Prolactin-releasing peptide Dotaz Zobrazit nápovědu
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
Obesity is an escalating epidemic, but an effective noninvasive therapy is still scarce. For obesity treatment, anorexigenic neuropeptides are promising tools, but their delivery from the periphery to the brain is complicated because peptides have a low stability and limited ability to cross the blood-brain barrier. In this review, we summarize results of several studies with our newly designed lipidized analogs of prolactin-releasing peptide (PrRP). PrRP is involved in feeding and energy balance regulation as demonstrated by obesity phenotypes of both PrRP- and PrRP-receptor-knockout mice. Lipidized PrRP analogs showed binding affinity and signaling in PrRP receptor-expressing cells similar to natural PrRP. Moreover, these analogs showed high binding affinity also to anorexigenic neuropeptide FF (NPFF)-2 receptor. Acute peripheral administration of myristoylated and palmitoylated PrRP analogs to mice and rats induced strong and long-lasting anorexigenic effects and neuronal activation in the brain areas involved in food intake regulation. Two-week-long subcutaneous administration of palmitoylated PrRP31 and myristoylated PrRP20 lowered food intake, body weight, improved metabolic parameters and attenuated lipogenesis in mice with diet-induced obesity. A strong anorexigenic, body weight-reducing and glucose tolerance-improving effect of palmitoylated-PrRP31 was shown also in diet-induced obese rats after its repeated 2-week-long peripheral administration. Thus, the strong anorexigenic and body weight-reducing effects of palmitoylated PrRP31 and myristoylated PrRP20 make these analogs attractive candidates for antiobesity treatment. Moreover, PrRP receptor might be a new target for obesity therapy.
- Klíčová slova
- GPR10, anorexigenic, lipidization, mice, obesity, prolactin-releasing peptide,
- MeSH
- hormon uvolňující prolaktin analogy a deriváty terapeutické užití MeSH
- látky proti obezitě farmakologie terapeutické užití MeSH
- lidé MeSH
- obezita farmakoterapie MeSH
- regulace chuti k jídlu * MeSH
- systémy cílené aplikace léků * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- hormon uvolňující prolaktin MeSH
- látky proti obezitě 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
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by the accumulation of extracellular amyloid plaques and intraneuronal neurofibrillary tangles. These tangles mainly consist of hyperphosphorylated tau protein. As it induces tau hyperphosphorylation in vitro and in vivo, hypothermia is a useful tool for screening potential neuroprotective compounds that ameliorate tau pathology. In this study, we examined the effect of prolactin-releasing peptide (PrRP), its lipidized analog palm11-PrRP31 and glucagon-like-peptide-1 agonist liraglutide, substances with anorexigenic and antidiabetic properties, on tau phosphorylation and on the main kinases and phosphatases involved in AD development. Our study was conducted in a neuroblastoma cell line SH-SY5Y and rat primary neuronal cultures under normothermic and hypothermic conditions. Hypothermia induced a significant increase in tau phosphorylation at the pThr212 and pSer396/pSer404 epitopes. The palmitoylated analogs liraglutide and palm11-PrRP31 attenuated tau hyperphosphorylation, suggesting their potential use in the treatment of neurodegenerative diseases.
- Klíčová slova
- Hypothermia, SH-SY5Y, lipidization, primary neuronal culture, prolactin-releasing peptide, tau phosphorylation,
- MeSH
- buněčné linie MeSH
- fosforylace účinky léků MeSH
- glukagonu podobný peptid 1 agonisté MeSH
- hormon uvolňující prolaktin analogy a deriváty farmakologie MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- liraglutid farmakologie MeSH
- neurodegenerativní nemoci farmakoterapie metabolismus MeSH
- neurony * účinky léků metabolismus MeSH
- neuroprotektivní látky farmakologie MeSH
- proteiny tau metabolismus MeSH
- terapeutická hypotermie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- glukagonu podobný peptid 1 MeSH
- hormon uvolňující prolaktin MeSH
- liraglutid MeSH
- neuroprotektivní látky MeSH
- palm11-PrRP31 MeSH Prohlížeč
- proteiny tau 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
AIM: Novel compounds for obesity treatment are currently being studied employing lipidized analogs of anorexigenic neuropeptides. Various analogs of prolactin-releasing peptide have demonstrated their ability to decrease food intake. Adequate analytical tools are required to support corresponding research. Methodology & results: An analytical method was developed that includes simple dilution of plasma samples prior to liquid chromatography-mass spectrometry and employs a monolithic column for the determination of lipidized analogs of prolactin-releasing peptide in complex biological samples. A multiple reaction monitoring approach was applied that included matrix calibration and an internal standard and produced a linear calibration range 20-200 ng ml-1 in rat and macaque plasma samples. CONCLUSION: A straightforward, simple and reliable analytical method was developed satisfying major validation criteria.
- Klíčová slova
- LC–MS, lipopeptides, monolithic column, prolactin-releasing peptide, stability,
- MeSH
- biochemická analýza krve metody MeSH
- chromatografie kapalinová metody MeSH
- hormon uvolňující prolaktin krev chemie MeSH
- kalibrace MeSH
- krysa rodu Rattus MeSH
- lipidy chemie MeSH
- metody pro přípravu analytických vzorků * MeSH
- sekvence aminokyselin MeSH
- tandemová hmotnostní spektrometrie metody MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- hormon uvolňující prolaktin MeSH
- lipidy MeSH
The situation following anti-obesity drug termination is rarely investigated, eventhough a decrease in body weight needs to be sustained. Therefore, this study examined the impact of twice-daily peripheral administration of 5 mg/kg [N-palm-γGlu-Lys11] prolactin-releasing peptide 31 (palm11-PrRP31) in mice with diet-induced obesity (DIO from consuming a high-fat diet) after 28 days of treatment (palm11-PrRP31 group) and after 14 days of peptide treatment followed by 14 days of discontinuation (palm11-PrRP31 + saline group). At the end of the treatment, cumulative food intake, body weight and subcutaneous fat weight/body weight ratio and leptin plasma level were reduced significantly in both the palm11-PrRP31 group and the palm11-PrRP31 + saline group compared to the saline control group. This reduction correlated with significantly increased FOSB, a marker of long-term neuronal potentiation, in the nucleus arcuatus and nucleus tractus solitarii, areas known to be affected by the anorexigenic effect of palm11-PrRP31. Moreover, activation of leptin-related hypothalamic signaling was registered through an increase in phosphoinositide-3-kinase, increased phosphorylation of protein kinase B (PKB, AKT) and enhanced extracellular signal-regulated kinase 1/2 phosphorylation. Besides, lowered apoptotic markers c-JUN N-terminal kinase and c-JUN phosphorylation were registered in the hypothalami of both palm11-PrRP31-treated groups. This study demonstrates that palm11-PrRP31 positively affects feeding and leptin-related hypothalamic signaling, not only after 28 days of treatment but even 14 days after the termination of a 14-day long treatment without the yo-yo effect.
- Klíčová slova
- FOSB, apoptotic activation, diet-induced obese mice, leptin signaling, prolactin-releasing peptide,
- MeSH
- apoptóza MeSH
- fosforylace MeSH
- hormon uvolňující prolaktin metabolismus MeSH
- hypothalamus metabolismus MeSH
- leptin metabolismus MeSH
- leptinové receptory metabolismus MeSH
- lidé MeSH
- messenger RNA genetika metabolismus MeSH
- myši inbrední C57BL MeSH
- myši obézní MeSH
- neurony metabolismus MeSH
- omezení příjmu potravy krev MeSH
- přijímání potravy MeSH
- signální transdukce * MeSH
- velikost orgánu MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- hormon uvolňující prolaktin MeSH
- leptin MeSH
- leptinové receptory MeSH
- messenger RNA 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) is an anorexigenic neuropeptide expressed in the brain where it regulates food intake and energy expenditure. The C-terminal Arg-Phe-NH2 of PrRP is crucial for its biological activity. In our previous study, we showed that PrRP analogs myristoylated or palmitoylated at the N- terminus seem to cross the blood-brain barrier and lower food intake following peripheral administration. In this study, myristoylated and palmitoylated PrRP31 analogs with a modified C-terminal Phe were designed and tested. Lipidized analogs containing Phe(31) replaced by aromatic non-coded amino acids or tyrosine revealed high binding affinity to rat pituitary RC-4B/C cells with endogenous PrRP and neuropeptide FF 2 receptors and to CHO-K1 cells overexpressing either PrRP or neuropeptide FF 2 receptors. The analogs also showed strong agonistic properties at the GPR10 receptor using the beta-lactamase reporter gene assay. Moreover, lipidized PrRP analogs, especially those that were palmitoylated, demonstrated strong and long-lasting anorexigenic effects in fasted mice after subcutaneous administration. The most efficient PrRP31 analogs with PheCl2(31), either palmitoylated or myristoylated at the N-terminus, are promising candidates for the study of food disorders, possibly for anti-obesity treatment. Despite the therapeutic potential in targeting central GPR10, the endogenous ligand PrRP cannot cross the blood-brain barrier. Understanding biological activity and transport of novel structural analogs of PrRP with a potential central anorexigenic effect is of key therapeutic significance.
- MeSH
- buněčné linie MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- hematoencefalická bariéra metabolismus MeSH
- hormon uvolňující prolaktin analogy a deriváty metabolismus farmakologie MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- lipidy MeSH
- mozek metabolismus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- neuropeptidy metabolismus farmakologie MeSH
- obezita farmakoterapie metabolismus MeSH
- přijímání potravy účinky léků MeSH
- receptory neuropeptidů metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- hormon uvolňující prolaktin MeSH
- lipidy MeSH
- neuropeptide FF receptor MeSH Prohlížeč
- neuropeptidy MeSH
- receptory neuropeptidů MeSH
Obesity is an escalating epidemic, but an effective non-invasive therapy is still scarce. For obesity treatment, anorexigenic neuropeptides are promising tools, but their delivery from the periphery to the brain is complicated by their peptide character. In order to overcome this unfavorable fact, we have applied the lipidization of neuropeptide prolactin-releasing peptide (PrRP), whose strong anorexigenic effect was demonstrated. A palmitoylated analog of human PrRP (h palm-PrRP31) was injected in free-fed Wistar rats by three routes: subcutaneous (s.c.), intraperitoneal (i.p) (both 5 mg/kg) and intravenous (i.v.) (from 0.01 to 0.5 mg/kg). We found a circulating compound in the blood after all three applications with the highest concentration after i.v. administration. This corresponds to the effect on food intake, which was also strongest after i.v. injection. Moreover, this is in agreement with the fact that the expression of c-Fos in specific brain regions involved in food intake regulation was also highest after intravenous application. Pharmacokinetic data are further supported by results obtained from dynamic light scattering and CD spectroscopy. Human palm-PrRP31 analog showed a strong tendency to micellize, and formation of aggregates suggested lower availability after i.p. or s.c. application. We have demonstrated that palm-PrRP influenced food intake even in free fed rats. Not surprisingly, the maximal effect was achieved after the intravenous application even though two orders of magnitude lower dose was used compared to both two other applications. We believe that palm-PrRP could have a potential as an antiobesity drug when its s.c. application would be improved.
- Klíčová slova
- CD spectroscopy, Food intake, Lipidization, Pharmacokinetics, Prolactin-releasing peptide, c-Fos,
- MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- energetický příjem účinky léků MeSH
- hormon uvolňující prolaktin aplikace a dávkování analogy a deriváty metabolismus farmakokinetika MeSH
- křečci praví MeSH
- krysa rodu Rattus MeSH
- látky proti obezitě aplikace a dávkování metabolismus farmakokinetika MeSH
- lidé MeSH
- mozek metabolismus MeSH
- neurony účinky léků metabolismus MeSH
- obezita farmakoterapie MeSH
- peptidové fragmenty aplikace a dávkování metabolismus farmakokinetika MeSH
- preklinické hodnocení léčiv MeSH
- protoonkogenní proteiny c-fos metabolismus MeSH
- receptory spřažené s G-proteiny metabolismus MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- hormon uvolňující prolaktin MeSH
- látky proti obezitě MeSH
- palmitoyl-PrRP31 peptide, human MeSH Prohlížeč
- peptidové fragmenty MeSH
- PRLHR protein, human MeSH Prohlížeč
- protoonkogenní proteiny c-fos MeSH
- receptory spřažené s G-proteiny MeSH