Alzheimer's disease (AD) is the most common form of dementia. Characterized by progressive neurodegeneration, AD typically begins with mild cognitive decline escalating to severe impairment in communication and responsiveness. It primarily affects cerebral regions responsible for cognition, memory, and language processing, significantly impeding the functional independence of patients. With nearly 50 million dementia cases worldwide, a number expected to triple by 2050, the need for effective treatments is more urgent than ever. Recent insights into the association between obesity, type 2 diabetes mellitus, and neurodegenerative disorders have led to the development of promising treatments involving antidiabetic and anti-obesity agents. One such novel promising candidate for addressing AD pathology is a lipidized analogue of anorexigenic peptide called prolactin-releasing peptide (palm11-PrRP31). Interestingly, anorexigenic and orexigenic peptides have opposite effects on food intake regulation, however, both types exhibit neuroprotective properties. Recent studies have also identified ghrelin, an orexigenic peptide, as a potential neuroprotective agent. Hence, we employed both anorexigenic and orexigenic compounds to investigate the common mechanisms underpinning their neuroprotective effects in a triple transgenic mouse model of AD (3xTg-AD mouse model) combining amyloid-beta (Aβ) pathology and Tau pathology, two hallmarks of AD. We treated 3xTg-AD mice for 4 months with two stable lipidized anorexigenic peptide analogues - palm11-PrRP31, and liraglutide, a glucagon-like peptide 1 (GLP-1) analogue - as well as Dpr3-ghrelin, a stable analogue of the orexigenic peptide ghrelin, and using the method of immunohistochemistry and western blot demonstrate the effects of these compounds on the development of AD-like pathology in the brain. Palm11-PrRP31, Dpr3-ghrelin, and liraglutide reduced intraneuronal deposits of Aβ plaque load in the hippocampi and amygdalae of 3xTg-AD mice. Palm11-PrRP31 and Dpr3-ghrelin reduced microgliosis in the hippocampi, amygdalae, and cortices of 3xTg-AD mice. Palm11-PrRP31 and liraglutide reduced astrocytosis in the amygdalae of 3xTg-AD mice. We propose that these peptides are involved in reducing inflammation, a common mechanism underlying their therapeutic effects. This is the first study to demonstrate improvements in AD pathology following the administration of both orexigenic and anorexigenic compounds, highlighting the therapeutic potential of food intake-regulating peptides in neurodegenerative disorders.

• Klíčová slova
• 3xTg-AD mice, Alzheimer’s disease, Anorexigenic peptide analogues, Neuroinflammation, Orexigenic peptide analogues,
• MeSH
• Alzheimerova nemoc * farmakoterapie   patologie   genetika   metabolismus   MeSH
• ghrelin * farmakologie   terapeutické užití   MeSH
• hormon uvolňující prolaktin * farmakologie   terapeutické užití   analogy a deriváty   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• myši MeSH
• neurozánětlivé nemoci * farmakoterapie   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ghrelin * MeSH
• hormon uvolňující prolaktin * MeSH

Since 1975, the incidence of obesity has increased to epidemic proportions, and the number of patients with obesity has quadrupled. Obesity is a major risk factor for developing other serious diseases, such as type 2 diabetes mellitus, hypertension, and cardiovascular diseases. Recent epidemiologic studies have defined obesity as a risk factor for the development of neurodegenerative diseases, such as Alzheimer's disease (AD) and other types of dementia. Despite all these serious comorbidities associated with obesity, there is still a lack of effective antiobesity treatment. Promising candidates for the treatment of obesity are anorexigenic neuropeptides, which are peptides produced by neurons in brain areas implicated in food intake regulation, such as the hypothalamus or the brainstem. These peptides efficiently reduce food intake and body weight. Moreover, because of the proven interconnection between obesity and the risk of developing AD, the potential neuroprotective effects of these two agents in animal models of neurodegeneration have been examined. The objective of this review was to explore anorexigenic neuropeptides produced and acting within the brain, emphasizing their potential not only for the treatment of obesity but also for the treatment of neurodegenerative disorders.

• Klíčová slova
• Alzheimer´s-like pathology, anorexigenic neuropeptides, antiobesity treatment, neuroprotection,
• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   patologie   prevence a kontrola   MeSH
• hypothalamus účinky léků   metabolismus   patologie   MeSH
• látky proti obezitě * farmakologie   terapeutické užití   MeSH
• lidé MeSH
• mozek účinky léků   metabolismus   patologie   MeSH
• neurodegenerativní nemoci farmakoterapie   metabolismus   prevence a kontrola   MeSH
• neuropeptidy * metabolismus   farmakologie   terapeutické užití   MeSH
• neuroprotektivní látky * farmakologie   terapeutické užití   MeSH
• obezita * farmakoterapie   metabolismus   MeSH
• přijímání potravy účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• látky proti obezitě * MeSH
• neuropeptidy * MeSH
• neuroprotektivní látky * MeSH

Hypothalamic Adult Neurogenesis (hAN) has been implicated in regulating energy homeostasis. Adult-generated neurons and adult Neural Stem Cells (aNSCs) in the hypothalamus control food intake and body weight. Conversely, diet-induced obesity (DIO) by high fat diets (HFD) exerts adverse influence on hAN. However, the effects of anti-obesity compounds on hAN are not known. To address this, we administered a lipidized analogue of an anti-obesity neuropeptide, Prolactin Releasing Peptide (PrRP), so-called LiPR, to mice. In the HFD context, LiPR rescued the survival of adult-born hypothalamic neurons and increased the number of aNSCs by reducing their activation. LiPR also rescued the reduction of immature hippocampal neurons and modulated calcium dynamics in iPSC-derived human neurons. In addition, some of these neurogenic effects were exerted by another anti-obesity compound, Liraglutide. These results show for the first time that anti-obesity neuropeptides influence adult neurogenesis and suggest that the neurogenic process can serve as a target of anti-obesity pharmacotherapy.

• Klíčová slova
• Adult neurogenesis, Anti-obesity peptides, Hypothalamus, Neural stem cells, Prolactin Releasing Peptide,
• MeSH
• hormon uvolňující prolaktin farmakologie   terapeutické užití   MeSH
• hypothalamus MeSH
• lidé MeSH
• myši MeSH
• neurogeneze MeSH
• neuropeptidy * MeSH
• obezita * farmakoterapie   MeSH
• tělesná hmotnost MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hormon uvolňující prolaktin MeSH
• neuropeptidy * MeSH

The worldwide increase in the incidence of obesity and cardiovascular and neurodegenerative diseases, e.g. Alzheimer's disease, is related to many factors, including an unhealthy lifestyle and aging populations. However, the interconnection between these diseases is not entirely clear, and it is unknown whether common mechanisms underlie these conditions. Moreover, there are currently no fully effective therapies for obesity and neurodegeneration. While there has been extensive research in preclinical models addressing these issues, the experimental findings have not been translated to the clinic. Another challenge relates to the time of onset of individual diseases, which may not be easily identified, since there are no specific indicators or biomarkers that define disease onset. Hence knowing when to commence preventive treatment is unclear. This is especially pertinent in neurodegenerative diseases, where the onset of the disease may be subtle and occur decades before the signs and symptoms manifest. In metabolic and cardiovascular disorders, the risk may occur in-utero, in line with the concept of fetal programming. This review provides a brief overview of the link between obesity, cardiovascular and neurodegenerative diseases and discusses potential common mechanisms including the role of the gut microbiome.

• MeSH
• Alzheimerova nemoc * metabolismus   MeSH
• lidé MeSH
• neurodegenerativní nemoci * metabolismus   MeSH
• obezita komplikace   diagnóza   epidemiologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND/OBJECTIVE: Anorexigenic palmitoylated prolactin-releasing peptide (palm11-PrRP) is able to act centrally after peripheral administration in rat and mouse models of obesity, type 2 diabetes mellitus and/or neurodegeneration. Functional leptin and intact leptin signaling pathways are necessary for the body weight reducing and glucose tolerance improving effect of palm11-PrRP. We have previously shown that palm11-PrRP31 had glucose-lowering properties but not anti-obesity effect in Koletsky rats with leptin signaling disturbances, so improvements in glucose metabolism appear to be completely independent of leptin signaling. The purpose of this study was to describe relationship between metabolic and neurodegenerative pathologies and explore if palm11-PrRP31 could ameliorate them in obese fa/fa rat model with leptin signaling disruption. SUBJECT/METHODS: The fa/fa rats and their age-matched lean controls at the age 32 weeks were used for this study. The rats were infused for 2 months with saline or palm11-PrRP31 (n = 7-8 per group) at a dose of 5 mg/kg per day using Alzet osmotic pumps. During the dosing period food intake and body weight were monitored. At the end of experiment the oral glucose tolerance test was performed; plasma and tissue samples were collected and arterial blood pressure was measured. Then, markers of leptin and insulin signaling, Tau phosphorylation, neuroinflammation, and synaptogenesis were measured by western blotting and immunohistochemistry. RESULTS: Fa/fa rats developed obesity, mild glucose intolerance, and peripheral insulin resistance but not hypertension while palm11-PrRP31 treatment neither lowered body weight nor attenuated glucose tolerance but ameliorated leptin and insulin signaling and synaptogenesis in hippocampus. CONCLUSION: We demonstrated that palm11-PrRP31 had neuroprotective features without anti-obesity and glucose lowering effects in fa/fa rats. This data suggest that this analog has the potential to exert neuroprotective effect despite of leptin signaling disturbances in this rat model.

• MeSH
• diabetes mellitus 2. typu * farmakoterapie   MeSH
• glukosa MeSH
• hormon uvolňující prolaktin farmakologie   terapeutické užití   MeSH
• inzulin terapeutické užití   MeSH
• krysa rodu Rattus MeSH
• leptin * MeSH
• myši MeSH
• obezita metabolismus   MeSH
• tělesná hmotnost MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• glukosa MeSH
• hormon uvolňující prolaktin MeSH
• inzulin MeSH
• leptin * MeSH

The anorexigenic neuropeptide prolactin-releasing peptide (PrRP) is involved in the regulation of food intake and energy expenditure. Lipidization of PrRP stabilizes the peptide, facilitates central effect after peripheral administration and increases its affinity for its receptor, GPR10, and for the neuropeptide FF (NPFF) receptor NPFF-R2. The two most potent palmitoylated analogs with anorectic effects in mice, palm11-PrRP31 and palm-PrRP31, were studied in vitro to determine their agonist/antagonist properties and mechanism of action on GPR10, NPFF-R2 and other potential off-target receptors related to energy homeostasis. Palmitoylation of both PrRP31 analogs increased the binding properties of PrRP31 to anorexigenic receptors GPR10 and NPFF-R2 and resulted in a high affinity for another NPFF receptor, NPFF-R1. Moreover, in CHO-K1 cells expressing GPR10, NPFF-R2 or NPFF-R1, palm11-PrRP and palm-PrRP significantly increased the phosphorylation of extracellular signal-regulated kinase (ERK), protein kinase B (Akt) and cAMP-responsive element-binding protein (CREB). Palm11-PrRP31, unlike palm-PrRP31, did not activate either c-Jun N-terminal kinase (JNK), p38, c-Jun, c-Fos or CREB pathways in cells expressing NPFF-1R. Palm-PrRP31 also has higher binding affinities for off-target receptors, namely, the ghrelin, opioid (KOR, MOR, DOR and OPR-L1) and neuropeptide Y (Y1, Y2 and Y5) receptors. Palm11-PrRP31 exhibited fewer off-target activities; therefore, it has a higher potential to be used as an anti-obesity drug with anorectic effects.

• Klíčová slova
• GPR10, NPFF-R1, NPFF-R2, binding properties, neuropeptide FF, prolactin-releasing peptide, signaling pathways,
• MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• hormon uvolňující prolaktin chemie   genetika   metabolismus   MeSH
• křečci praví MeSH
• lidé MeSH
• lipoylace * MeSH
• receptory neuropeptidů genetika   metabolismus   MeSH
• receptory spřažené s G-proteiny genetika   metabolismus   MeSH
• techniky in vitro MeSH
• vápník metabolismus   MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hormon uvolňující prolaktin MeSH
• neuropeptide FF receptor MeSH Prohlížeč
• PRLH protein, human MeSH Prohlížeč
• PRLHR protein, human MeSH Prohlížeč
• receptory neuropeptidů MeSH
• receptory spřažené s G-proteiny MeSH
• vápník 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.

• Klíčová slova
• SH-SY5Y, cellular signaling, inhibitors, methylglyoxal, neuroprotection, primary neuronal culture, prolactin-releasing peptide,
• 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
• Názvy látek
• hormon uvolňující prolaktin MeSH
• neuropeptidy MeSH
• neuroprotektivní látky MeSH
• proteiny regulující apoptózu 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.

• Klíčová slova
• GPR10, RF-amide peptides, energy expenditure, food intake regulation, neuroprotection, prolactin-releasing peptide, signaling,
• 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
• Názvy látek
• hormon uvolňující prolaktin MeSH
• neuroprotektivní látky MeSH
• PRLHR protein, human MeSH Prohlížeč
• receptory spřažené s G-proteiny MeSH