metabolismus   patofyziologie   MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• myši MeSH
• obezita komplikace   etiologie   MeSH
• omezení pohyblivosti MeSH
• proteiny tau MeSH
• sexuální faktory MeSH
• stárnutí metabolismus   MeSH
• tauopatie komplikace   genetika   MeSH
• zánět MeSH
• ztučnělá játra metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Prolactin-releasing peptide (PrRP), a natural ligand for the GPR10 receptor, is a neuropeptide with anorexigenic and antidiabetic properties. Due to its role in the regulation of food intake, PrRP is a potential drug for obesity treatment and associated type 2 diabetes mellitus (T2DM). Recently, the neuroprotective effects of lipidized PrRP analogs have been proven. In this study, we focused on the molecular mechanisms of action of natural PrRP31 and its lipidized analog palm11-PrRP31 in the human neuroblastoma cell line SH-SY5Y to describe their cellular signaling and possible anti-apoptotic properties. PrRP31 significantly upregulated the phosphoinositide-3 kinase-protein kinase B/Akt (PI3K-PKB/Akt) and extracellular signal-regulated kinase/cAMP response element-binding protein (ERK-CREB) signaling pathways that promote metabolic cell survival and growth. In addition, we proved via protein kinase inhibitors that activation of signaling pathways is mediated specifically by PrRP31 and its palmitoylated analog. Furthermore, the potential neuroprotective properties were studied through activation of anti-apoptotic pathways of PrRP31 and palm11-PrRP31 using the SH-SY5Y cell line and rat primary neuronal culture stressed with toxic methylglyoxal (MG). The results indicate increased viability of the cells treated with PrRP and palm11-PrRP31 and a reduced degree of apoptosis induced by MG, suggesting their potential use in the treatment of neurological disorders.

• MeSH
• apoptóza * MeSH
• hormon uvolňující prolaktin chemie   farmakologie   MeSH
• lidé MeSH
• nádorové buňky kultivované MeSH
• neuroblastom farmakoterapie   metabolismus   patologie   MeSH
• neuropeptidy chemie   farmakologie   MeSH
• neuroprotektivní látky chemie   farmakologie   MeSH
• proteiny regulující apoptózu metabolismus   MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Obesity and type 2 diabetes mellitus (T2DM) are important risk factors for Alzheimer's disease (AD). Drugs originally developed for T2DM treatment, e.g., analog of glucagon-like peptide 1 liraglutide, have shown neuroprotective effects in mouse models of AD. We previously examined the neuroprotective properties of palm11-PrRP31, an anorexigenic and glucose-lowering analog of prolactin-releasing peptide, in a mouse model of AD-like Tau pathology, THY-Tau22 mice. Here, we demonstrate the neuroprotective effects of palm11-PrRP31 in double transgenic APP/PS1 mice, a model of AD-like β-amyloid (Aβ) pathology. The 7-8-month-old APP/PS1 male mice were subcutaneously injected with liraglutide or palm11-PrRP31 for 2 months. Both the liraglutide and palm11-PrRP31 treatments reduced the Aβ plaque load in the hippocampus. Palm11-PrRP31 also significantly reduced hippocampal microgliosis, consistent with our observations of a reduced Aβ plaque load, and reduced cortical astrocytosis, similar to the treatment with liraglutide. Palm11-PrRP31 also tended to increase neurogenesis, as indicated by the number of doublecortin-positive cells in the hippocampus. After the treatment with both anorexigenic compounds, we observed a significant decrease in Tau phosphorylation at Thr231, one of the first epitopes phosphorylated in AD. This effect was probably caused by elevated activity of protein phosphatase 2A subunit C, the main Tau phosphatase. Both liraglutide and palm11-PrRP31 reduced the levels of caspase 3, which has multiple roles in the pathogenesis of AD. Palm11-PrRP31 increased protein levels of the pre-synaptic marker synaptophysin, suggesting that palm11-PrRP31 might help preserve synapses. These results indicate that palm11-PrRP31 has promising potential for the treatment of neurodegenerative diseases.

• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   patologie   MeSH
• amyloidní beta-protein metabolismus   MeSH
• amyloidní plaky farmakoterapie   metabolismus   patologie   MeSH
• amyloidóza farmakoterapie   metabolismus   patologie   MeSH
• glióza farmakoterapie   metabolismus   patologie   MeSH
• hipokampus účinky léků   metabolismus   patologie   MeSH
• hormon uvolňující prolaktin analogy a deriváty   MeSH
• lidé MeSH
• liraglutid farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• náhodné rozdělení MeSH
• neurogeneze účinky léků   MeSH
• neuroprotektivní látky farmakologie   MeSH
• proteiny tau metabolismus   MeSH
• zánět farmakoterapie   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Prolactin-releasing peptide (PrRP) belongs to the large RF-amide neuropeptide family with a conserved Arg-Phe-amide motif at the C-terminus. PrRP plays a main role in the regulation of food intake and energy expenditure. This review focuses not only on the physiological functions of PrRP, but also on its pharmacological properties and the actions of its G-protein coupled receptor, GPR10. Special attention is paid to structure-activity relationship studies on PrRP and its analogs as well as to their effect on different physiological functions, mainly their anorexigenic and neuroprotective features and the regulation of the cardiovascular system, pain, and stress. Additionally, the therapeutic potential of this peptide and its analogs is explored.

• MeSH
• energetický metabolismus účinky léků   MeSH
• hormon uvolňující prolaktin chemie   metabolismus   farmakologie   MeSH
• lidé MeSH
• neurodegenerativní nemoci farmakoterapie   patologie   MeSH
• neuroprotektivní látky chemie   farmakologie   terapeutické užití   MeSH
• přijímání potravy účinky léků   MeSH
• receptory spřažené s G-proteiny chemie   genetika   metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The selection of a suitable matrix and deposition technique constitutes a critical step in successful matrix-assisted laser desorption/ionization mass spectrometry imaging measurement. In the present work, we compared three techniques of matrix deposition, specifically, sublimation and spraying of 1,5-diaminonaphthalene with two automatic sprayers, ImagePrep and iMatrixSpray. The studied methods were evaluated in experiments for the analysis of lipid composition in the brains of two mouse models of neurodegeneration: APP/PS1 mice with plaques of amyloid β (Aβ) peptides and THY-Tau22 mice with pathologically hyperphosphorylated Tau protein, two hallmarks of Alzheimer's disease-like pathology. The sublimation method provided irreproducible results because of significant matrix loss due to the high vacuum in the ion source and laser irradiation. In contrast, the ImagePrep and iMatrixSpray provided stable film of the matrix. The deposited matrix was stable during the measurement, and highly reproducible datasets were obtained. Both spraying methods yielded similar results with approximately the same number of detected lipids and comparable signal intensity. However, iMatrixSpray has two main advantages: a faster matrix deposition and the formation of smaller matrix crystals leading to better spatial resolution. In the APP/PS1 mouse model at an age of 6 months, we found colocalization of Aβ plaques with different phospholipids, sphingolipids and lysophospholipids. We did not find a difference in lipid composition between the THY-Tau22 mice and the wild-type controls. The results indicate that hyperphosphorylation of tau protein in the THY-Tau22 mouse model at the age of 6 months is not accompanied with a significant change in lipid content in the brain. However, considering limitations of the used method, a definitive conclusion in this respect will need further research.

• MeSH
• 2-naftylamin analogy a deriváty   chemie   MeSH
• Alzheimerova nemoc metabolismus   MeSH
• amyloidní beta-protein metabolismus   MeSH
• gangliosidy analýza   metabolismus   MeSH
• glycerofosfolipidy analýza   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• mozek metabolismus   MeSH
• myši inbrední C57BL MeSH
• proteiny tau metabolismus   MeSH
• reprodukovatelnost výsledků MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice metody   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the elderly population. Numerous epidemiological and experimental studies have demonstrated that patients who suffer from obesity or type 2 diabetes mellitus have a higher risk of cognitive dysfunction and AD. Several recent studies demonstrated that food intake-lowering (anorexigenic) peptides have the potential to improve metabolic disorders and that they may also potentially be useful in the treatment of neurodegenerative diseases. In this review, the neuroprotective effects of anorexigenic peptides of both peripheral and central origins are discussed. Moreover, the role of leptin as a key modulator of energy homeostasis is discussed in relation to its interaction with anorexigenic peptides and their analogs in AD-like pathology. Although there is no perfect experimental model of human AD pathology, animal studies have already proven that anorexigenic peptides exhibit neuroprotective properties. This phenomenon is extremely important for the potential development of new drugs in view of the aging of the human population and of the significantly increasing incidence of AD.

• MeSH
• Alzheimerova nemoc metabolismus   prevence a kontrola   MeSH
• anorektika metabolismus   farmakologie   MeSH
• energetický metabolismus účinky léků   MeSH
• homeostáza účinky léků   MeSH
• kyselina pyrrolidonkarboxylová analogy a deriváty   metabolismus   farmakologie   MeSH
• leptin metabolismus   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• neuroprotektivní látky farmakologie   MeSH
• oligopeptidy metabolismus   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Obesity and type 2 diabetes mellitus (T2DM) were characterized as risk factors for Alzheimer's disease (AD) development. Subsequently, T2DM drugs, such as liraglutide, were proven to be neuroprotective compounds attenuating levels of amyloid deposits, and tau hyperphosphorylation, both hallmarks of AD. The central anorexigenic effects of liraglutide inspired us to examine the potential neuroprotective effects of palm11-PrRP31, a strong anorexigenic analog with glucose-lowering properties, in THY-Tau22 mice overexpressing mutated human tau, a model of AD-like tau pathology. Seven-month-old THY-Tau22 mice were subcutaneously infused with palm11-PrRP31 for 2 months. Spatial memory was tested before and after the treatment, using a Y-maze. At the end of the treatment, mice were sacrificed by decapitation and hippocampi were dissected and analyzed by immunoblotting with specific antibodies. Treatment with palm11-PrRP31 resulted in significantly improved spatial memory. In the hippocampi of palm11-PrRP31-treated THY-Tau22 mice, tau protein phosphorylation was attenuated at Thr231, Ser396, and Ser404, the epitopes linked to AD progression. The mechanism of this attenuation remains unclear, since the activation of those kinases most implicated in tau hyperphosphorylation, such as GSK-3β, JNK, or MAPK/ERK1/2, remained unchanged by palm11-PrRP31 treatment. Furthermore, we observed a significant increase in the amount of postsynaptic density protein PSD95, and a non-significant increase of synaptophysin, both markers of increased synaptic plasticity, which could also result in improved spatial memory of THY-Tau22 mice treated with palm11-PrRP31. Palm11-PrRP31 seems to be a potential tool for the attenuation of neurodegenerative disorders in the brain. However, the exact mechanism of its action must be elucidated.

• MeSH
• bludiště - učení účinky léků   fyziologie   MeSH
• fosforylace účinky léků   MeSH
• hipokampus účinky léků   metabolismus   patologie   MeSH
• hormon uvolňující prolaktin analogy a deriváty   farmakologie   terapeutické užití   MeSH
• krátkodobá paměť účinky léků   fyziologie   MeSH
• modely nemocí na zvířatech MeSH
• myši transgenní MeSH
• neuroprotektivní látky farmakologie   MeSH
• poruchy paměti farmakoterapie   metabolismus   patologie   MeSH
• prostorová paměť účinky léků   fyziologie   MeSH
• proteiny tau metabolismus   MeSH
• tauopatie farmakoterapie   metabolismus   patologie   psychologie   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Analogs of anorexigenic neuropeptides, such as prolactin-releasing peptide (PrRP), have a potential as new anti-obesity drugs. In our previous study, palmitic acid attached to the N-terminus of PrRP enabled its central anorexigenic effects after peripheral administration. In this study, two linkers, γ-glutamic acid at Lys11 and a short, modified polyethylene glycol at the N-terminal Ser and/or Lys11, were applied for the palmitoylation of PrRP31 to improve its bioavailability. These analogs had a high affinity and activation ability to the PrRP receptor GPR10 and the neuropeptide FF2 receptor, as well as short-term anorexigenic effect similar to PrRP palmitoylated at the N-terminus. Two-week treatment with analogs that were palmitoylated through linkers to Lys11 (analogs 1 and 2), but not with analog modified both at the N-terminus and Lys11 (analog 3) decreased body and liver weights, insulin, leptin, triglyceride, cholesterol and free fatty acid plasma levels in a mouse model of diet-induced obesity. Moreover, the expression of uncoupling protein-1 was increased in brown fat suggesting an increase in energy expenditure. In addition, treatment with analogs 1 and 2 but not analog 3 significantly decreased urinary concentrations of 1-methylnicotinamide and its oxidation products N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-3-carboxamide, as shown by NMR-based metabolomics. This observation confirmed the previously reported increase in nicotinamide derivatives in obesity and type 2 diabetes mellitus and the effectiveness of analogs 1 and 2 in the treatment of these disorders.

• MeSH
• beta-laktamasy metabolismus   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• dieta * MeSH
• hormon uvolňující prolaktin chemie   metabolismus   MeSH
• kompetitivní vazba MeSH
• křečci praví MeSH
• metabolomika MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nukleární magnetická rezonance biomolekulární MeSH
• obezita etiologie   metabolismus   MeSH
• peptidy chemie   farmakologie   MeSH
• sekvence aminokyselin MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH