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1.
Aging (Albany NY) ; 14(18): 7300-7327, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-36126192

RESUMO

The most important risk factor for the development of sporadic Alzheimer's disease (AD) is ageing. Senescence accelerated mouse prone 8 (SAMP8) is a model of sporadic AD, with senescence accelerated resistant mouse (SAMR1) as a control. In this study, we aimed to determine the onset of senescence-induced neurodegeneration and the related potential therapeutic window using behavioral experiments, immunohistochemistry and western blotting in SAMP8 and SAMR1 mice at 3, 6 and 9 months of age. The Y-maze revealed significantly impaired working spatial memory of SAMP8 mice from the 6th month. With ageing, increasing plasma concentrations of proinflammatory cytokines in SAMP8 mice were detected as well as significantly increased astrocytosis in the cortex and microgliosis in the brainstem. Moreover, from the 3rd month, SAMP8 mice displayed a decreased number of neurons and neurogenesis in the hippocampus. From the 6th month, increased pathological phosphorylation of tau protein at Thr231 and Ser214 was observed in the hippocampi of SAMP8 mice. In conclusion, changes specific for neurodegenerative processes were observed between the 3rd and 6th month of age in SAMP8 mice; thus, potential neuroprotective interventions could be applied between these ages.


Assuntos
Hipocampo , Proteínas tau , Envelhecimento/fisiologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Camundongos , Proteínas tau/genética , Proteínas tau/metabolismo
2.
Curr Alzheimer Res ; 18(8): 607-622, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34551697

RESUMO

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-ß (Aß) pathology, reducing the Aß 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 Aß 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 Aß 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 Aß 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.


Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Cerebelo , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Placa Amiloide/patologia , Presenilina-1/genética , Presenilina-1/metabolismo , Hormônio Liberador de Prolactina/metabolismo , Hormônio Liberador de Prolactina/farmacologia
3.
J Neuroinflammation ; 18(1): 141, 2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34158075

RESUMO

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.


Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Obesidade/complicações , Tauopatias/complicações , Animais , Modelos Animais de Doenças , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Feminino , Hipocampo/metabolismo , Inflamação , Masculino , Memória de Curto Prazo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Limitação da Mobilidade , Obesidade/etiologia , Fosforilação , Fatores Sexuais , Tauopatias/genética , Proteínas tau
4.
Analyst ; 145(13): 4595-4605, 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32436545

RESUMO

Mass spectrometry imaging (MSI) is a modern analytical technique capable of monitoring the spatial distribution of compounds within target tissues. Collection and storage are important steps in sample preparation. The recommended and most widely used preservation procedure for MSI is freezing samples in isopentane and storing them at temperatures below -80 °C. On the other hand, the most common and general method for preserving biological samples in clinical practice is fixation in paraformaldehyde. Special types of samples prepared from these fixed tissues that are used for histology and immunohistochemistry are free-floating sections. It would be very beneficial if the latter procedure could also be applicable for the samples intended for subsequent MSI analysis. In the present work, we optimized and evaluated paraformaldehyde-fixed free-floating sections for the analysis of lipids in mouse brains and used the sections for the study of lipid changes in double transgenic APP/PS1 mice, a model of Alzheimer's-like pathology. Moreover, we examined the neuroprotective properties of palm11-PrRP31, an anorexigenic and glucose-lowering analog of prolactin-releasing peptide, and liraglutide, a type 2 diabetes drug. From the free-floating sections, we obtained lipid images without interference or delocalization, and we demonstrated that free-floating sections can be used for the MSI of lipids. In the APP/PS1 mice, we observed a changed distribution of various lipids compared to the controls. The most significant changes in lipids in the brains of APP/PS1 mice compared to wild-type controls were related to gangliosides (GM2 36:1, GM3 36:1) and phosphatidylinositols (PI 38:4, 36:4) in regions where the accumulation of senile plaques occurred. In APP/PS1 mice peripherally treated with palm11-PrRP31 or liraglutide for 2 months, we found that both peptides reduced the amount and space occupied by lipids, which were linked to the senile plaques. These results indicate that palm11-PrRP31 as well as liraglutide might be potentially useful in the treatment of neurodegenerative diseases.


Assuntos
Doença de Alzheimer/metabolismo , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Metabolismo dos Lipídeos , Lipídeos/análise , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Astrócitos/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Formaldeído/química , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Liraglutida/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Placa Amiloide/metabolismo , Polímeros/química , Presenilina-1/genética , Hormônio Liberador de Prolactina/análogos & derivados , Hormônio Liberador de Prolactina/farmacologia , Manejo de Espécimes , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
5.
J Mol Endocrinol ; 64(2): 77-90, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31855558

RESUMO

Lack of leptin production in ob/ob mice results in obesity and prediabetes that could be partly reversed by leptin supplementation. In the hypothalamus, leptin supports the production of prolactin-releasing peptide (PrRP), an anorexigenic neuropeptide synthesized and active in the brain. In our recent studies, the palmitoylated PrRP analog palm11-PrRP31 showed a central anorexigenic effect after peripheral administration. This study investigates whether PrRP could compensate for the deficient leptin in ob/ob mice. In two separate experiments, palm11-PrRP31 (5 mg/kg) and leptin (5 or 10 µg/kg) were administered subcutaneously twice daily for 2 or 8 weeks to 8- (younger) or 16-(older) week-old ob/ob mice, respectively, either separately or in combination. The body weight decreasing effect of palm11-PrRP31 in both younger and older ob/ob mice was significantly powered by a subthreshold leptin dose, the combined effect could be then considered synergistic. Leptin and palm11-PrRP31 also synergistically lowered liver weight and blood glucose in younger ob/ob mice. Reduced liver weight was linked to decreased mRNA expression of lipogenic enzymes. In the hypothalamus of older ob/ob mice, two main leptin anorexigenic signaling pathways, namely, Janus kinase, signal transducer and activator of transcription-3 activation and AMP-activated protein kinase de-activation, were induced by leptin, palm11-PrRP31, and their combination. Thus, palm11-PrRP31 could partially compensate for leptin deficiency in ob/ob mice. In conclusion, the results demonstrate a synergistic effect of leptin and our lipidized palm11-PrRP31 analog.


Assuntos
Leptina/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Hormônio Liberador de Prolactina/análogos & derivados , Hormônio Liberador de Prolactina/farmacologia , Animais , Temperatura Corporal , Peso Corporal/efeitos dos fármacos , Sinergismo Farmacológico , Ingestão de Alimentos/efeitos dos fármacos , Teste de Tolerância a Glucose , Leptina/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Obesos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Hormônio Liberador de Prolactina/química , Hormônio Liberador de Prolactina/uso terapêutico
6.
J Alzheimers Dis ; 67(4): 1187-1200, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30689580

RESUMO

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.


Assuntos
Liraglutida/farmacologia , Neurônios , Fosforilação/efeitos dos fármacos , Hormônio Liberador de Prolactina/análogos & derivados , Animais , Linhagem Celular , Peptídeo 1 Semelhante ao Glucagon/agonistas , Humanos , Hipotermia Induzida , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Hormônio Liberador de Prolactina/farmacologia , Ratos , Proteínas tau/metabolismo
7.
Appl Biochem Biotechnol ; 188(1): 165-184, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30393821

RESUMO

Type 2 diabetes mellitus (T2DM) is a major epidemiological problem. Metformin and vildagliptin are well-established antidiabetic drugs. The aim of the study was to evaluate the changes of plasma metabolic profile induced by a high-fat diet (HFD) and subsequent oral administration of metformin, vildagliptin, and their combination in a mouse model of diet-induced obesity (DIO)/T2DM analyzed using quadrupole-time-of-flight mass spectrometry (qTOF-MS). Metformin treatment increased the levels of butyrylcarnitine and acylcarnitine C18:1 concentrations and decreased the levels of isoleucine concentrations compared to untreated HFD mice. Vildagliptin treatment increased levels of butyrylcarnitine and acetylcarnitine. In summary, our metabolomics study revealed multiple differences between obese diabetic HFD mice and lean standard chow diet (SCD) mice, which were partially modifiable by subsequent metformin and vildagliptin treatment.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/uso terapêutico , Metabolômica , Metformina/uso terapêutico , Obesidade/metabolismo , Vildagliptina/uso terapêutico , Animais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Modelos Animais de Doenças , Quimioterapia Combinada , Hipoglicemiantes/administração & dosagem , Masculino , Espectrometria de Massas , Metformina/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/complicações , Reprodutibilidade dos Testes , Vildagliptina/administração & dosagem
8.
Neuropharmacology ; 144: 377-387, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30428311

RESUMO

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 ß-amyloid (Aß) 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 Aß plaque load in the hippocampus. Palm11-PrRP31 also significantly reduced hippocampal microgliosis, consistent with our observations of a reduced Aß 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.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Amiloidose/tratamento farmacológico , Liraglutida/farmacologia , Fármacos Neuroprotetores/farmacologia , Placa Amiloide/tratamento farmacológico , Hormônio Liberador de Prolactina/análogos & derivados , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Amiloidose/metabolismo , Amiloidose/patologia , Animais , Modelos Animais de Doenças , Gliose/tratamento farmacológico , Gliose/metabolismo , Gliose/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/efeitos dos fármacos , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Distribuição Aleatória , Proteínas tau/metabolismo
9.
J Pharmacol Exp Ther ; 366(3): 422-432, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29914876

RESUMO

Ghrelin, the only known orexigenic gut hormone produced primarily in the stomach, has lately gained attention as a potential treatment of anorexia and cachexia. However, its biologic stability is highly limited; therefore, a number of both peptide and nonpeptide ghrelin analogs have been synthesized. In this study, we provide in vitro and in vivo characterization of a series of novel peptide growth hormone secretagogue receptor (GHS-R1a) agonists, both under nonpathologic conditions and in the context of lipopolysaccharide (LPS)-induced anorexia. These analogs were based on our previous series modified by replacing the Ser3 with diaminopropionic acid (Dpr), the N-terminal Gly with sarcosine, and Phe4 with various noncoded amino acids. New analogs were further modified by replacing the n-octanoyl bound to Dpr3 with longer or unsaturated fatty acid residues, by incorporation of the second fatty acid residue into the molecule, or by shortening the peptide chain. These modifications preserved the ability of ghrelin analogs to bind to the membranes of cells transfected with GHS-R1a, as well as the GHS-R1a signaling activation. The selected analogs exhibited long-lasting and potent orexigenic effects after a single s.c. administration in mice. The stability of new ghrelin analogs in mice after s.c. administration was significantly higher when compared with ghrelin and [Dpr3]ghrelin, with half-lives of approximately 2 hours. A single s.c. injection of the selected ghrelin analogs in mice with LPS-induced anorexia significantly increased food intake via the activation of orexigenic pathways and normalized blood levels of proinflammatory cytokines, demonstrating the anti-inflammatory potential of the analogs.


Assuntos
Anorexia/induzido quimicamente , Anorexia/tratamento farmacológico , Grelina/análogos & derivados , Grelina/farmacologia , Lipopolissacarídeos/efeitos adversos , Sequência de Aminoácidos , Animais , Anorexia/metabolismo , Anorexia/fisiopatologia , Ligação Competitiva , Ingestão de Alimentos/efeitos dos fármacos , Grelina/metabolismo , Grelina/farmacocinética , Hormônio do Crescimento/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estabilidade Proteica , Receptores de Grelina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual , beta-Lactamases/metabolismo
10.
J Alzheimers Dis ; 62(4): 1725-1736, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29614684

RESUMO

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-3ß, 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.


Assuntos
Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Hormônio Liberador de Prolactina/análogos & derivados , Tauopatias/tratamento farmacológico , Proteínas tau/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Memória de Curto Prazo/efeitos dos fármacos , Memória de Curto Prazo/fisiologia , Camundongos Transgênicos , Fosforilação/efeitos dos fármacos , Hormônio Liberador de Prolactina/farmacologia , Hormônio Liberador de Prolactina/uso terapêutico , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia , Tauopatias/metabolismo , Tauopatias/patologia , Tauopatias/psicologia
11.
Nutr Diabetes ; 8(1): 5, 2018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29339795

RESUMO

BACKGROUND/OBJECTIVES: Prolactin-releasing peptide (PrRP) has a potential to decrease food intake and ameliorate obesity, but is ineffective after peripheral administration. We have previously shown that our novel lipidized analogs PrRP enhances its stability in the circulation and enables its central effect after peripheral application. The purpose of this study was to explore if sub-chronic administration of novel PrRP analog palmitoylated in position 11 (palm11-PrRP31) to Koletsky-spontaneously hypertensive obese rats (SHROB) could lower body weight and glucose intolerance as well as other metabolic parameters. SUBJECTS/METHODS: The SHROB rats (n = 16) were used for this study and age-matched hypertensive lean SHR littermates (n = 16) served as controls. Palm11-PrRP31 was administered intraperitoneally to SHR and SHROB (n = 8) at a dose of 5 mg/kg once-daily for 3 weeks. During the dosing period food intake and body weight were monitored. At the end of the experiment the oral glucose tolerance test was performed; plasma and tissue samples were collected. Thereafter, arterial blood pressure was measured. RESULTS: At the end of the experiment, vehicle-treated SHROB rats showed typical metabolic syndrome parameters, including obesity, glucose intolerance, dyslipidemia, and hypertension. Peripheral treatment with palm11-PrRP31 progressively decreased the body weight of SHR rats but not SHROB rats, though glucose tolerance was markedly improved in both strains. Moreover, in SHROB palm11-PrRP31 ameliorated the HOMA index, insulin/glucagon ratio, and increased insulin receptor substrate 1 and 2 expression in fat and insulin signaling in the hypothalamus, while it had no effect on blood pressure. CONCLUSIONS: We demonstrated that our new lipidized PrRP analog is capable of improving glucose tolerance in obese SHROB rats after peripheral application, suggesting that its effect on glucose metabolism is independent of leptin signaling and body weight lowering. These data suggest that this analog has the potential to be a compound with both anti-obesity and glucose-lowering properties.


Assuntos
Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Intolerância à Glucose , Hipertensão/sangue , Síndrome Metabólica , Obesidade , Hormônio Liberador de Prolactina/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Glucagon/sangue , Intolerância à Glucose/sangue , Intolerância à Glucose/tratamento farmacológico , Teste de Tolerância a Glucose , Hipertensão/tratamento farmacológico , Insulina/sangue , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina , Lipídeos/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Obesidade/sangue , Obesidade/tratamento farmacológico , Hormônio Liberador de Prolactina/administração & dosagem , Hormônio Liberador de Prolactina/análogos & derivados , Hormônio Liberador de Prolactina/uso terapêutico , Ratos Endogâmicos SHR
12.
J Mol Endocrinol ; 60(2): 85-94, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29233862

RESUMO

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.


Assuntos
Hipotálamo/metabolismo , Leptina/metabolismo , Hormônio Liberador de Prolactina/metabolismo , Transdução de Sinais , Animais , Apoptose , Ingestão de Alimentos , Jejum/sangue , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Neurônios/metabolismo , Tamanho do Órgão , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores para Leptina/metabolismo
13.
PLoS One ; 12(8): e0183449, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28820912

RESUMO

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.


Assuntos
Dieta , Obesidade/metabolismo , Peptídeos/farmacologia , Hormônio Liberador de Prolactina/metabolismo , Sequência de Aminoácidos , Animais , Ligação Competitiva , Células CHO , Cricetinae , Cricetulus , Masculino , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Ressonância Magnética Nuclear Biomolecular , Obesidade/etiologia , Peptídeos/química , Hormônio Liberador de Prolactina/química , beta-Lactamases/metabolismo
14.
J Endocrinol ; 233(1): 93-104, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28138003

RESUMO

Liraglutide is the glucagon-like peptide-1 receptor agonist widely used for the treatment of type 2 diabetes mellitus. Recently, it has been demonstrated to decrease cardiovascular morbidity and mortality in patients with type 2 diabetes and high cardiovascular risk. Although the major modes of liraglutide action are well-known, its detailed action at the metabolic level has not been studied. To this end, we explored the effect of 2-week liraglutide treatment in C57BL/6 male mice with obesity and diabetes induced by 13 weeks of high-fat diet using NMR spectroscopy to capture the changes in urine metabolic profile induced by the therapy. The liraglutide treatment decreased body and fat pads weight along with blood glucose and triglyceride levels. NMR spectroscopy identified 11 metabolites significantly affected by liraglutide treatment as compared to high-fat diet-fed control group. These metabolites included ones involved in nicotinamide adenine dinucleotide metabolism, ß-oxidation of fatty acids and microbiome changes. Although majority of the metabolites changed after liraglutide treatment were similar as the ones previously identified after vildagliptin administration in a similar mouse model, the changes in creatinine, taurine and trigonelline were specific for liraglutide administration. The significance of these changes and its possible use in the personalization of antidiabetic therapy in humans requires further research.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Liraglutida/farmacologia , Obesidade/tratamento farmacológico , Tecido Adiposo/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Hipoglicemiantes/uso terapêutico , Liraglutida/uso terapêutico , Espectroscopia de Ressonância Magnética , Masculino , Metabolômica , Camundongos , Obesidade/metabolismo , Triglicerídeos/sangue
15.
Mol Cell Endocrinol ; 431: 88-100, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27164444

RESUMO

Metformin, vildagliptin and their combination are widely used for the treatment of diabetes, but little is known about the metabolic responses to these treatments. In the present study, NMR-based metabolomics was applied to detect changes in the urinary metabolomic profile of a mouse model of diet-induced obesity in response to these treatments. Additionally, standard biochemical parameters and the expression of enzymes involved in glucose and fat metabolism were monitored. Significant correlations were observed between several metabolites (e.g., N-carbamoyl-ß-alanine, N1-methyl-4-pyridone-3-carboxamide, N1-methyl-2-pyridone-5-carboxamide, glucose, 3-indoxyl sulfate, dimethylglycine and several acylglycines) and the area under the curve of glucose concentrations during the oral glucose tolerance test. The present study is the first to present N-carbamoyl-ß-alanine as a potential marker of type 2 diabetes mellitus and consequently to demonstrate the efficacies of the applied antidiabetic interventions. Moreover, the elevated acetate level observed after vildagliptin administration might reflect increased fatty acid oxidation.


Assuntos
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Metformina/farmacologia , Nitrilas/farmacologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Pirrolidinas/farmacologia , Adamantano/farmacologia , Animais , Diabetes Mellitus Tipo 2/urina , Dieta , Teste de Tolerância a Glucose/métodos , Hipoglicemiantes/farmacologia , Masculino , Metabolômica/métodos , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/urina , Piridonas/metabolismo , Vildagliptina , beta-Alanina/análogos & derivados , beta-Alanina/metabolismo
16.
J Endocrinol ; 229(2): 85-96, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26906745

RESUMO

Anorexigenic neuropeptides produced and acting in the brain have the potential to decrease food intake and ameliorate obesity, but are ineffective after peripheral application, owing to a limited ability to cross the blood-brain barrier. We have designed lipidized analogs of prolactin-releasing peptide (PrRP), which is involved in energy balance regulation as demonstrated by obesity phenotypes of both Prrp-knockout and Prrp receptor-knockout mice. The aim of this study was to characterize the subchronic effect of a palmitoylated PrRP analog in two rat models of obesity and diabetes: diet-induced obese Sprague-Dawley rats and leptin receptor-deficient Zucker diabetic (ZDF) rats. In the rats with diet-induced obesity (DIO), a two-week intraperitoneal treatment with palmitoylated PrRP lowered food intake by 24% and body weight by 8%. This treatment also improved glucose tolerance and tended to decrease leptin levels and adipose tissue masses in a dose-dependent manner. In contrast, in ZDF rats, the same treatment with palmitoylated PrRP lowered food intake but did not significantly affect body weight or glucose tolerance, probably in consequence of severe leptin resistance due to a nonfunctional leptin receptor. Our data indicate a good efficacy of lipidized PrRP in DIO rats. Thus, the strong anorexigenic, body weight-reducing, and glucose tolerance-improving effects make palmitoylated PrRP an attractive candidate for anti-obesity treatment.


Assuntos
Peso Corporal/efeitos dos fármacos , Obesidade/tratamento farmacológico , Hormônio Liberador de Prolactina/análogos & derivados , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Depressores do Apetite/farmacologia , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica/efeitos adversos , Desenho de Fármacos , Ingestão de Alimentos/efeitos dos fármacos , Teste de Tolerância a Glucose , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Lipoilação , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Obesidade/metabolismo , Obesidade/patologia , Hormônio Liberador de Prolactina/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Receptores para Leptina/deficiência
17.
Anal Bioanal Chem ; 408(2): 567-78, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26577083

RESUMO

Obesity with related complications represents a widespread health problem. The etiopathogenesis of obesity is often studied using numerous rodent models. The mouse model of monosodium glutamate (MSG)-induced obesity was exploited as a model of obesity combined with insulin resistance. The aim of this work was to characterize the metabolic status of MSG mice by NMR-based metabolomics in combination with relevant biochemical and hormonal parameters. NMR analysis of urine at 2, 6, and 9 months revealed altered metabolism of nicotinamide and polyamines, attenuated excretion of major urinary proteins, increased levels of phenylacetylglycine and allantoin, and decreased concentrations of methylamine in urine of MSG-treated mice. Altered levels of creatine, citrate, succinate, and acetate were observed at 2 months of age and approached the values of control mice with aging. The development of obesity and insulin resistance in 6-month-old MSG mice was also accompanied by decreased mRNA expressions of adiponectin, lipogenetic and lipolytic enzymes and peroxisome proliferator-activated receptor-gamma in fat while mRNA expressions of lipogenetic enzymes in the liver were enhanced. At the age of 9 months, biochemical parameters of MSG mice were normalized to the values of the controls. This fact pointed to a limited predictive value of biochemical data up to age of 6 months as NMR metabolomics confirmed altered urine metabolic composition even at 9 months.


Assuntos
Metabolômica , Obesidade/urina , Glutamato de Sódio/efeitos adversos , Urina/química , Animais , Glicemia/metabolismo , Humanos , Insulina/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Masculino , Camundongos , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/genética , Receptores Ativados por Proliferador de Peroxissomo/metabolismo
18.
J Alzheimers Dis ; 45(3): 823-35, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25624414

RESUMO

Numerous epidemiological and experimental studies have demonstrated that patients who suffer from metabolic disorders, such as type 2 diabetes mellitus (T2DM) or obesity, have higher risks of cognitive dysfunction and of Alzheimer's disease (AD). Impaired insulin signaling in the brain could contribute to the formation of neurofibrillary tangles, which contain an abnormally hyperphosphorylated tau protein. This study aimed to determine whether potential tau hyperphosphorylation could be detected in an obesity-induced pre-diabetes state and whether anorexigenic agents could affect this state. We demonstrated that 6-month-old mice with monosodium glutamate (MSG) obesity, which represent a model of obesity-induced pre-diabetes, had increased tau phosphorylation at Ser396 and Thr231 in the hippocampus compared with the controls, as determined by western blots. Two weeks of subcutaneous treatment with a lipidized analog of prolactin-releasing peptide (palm-PrRP31) or with the T2DM drug liraglutide, which both had a central anorexigenic effect, resulted in increased phosphorylation of the insulin cascade kinases PDK1 (Ser241), Akt (Thr308), and GSK-3ß (Ser9). Furthermore, these drugs attenuated phosphorylation at Ser396, Thr231, and Thr212 of tau and of the primary tau kinases in the hippocampi of 6-month-old MSG-obese mice. We identified tau hyperphosphorylation in the obesity-induced pre-diabetes state in MSG-obese mice and demonstrated the beneficial effects of palm-PrRP31 and liraglutide, both of known central anorexigenic effects, on hippocampal insulin signaling and on tau phosphorylation.


Assuntos
Aromatizantes/toxicidade , Hipocampo/efeitos dos fármacos , Insulinas/metabolismo , Lipopeptídeos/metabolismo , Obesidade , Transdução de Sinais/efeitos dos fármacos , Glutamato de Sódio/toxicidade , Proteínas tau/metabolismo , Análise de Variância , Animais , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon/genética , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Teste de Tolerância a Glucose , Hipocampo/metabolismo , Lipopeptídeos/uso terapêutico , Masculino , Camundongos , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Obesidade/patologia , Fosforilação/efeitos dos fármacos , Hormônio Liberador de Prolactina/efeitos dos fármacos , Hormônio Liberador de Prolactina/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Fatores de Tempo
19.
J Pharmacol Exp Ther ; 340(3): 781-6, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22182933

RESUMO

Ghrelin, the only known peripherally produced and centrally acting peptide that stimulates food intake, is synthesized primarily in the stomach and acts through the growth hormone secretagogue receptor (GHS-R1a). In addition to its orexigenic effect, ghrelin stimulates the release of growth hormone (GH). In this study, we investigated the biological properties of full-length and shortened ghrelin analogs in which octanoylated Ser(3) is replaced with an octanoic acid moiety coupled to diaminopropionic acid (Dpr). Ghrelin analogs stabilized with Dpr(N-octanoyl) in position 3 and noncoded amino acids in position 1 (sarcosine) and/or position 4 (naphthylalanine or cyclohexylalanine) were found to possess affinities similar to those of ghrelin for cell membranes with transfected GHS-R1a. In vivo, the prolonged orexigenic effects of analogs containing Dpr(N-octanoyl)(3) compared with that of ghrelin in adult mice and a similar impact on GH secretion in young mice were found. Full-length [Dpr(N-octanoyl)(3)]ghrelin and its analogs with a noncoded amino acid in position 1 and/or 4 showed significantly prolonged stability in blood plasma compared with that of ghrelin. Ghrelin analogs with a prolonged orexigenic effect are potential treatments for GH deficiency or cachexia that accompanies chronic diseases. Desoctanoylated ghrelin analogs and N-terminal penta- and octapeptides of ghrelin did not show any biological activity.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Grelina/análogos & derivados , Sequência de Aminoácidos , Animais , Grelina/síntese química , Grelina/metabolismo , Hormônio do Crescimento/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Receptores de Grelina/metabolismo , Relação Estrutura-Atividade
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