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1.
Eur J Pharmacol ; 880: 173186, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32416182

RESUMO

The melanocortin MC1 and MC3 receptors elicit anti-inflammatory actions in leukocytes and activation of these receptors has been shown to alleviate arterial inflammation in experimental atherosclerosis. Thus, we aimed to investigate whether selective targeting of melanocortin MC3 receptor protects against atherosclerosis. Apolipoprotein E deficient (ApoE-/-) mice were fed high-fat diet for 12 weeks and randomly assigned to receive either vehicle (n = 11) or the selective melanocortin MC3 receptor agonist [D-Trp(8)]-gamma-melanocyte-stimulating hormone ([D-Trp8]-γ-MSH; 15 µg/day, n = 10) for the last 4 weeks. Lesion size as well as macrophage and collagen content in the aortic root plaques were determined. Furthermore, leukocyte counts in the blood and aorta and cytokine mRNA expression levels in the spleen, liver and aorta were quantified. No effect was observed in the body weight development or plasma cholesterol level between the two treatment groups. However, [D-Trp8]-γ-MSH treatment significantly reduced plasma levels of chemokine (C-C motif) ligands 2, 4 and 5. Likewise, cytokine and adhesion molecule expression levels were reduced in the spleen and liver of γ-MSH-treated mice, but not substantially in the aorta. In line with these findings, [D-Trp8]-γ-MSH treatment reduced leukocyte counts in the blood and aorta. Despite reduced inflammation, [D-Trp8]-γ-MSH did not change lesion size, macrophage content or collagen deposition of aortic root plaques. In conclusion, the findings indicate that selective activation of melanocortin MC3 receptor by [D-Trp8]-γ-MSH suppresses systemic and local inflammation and thereby also limits leukocyte accumulation in the aorta. However, the treatment was ineffective in reducing atherosclerotic plaque size.


Assuntos
Anti-Inflamatórios/uso terapêutico , Hormônios Estimuladores de Melanócitos/uso terapêutico , Placa Aterosclerótica/tratamento farmacológico , Receptor Tipo 3 de Melanocortina/agonistas , Animais , Anti-Inflamatórios/farmacologia , Aorta/efeitos dos fármacos , Aorta/imunologia , Aorta/patologia , Células Cultivadas , Colesterol/sangue , Citocinas/sangue , Citocinas/genética , Dieta Hiperlipídica , Células Endoteliais , Feminino , Inflamação/imunologia , Contagem de Leucócitos , Fígado/efeitos dos fármacos , Fígado/imunologia , Hormônios Estimuladores de Melanócitos/farmacologia , Camundongos Knockout para ApoE , Placa Aterosclerótica/imunologia , Placa Aterosclerótica/patologia , Receptor Tipo 3 de Melanocortina/imunologia , Baço/efeitos dos fármacos , Baço/imunologia
2.
Anticancer Agents Med Chem ; 20(4): 402-416, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31889492

RESUMO

BACKGROUND: Cancer is the leading cause of death worldwide. Early detection can reduce the disadvantageous effects of diseases and the mortality in cancer. Nuclear medicine is a powerful tool that has the ability to diagnose malignancy without harming normal tissues. In recent years, radiolabeled peptides have been investigated as potent agents for cancer detection. Therefore, it is necessary to modify radiopeptides in order to achieve more effective agents. OBJECTIVE: This review describes modifications in the structure of radioconjugates with spacers who have improved the specificity and sensitivity of the peptides that are used in oncologic diagnosis and therapy. METHODS: To improve the biological activity, researchers have conjugated these peptide analogs to different spacers and bifunctional chelators. Many spacers of different kinds, such as hydrocarbon chain, amino acid sequence, and poly (ethyleneglycol) were introduced in order to modify the pharmacokinetic properties of these biomolecules. RESULTS: Different spacers have been applied to develop radiolabeled peptides as potential tracers in nuclear medicine. Spacers with different charge and hydrophilicity affect the characteristics of peptide conjugate. For example, the complex with uncharged and hydrophobic spacers leads to increased liver uptake, while the composition with positively charged spacers results in high kidney retention. Therefore, the pharmacokinetics of radio complexes correlates to the structure and total charge of the conjugates. CONCLUSION: Radio imaging technology has been successfully applied to detect a tumor in the earliest stage. For this purpose, the assessment of useful agents to diagnose the lesion is necessary. Developing peptide radiopharmaceuticals using spacers can improve in vitro and in vivo behavior of radiotracers leading to better noninvasive detection and monitoring of tumor growth.


Assuntos
Neoplasias/diagnóstico , Neoplasias/radioterapia , Peptídeos/química , Peptídeos/uso terapêutico , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/uso terapêutico , Animais , Bombesina/química , Bombesina/uso terapêutico , Gastrinas/química , Gastrinas/uso terapêutico , Humanos , Hormônios Estimuladores de Melanócitos/química , Hormônios Estimuladores de Melanócitos/uso terapêutico , Neurotensina/química , Neurotensina/uso terapêutico , Oligopeptídeos/química , Oligopeptídeos/uso terapêutico , Somatostatina/química , Somatostatina/uso terapêutico
3.
Epilepsy Res ; 152: 31-34, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30875634

RESUMO

Epileptic spasms during infancy (infantile spasms) represent a serious treatment and social problem despite their rare occurrence. Current treatments include hormonal therapy (adrenocorticotropin-ACTH or corticosteroids) or vigabatrin (per se or in the combination). These treatments are partially effective and with potentially significant adverse effects. Thus, the search for new effective drugs is warranted. We tested efficacy of a novel fusion peptide AQB-565 developed by Aequus Biopharma in a model of infantile spasms consisting of prenatal exposure to betamethasone and repeated postnatal trigger of spasms with N-methyl-d-aspartic acid (NMDA). AQB-565 molecule includes the first 24 amino acids of ACTH, a ten amino acid linker and a modified melanocyte-stimulating hormone molecule. In contrast to ACTH with almost uniform activity over all peripheral and central melanocortin receptor isoforms, AQB is preferentially active on central melanocortin receptors MC3 and MC4. Here, we used equivalent doses of rat ACTH (full molecule) and AQB-565 and compared their efficacy in a prospective randomized test against of repeated bouts of spasms on postnatal days (P)12, P13 and P15 in the rat model. All doses of ACTH (range 0.02-1.0 mg/kg s.c.) and all doses but one of AQB-565 in the same range suppressed spasms in P15 rats (treatment stopped on P14). There was no dose-dependent effect and both compounds had all-or-none effect that is similar to clinical outcome of hormonal treatment of infantile spasms in children. Thus, AQB-565 may represent a novel treatment of infantile spasms similarly effective as ACTH but with potentially limited side effects.


Assuntos
Hormônio Adrenocorticotrópico/uso terapêutico , Hormônios Estimuladores de Melanócitos/uso terapêutico , Espasmos Infantis/tratamento farmacológico , Hormônio Adrenocorticotrópico/química , Hormônio Adrenocorticotrópico/metabolismo , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletroencefalografia , Agonistas de Aminoácidos Excitatórios/toxicidade , Feminino , Humanos , Lactente , Masculino , Hormônios Estimuladores de Melanócitos/química , Hormônios Estimuladores de Melanócitos/metabolismo , N-Metilaspartato/toxicidade , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/uso terapêutico , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Espasmos Infantis/induzido quimicamente , Resultado do Tratamento
4.
Ann Rheum Dis ; 71(1): 143-9, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21998117

RESUMO

OBJECTIVE: To facilitate the targeting to inflammation sites of small anti-inflammatory peptides, with short half-lives, by fusion with the latency-associated peptide (LAP) of transforming growth factor ß1 through a cleavable matrix metalloproteinase (MMP) linker. This design improves efficacy, overcoming the limitations to their clinical use. METHODS: We generated latent forms of vasoactive intestinal peptide (VIP), α-melanocyte-stimulating hormone (MSH) and γ(3)MSH by fusion to LAP through an MMP cleavage site using recombinant DNA technology. The biological activities of these latent therapeutics were studied in vivo using monosodium urate (MSU)-induced peritonitis and collagen-induced arthritis (CIA) models. We assessed gene therapy and purified protein therapy. RESULTS: The recruitment of the polymorphonuclear cells induced by MSU injection into mouse peritoneal cavity was reduced by 35% with γ(3)MSH (1 nmol), whereas administration of a much lower dose of purified latent LAP-MMP-γ(3)MSH (0.03 nmol) attenuated leucocyte influx by 50%. Intramuscular gene delivery of plasmids coding LAP-MMP-VIP and LAP-MMP-αMSH at disease onset reduced the development of CIA compared with LAP-MMP, which does not contain any therapeutic moiety. Histological analysis confirmed a significantly lower degree of inflammation, bone and cartilage erosion in groups treated with LAP-MMP-VIP or LAP-MMP-αMSH. Antibody titres to collagen type II and inflammatory cytokine production were also reduced in these two groups. CONCLUSION: Incorporation of small anti-inflammatory peptides within the LAP shell and delivered as recombinant protein or through gene therapy can control inflammatory and arthritic disease. This platform delivery can be developed to control human arthritides and other autoimmune diseases.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/terapia , Hormônios Estimuladores de Melanócitos/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Peritonite/terapia , Proteínas Recombinantes de Fusão/uso terapêutico , Fator de Crescimento Transformador beta/uso terapêutico , Peptídeo Intestinal Vasoativo/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Citocinas/sangue , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Terapia Genética/métodos , Meia-Vida , Masculino , Hormônios Estimuladores de Melanócitos/genética , Hormônios Estimuladores de Melanócitos/farmacocinética , Camundongos , Camundongos Endogâmicos DBA , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/farmacocinética , Peritonite/tratamento farmacológico , Peritonite/metabolismo , Proteínas Recombinantes de Fusão/farmacocinética , Distribuição Tecidual , Resultado do Tratamento , Peptídeo Intestinal Vasoativo/genética , Peptídeo Intestinal Vasoativo/farmacocinética
5.
Neurosci Lett ; 506(1): 126-30, 2012 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-22075225

RESUMO

Neuronostatin, a newly identified peptide encoded by the somatostatin (SST) gene, was proved to produce significant antinociceptive effect in mouse tail immersion test. However, the effect of neuronostatin on tonic pain was still not clear. The aim of this study was to investigate the effect of neuronostatin in the formalin test and its possible mechanism. We found that intracerebroventricular (i.c.v.) administration of neuronostatin (1, 3, 6, 12nmol/mouse) increased licking in a dose-related manner during the late phase, but did not affect the early phase of formalin test in mice. In addition, the hyperalgesic effect during the late phase was completely reversed by melanocortin 3/4 receptor antagonist SHU9119 (50pmol/mouse) or opioid receptor antagonist naloxone (5nmol/mouse), but not GABAA receptor antagonist bicuculline (1086pmol/mouse). These data suggested that the hyperalgesic response induced by neuronostatin was dependent upon the central melanocortin system and endogenous opioid system. In conclusion, these results indicated that neuronostatin may be a new neuropeptide with important role in the modulation of acute and tonic pain.


Assuntos
Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Fragmentos de Peptídeos/efeitos adversos , Somatostatina/efeitos adversos , Análise de Variância , Animais , Bicuculina/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Antagonistas de Receptores de GABA-A/uso terapêutico , Injeções Intraventriculares , Masculino , Hormônios Estimuladores de Melanócitos/uso terapêutico , Camundongos , Camundongos Endogâmicos , Fatores de Tempo
7.
Eur J Pharmacol ; 660(1): 188-93, 2011 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-21315067

RESUMO

Peptides serve as effective drugs and contrast agents in the clinic today. However the inherent drawbacks of peptide structures can limit their efficacy as drugs. To overcome this we have been developing new methods to create 'tailor-made' peptides and peptide mimetics with improved pharmacological and physical properties. In this work we introduce novel peptide and small molecule conjugated molecules for earlier diagnosis and treatment of melanoma.


Assuntos
Detecção Precoce de Câncer , Hormônios Estimuladores de Melanócitos/química , Hormônios Estimuladores de Melanócitos/farmacologia , Melanoma/diagnóstico , Melanoma/tratamento farmacológico , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Células HEK293 , Humanos , Hormônios Estimuladores de Melanócitos/metabolismo , Hormônios Estimuladores de Melanócitos/uso terapêutico , Melanoma/metabolismo , Camundongos , Receptor Tipo 1 de Melanocortina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Br J Pharmacol ; 162(4): 917-28, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21039420

RESUMO

BACKGROUND AND PURPOSE: Melanocortins reverse circulatory shock and improve survival by counteracting the systemic inflammatory response, and through the activation of the vagus nerve-mediated cholinergic anti-inflammatory pathway. To gain insight into the potential therapeutic value of melanocortins against multiple organ damage following systemic inflammatory response, here we investigated the effects of the melanocortin analogue [Nle4 D-Phe7]α-MSH (NDP-α-MSH) in a widely used murine model of multiple organ dysfunction syndrome (MODS). EXPERIMENTAL APPROACH: MODS was induced in mice by a single intraperitoneal injection of lipopolysaccharide followed, 6 days later (= day 0), by zymosan. After MODS or sham MODS induction, animals were randomized to receive intraperitoneally NDP-α-MSH (340 µg·kg⁻¹ day) or saline for up to 16 days. Additional groups of MODS mice were concomitantly treated with the melanocortin MC4 receptor antagonist HS024, or the nicotinic acetylcholine receptor antagonist chlorisondamine, and NDP-α-MSH. KEY RESULTS: At day 7, in the liver and lung NDP-α-MSH, significantly reduced mRNA expression of tumour necrosis factor-α (TNF-α), increased mRNA expression of interleukin-10 and improved the histological picture, as well as reduced TNF-α plasma levels; furthermore, NDP-α-MSH dose-dependently increased survival rate, as assessed throughout the 16 day observation period. HS024 and chlorisondamine prevented all the beneficial effects of NDP-α-MSH in MODS mice. CONCLUSIONS AND IMPLICATIONS: These data indicate that NDP-α-MSH protects against experimental MODS by counteracting the systemic inflammatory response, probably through brain MC4 receptor-triggered activation of the cholinergic anti-inflammatory pathway. These findings reveal previously undescribed effects of melanocortins and could have clinical relevance in the MODS setting.


Assuntos
Mediadores da Inflamação/metabolismo , Melanocortinas/metabolismo , Hormônios Estimuladores de Melanócitos/uso terapêutico , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/metabolismo , Ácido Pentético/análogos & derivados , Substâncias Protetoras/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Mediadores da Inflamação/sangue , Interleucina-10/genética , Interleucina-10/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Hormônios Estimuladores de Melanócitos/administração & dosagem , Hormônios Estimuladores de Melanócitos/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/patologia , Antagonistas Nicotínicos/farmacologia , Ácido Pentético/administração & dosagem , Ácido Pentético/antagonistas & inibidores , Ácido Pentético/uso terapêutico , Substâncias Protetoras/administração & dosagem , RNA Mensageiro/metabolismo , Distribuição Aleatória , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Análise de Sobrevida , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
9.
Curr Top Med Chem ; 9(6): 554-63, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19689365

RESUMO

Current biological and pharmacological evidence suggests that the melanocortin 4 and melanocortin 3 receptors which are seven transmembrane G-protein coupled receptors (GPCRs) are involved in various aspects of energy balance and feeding behaviors in animals including humans. The natural endogenous ligands for these receptors are products of the gene pro-opiomelanocortin (POMC), and include alpha-melanocyte stimulating hormone, gamma-melanocyte stimulating hormone and perhaps other modified products of POMC. Thus well designed agonists and antagonists of these ligands might serve as drugs for the treatment of feeding disorders. However, these melanotropin peptides also can have other biological activities that involve the MC3R and MC4R, and these other biological properties will need to be modulated in ligands that are likely to be useful drugs for feeding disorders. Current progress in these areas with special emphasis on the MC3R will be discussed along with possible new directions that might be fruitful in these important aspects of contemporary biology and medicine.


Assuntos
Fármacos Antiobesidade/química , Fármacos Antiobesidade/uso terapêutico , Hormônios Estimuladores de Melanócitos/química , Hormônios Estimuladores de Melanócitos/uso terapêutico , Distúrbios Nutricionais/tratamento farmacológico , Animais , Fármacos Antiobesidade/farmacologia , Avaliação Pré-Clínica de Medicamentos , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Humanos , Hormônios Estimuladores de Melanócitos/farmacologia , Distúrbios Nutricionais/metabolismo , Receptor Tipo 3 de Melanocortina/agonistas , Receptor Tipo 3 de Melanocortina/antagonistas & inibidores , Receptor Tipo 3 de Melanocortina/química , Receptor Tipo 3 de Melanocortina/fisiologia , Receptor Tipo 4 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Receptor Tipo 4 de Melanocortina/fisiologia , Relação Estrutura-Atividade
10.
Diabetes ; 58(8): 1749-56, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19491210

RESUMO

OBJECTIVE: We recently showed that leptin has powerful central nervous system (CNS)-mediated antidiabetic and cardiovascular actions. This study tested whether the CNS melanocortin system mediates these actions of leptin in diabetic rats. RESEARCH DESIGN AND METHODS: A cannula was placed in the lateral ventricle of Sprague-Dawley rats for intracerebroventricular infusions, and arterial and venous catheters were implanted to measure mean arterial pressure (MAP) and heart rate 24 h/day and for intravenous infusions. After recovery from surgery for 8 days, rats were injected with streptozotocin (STZ), and 5 days later, either saline or the melanocortin 3 and 4 receptor (MC3/4R) antagonist SHU-9119 (1 nmol/h) was infused intracerebroventricularly for 17 days. Seven days after starting the antagonist, leptin (0.62 microg/h) was added to the intracerebroventricular infusion for 10 days. Another group of diabetic rats was infused with the MC3/4R agonist MTII (10 ng/h i.c.v.) for 12 days, followed by 7 days at 50 ng/h. RESULTS: Induction of diabetes caused hyperphagia, hyperglycemia, and decreases in heart rate (-76 bpm) and MAP (-7 mmHg). Leptin restored appetite, blood glucose, heart rate, and MAP back to pre-diabetic values in vehicle-treated rats, whereas it had no effect in SHU-9119-treated rats. MTII infusions transiently reduced blood glucose and raised heart rate and MAP, which returned to diabetic values 5-7 days after starting the infusion. CONCLUSIONS: Although a functional melanocortin system is necessary for the CNS-mediated antidiabetic and cardiovascular actions of leptin, chronic MC3/4R activation is apparently not sufficient to mimic these actions of leptin that may involve interactions of multiple pathways.


Assuntos
Sistema Nervoso Central/fisiologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/fisiopatologia , Hipoglicemiantes/uso terapêutico , Leptina/uso terapêutico , Melanocortinas/fisiologia , Hormônios Estimuladores de Melanócitos/uso terapêutico , Receptores da Corticotropina/antagonistas & inibidores , Animais , Apetite/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Ratos , Ratos Endogâmicos WKY , Ratos Sprague-Dawley
11.
Regul Pept ; 149(1-3): 79-83, 2008 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-18442862

RESUMO

The nose provides an effective way for delivering neuropeptides to the central nervous system, bypassing the blood-brain barrier and avoiding systemic side effects. Thereby intranasal neuropeptide administration enables the modulation of central nervous signaling pathways of body weight regulation and cognitive functions. Central nervous control of energy homeostasis is assumed to rely on hypothalamic neuropeptidergic pathways that are triggered by the peripheral adiposity signals insulin and leptin conveying the amount of body fat to the brain. Melanocortins, including alpha-melanocyte stimulating hormone (alpha-MSH), are essential for inducing anorexigenic/catabolic effects, i.e. for inhibiting caloric intake and increasing energy expenditure. Insulin, in addition to its function as an adiposity signal, also influences memory formation. Here we present a series of studies on the intranasal administration of MSH/ACTH4-10, a melanocortin receptor agonist, and of insulin. Prolonged administration of MSH/ACTH4-10 induced weight loss in normal-weight, but not in overweight humans. Intranasal insulin reduced body fat and improved memory functions in the absence of adverse peripheral side effects. Our results may contribute to the future development of therapeutic strategies in disorders like obesity and cognitive impairments that derive from dysfunctions of central nervous neuropeptidergic pathways.


Assuntos
Peso Corporal/fisiologia , Sistema Nervoso Central/metabolismo , Transtornos Cognitivos/terapia , Doenças Metabólicas/terapia , Neuropeptídeos/uso terapêutico , Tecido Adiposo/efeitos dos fármacos , Administração Intranasal , Hormônio Adrenocorticotrópico/administração & dosagem , Hormônio Adrenocorticotrópico/farmacologia , Hormônio Adrenocorticotrópico/uso terapêutico , Peso Corporal/efeitos dos fármacos , Transtornos Cognitivos/metabolismo , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/administração & dosagem , Insulina/farmacologia , Insulina/uso terapêutico , Masculino , Hormônios Estimuladores de Melanócitos/administração & dosagem , Hormônios Estimuladores de Melanócitos/farmacologia , Hormônios Estimuladores de Melanócitos/uso terapêutico , Doenças Metabólicas/metabolismo , Neuropeptídeos/administração & dosagem , Neuropeptídeos/farmacologia , Nootrópicos/administração & dosagem , Nootrópicos/farmacologia , Nootrópicos/uso terapêutico , Obesidade/metabolismo , Obesidade/terapia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/uso terapêutico , Receptores de Melanocortina/agonistas , Resposta de Saciedade/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
12.
Gastroenterology ; 134(1): 166-78, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18061177

RESUMO

BACKGROUND & AIMS: KPV is a tripeptide (Lys-Pro-Val), which possesses anti-inflammatory properties; however, its mechanisms of action still remain unknown. PepT1 is a di/tripeptide transporter normally expressed in the small intestine and induced in colon during inflammatory bowel disease (IBD). The aim of this study was to 1) investigate whether the KPV anti-inflammatory effect is PepT1-mediated in intestinal epithelian and immune cells, and 2) examine the anti-inflammatory effects in two models of mice colitis. METHODS: Human intestinal epithelial cells Caco2-BBE, HT29-Cl.19A, and human T cells (Jurkat) were stimulated with pro-inflammatory cytokines in the present or absence of KPV. KPV anti-inflammatory effect was assessed using a NF-kappaB luciferase gene reporter, Western blot, real-time RT-PCR and ELISA. Uptake experiments were performed using cold KPV as a competitor for PepT1 radiolabelled substrate or using [(3)H]KPV to determine kinetic characteristics of KPV uptake. Anti-inflammatory effect of KPV was also investigated in DSS- and TNBS-induced colitis in mice. KPV was added to drinking water and inflammation was assessed at the histologic level and by proinflammatory cytokine mRNA expression. RESULTS: Nanomolar concentrations of KPV inhibit the activation of NF-kappaB and MAP kinase inflammatory signaling pathways, and reduce pro-inflammatory cytokine secretion. We found that KPV acts via PepT1 expressed in immune and intestinal epithelial cells. Furthermore, oral administration of KPV reduces the incidence of DSS- and TNBS-induced colitis indicated by a decrease in pro-inflammatory cytokine expression. CONCLUSIONS: This study indicates tht KPV is transported into cells by PepT1 and might be a new therapeutic agent for IBD.


Assuntos
Colite/metabolismo , Colite/prevenção & controle , Hormônios Estimuladores de Melanócitos/farmacocinética , Hormônios Estimuladores de Melanócitos/uso terapêutico , Fragmentos de Peptídeos/farmacocinética , Fragmentos de Peptídeos/uso terapêutico , Simportadores/metabolismo , Animais , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Colite/patologia , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Feminino , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transportador 1 de Peptídeos
13.
J Neural Transm (Vienna) ; 113(4): 463-76, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16550325

RESUMO

The possibility that local administration of low molecular weight non-peptide compounds with varying affinities at melanocortin receptors in the spinal cord will influence pathophysiological outcome of spinal cord injury (SCI) was examined in a rat model. Five new Melacure compounds ME10092, ME10354, ME10393, ME10431 and ME10501 were used in this investigation. Each compound was dissolved in saline and tested at 3 different doses, i.e. 1 microg, 5 microg and 10 microg total dose in 10 microl applied topically 5 min after SCI. The animals were allowed to survive 5 h and trauma induced edema formation, breakdown of the blood-spinal cord barrier (BSCB) and cell injuries were examined and compared with untreated injured rats. A focal SCI inflicted by an incision into the right dorsal horn of the T10-11 segments resulted in marked edema formation, breakdown of the BSCB to Evans blue albumin and caused profound nerve cell injury in the T9 and the T12 segments. Topical application of ME10501 (a compound with high affinity at melanocortin, MC-4 receptors) in high doses (10 microg) resulted in most marked neuroprotection in the perifocal spinal cord (T9 and T12) segments. On the other hand, only a mild or no effect on spinal cord pathology was observed in the traumatized animals that received ME10092, ME10354, ME10393 and ME10431 at 3 different doses. These observations suggest that non-peptide compounds with varying affinity to melanocortin receptors are able to influence the pathophysiology of SCI. Furthermore, compounds acting at melanocortin, MCR4 receptors are capable to induce neuroprotection in spinal cord following trauma.


Assuntos
Hormônios Estimuladores de Melanócitos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/terapia , Administração Tópica , Animais , Permeabilidade Capilar/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Edema/etiologia , Hormônios Estimuladores de Melanócitos/administração & dosagem , Camundongos , Fármacos Neuroprotetores/administração & dosagem , Ratos , Receptores de Melanocortina/efeitos dos fármacos , Traumatismos da Medula Espinal/complicações
14.
Eur Neuropsychopharmacol ; 16(6): 403-12, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16360312

RESUMO

Activity-based anorexia (ABA) mimics starvation and hyperactivity of anorexia nervosa patients in rats. Activation of the melanocortin (MC) system leads to hypophagia and increased energy expenditure in ad libitum fed rats. Therefore, activation of the MC system might underlie the development and propagation of ABA. Pro-opiomelanocortin (POMC) gene expression is normally decreased during negative energy balance. Strikingly, we found a transient up-regulation of POMC mRNA levels in the arcuate nucleus during the development of ABA, indicating a hyperactive MC system. However, wheel running and food intake were not influenced by treating ABA rats with the competitive antagonist SHU9119. This suggests that agonism of MC receptors by endogenous alpha-melanocyte-stimulating hormone (alpha-MSH) levels does not underlie ABA. Instead, treatment with the inverse agonist AgRP(83-132) did ameliorate signs of ABA. This implies that modulation of constitutive MC receptor activity rather than antagonizing putative alpha-MSH release contributes to the development and propagation of ABA.


Assuntos
Anorexia/tratamento farmacológico , Hormônios Estimuladores de Melanócitos/uso terapêutico , Atividade Motora/efeitos dos fármacos , Fragmentos de Peptídeos/uso terapêutico , Proteína Relacionada com Agouti , Animais , Anorexia/metabolismo , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Feminino , Humanos , Hormônios Estimuladores de Melanócitos/farmacologia , Atividade Motora/fisiologia , Fragmentos de Peptídeos/farmacologia , Pró-Opiomelanocortina/biossíntese , Ratos , Ratos Wistar , Receptores de Melanocortina/agonistas , Receptores de Melanocortina/antagonistas & inibidores , Receptores de Melanocortina/metabolismo
15.
Ann N Y Acad Sci ; 1053: 407-21, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16179548

RESUMO

Spinal cord injury (SCI) induces lifetime disability, and no suitable therapy is available to treat victims or to minimze their sufferings. Recently, neurotrophins and compounds acting at melanocortin receptors have been been identified as potential neuroprotective agents. In this investigation, the neuroprotective effects of neurotrophins and melanocortins on the pathophysiology of SCI were examined in a rat model. The SCI was produced by making a longitudinal incision into the right dorsal horn of the T10-11 segments under equithesin anesthesia. In separate groups, neurotrophins [BDNF or IGF-1 (0.1-1 microg/10 microL in saline)] or melanocortins (ME10092, ME10354, ME10393, ME10431, and ME10501, having affinities to melanocortin receptors; 1-10 mug in saline) were applied topically over the traumatized cord segment within 5-10 min after SCI and the rats were allowed to survive for 5 h. A focal SCI resulted in widespread disruption of the blood-spinal cord barrier (BSCB) to Evans blue albumin (EBA), ([131])iodine, or lanthanum tracers and exhibited profound edema formation and cell or tissue destruction. Topical application of BDNF, IGF-1, or ME10501 (having high affinity to melanocortin-4 receptor, MCR-4) in high quantity markedly attenuated BSCB disruption, edema formation, and nerve cell, glial cell, and axonal injuries. On the other hand, low doses of neurotrophins or melanocortins were not effective in attenuating pathophysiology of SCI. These observations suggest that neurotrophins (BDNF and IGF-1) and melanocortins (with high affinity to MCR-4) are capable of inducing neuroprotection if applied shortly after trauma in high doses. Taken together, the results indicate that neurotrophins and melanocortins participate in the pathophysiology of spinal cord cell and tissue injury following trauma.


Assuntos
Hormônios Estimuladores de Melanócitos/farmacologia , Fatores de Crescimento Neural/farmacologia , Fármacos Neuroprotetores/farmacologia , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Astrócitos/efeitos dos fármacos , Axônios/patologia , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Edema/patologia , Edema/prevenção & controle , Fator de Crescimento Insulin-Like I/farmacologia , Lantânio/farmacologia , Masculino , Hormônios Estimuladores de Melanócitos/uso terapêutico , Fatores de Crescimento Neural/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Wistar , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia
16.
Fertil Steril ; 78(3): 520-8, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12215327

RESUMO

OBJECTIVE: To demonstrate that highly purified human menopausal gonadotropin (HP-hMG) is as efficient and safe as recombinant FSH in females undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment cycles. DESIGN: Multinational, open label, randomized, parallel group, comparative phase III trial. SETTING: In 22 centers across six countries; Belgium (1 center), Germany (6 centers), Israel (6 centers), The Netherlands (2 centers), Switzerland (1 center) and the United Kingdom (6 centers). PATIENT(S): A total of 781 women were enrolled between May 1999 and November 2000. INTERVENTION(S): In the all-patients-treated population, 373 patients received HP-hMG and 354 received recombinant FSH. A long protocol GnRH agonist regimen was used. MAIN OUTCOME MEASURE(S): The primary end point was ongoing pregnancy rate following one IVF/ICSI treatment cycle. Safety was assessed as a secondary end point. RESULT(S): Ongoing pregnancy rates 10 weeks after ovum pickup in the per-protocol population were 25% (n = 85/344) in the HP-hMG group and 22% (n = 71/317) in the recombinant FSH group. The incidence of ovarian hyperstimulation syndrome, miscarriage, adverse events, and injection site reactions (tolerability) were similar in both treatment groups. CONCLUSION(S): We found HP-hMG to be as effective as recombinant FSH in terms of ongoing clinical pregnancy. Both treatments have a similar safety/tolerability profile.


Assuntos
Fertilização in vitro , Hormônio Foliculoestimulante/uso terapêutico , Hormônios Estimuladores de Melanócitos/uso terapêutico , Injeções de Esperma Intracitoplásmicas , Adulto , Estradiol/sangue , Feminino , Fertilização/fisiologia , Humanos , Infertilidade Feminina/etiologia , Infertilidade Masculina/etiologia , Masculino , Indução da Ovulação , Gravidez , Resultado da Gravidez , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento
17.
Endocrinology ; 142(8): 3292-301, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11459770

RESUMO

Anorexia is a debilitating manifestation of many malignancies. The etiology of cancer anorexia is poorly understood, and effective treatment options are limited. To investigate the role of central melanocortin receptor signaling in the pathogenesis of cancer anorexia, we assessed the effects on food intake of the melanocortin receptor antagonist SHU9119 administered into the third cerebral ventricle of Lobund-Wistar rats that were anorexic from prostate cancer. In anorexic tumor-bearing rats, daily treatment with SHU9119 (0.35 nmol, intracerebroventricularly) increased food intake from 71 +/- 3% to 110 +/- 6% of preanorectic baseline and caused significant weight gain (13 +/- 5 vs. 5 +/- 1 g/3 d, SHU9119 vs. baseline in tumor-bearing rats). In control rats pair-fed to the intake of tumor-bearing animals, SHU9119 was ineffective at increasing food intake. The specificity of the SHU9119 feeding response was assessed using two other orexigenic peptides, NPY and the novel hormone ghrelin. Treatment of tumor-bearing rats with intracerebroventricular ghrelin (10 microg) increased food intake, but the effect was blunted relative to that in controls. Intracerebroventricular injections of NPY (1 microg) also failed to reverse anorexia in tumor-bearing rats. Because SHU9119 completely reverses cancer anorexia in this model, whereas ghrelin and NPY do not, increased central nervous system melanocortin signaling is implicated in the pathogenesis of this disorder. This suggests that new targets for the treatment of cancer anorexia may be found in the melanocortin pathways.


Assuntos
Adenocarcinoma/complicações , Anorexia/tratamento farmacológico , Anorexia/etiologia , Encéfalo/metabolismo , Hormônios Estimuladores de Melanócitos/uso terapêutico , Hormônios Peptídicos , Neoplasias da Próstata/complicações , Receptores da Corticotropina/antagonistas & inibidores , Animais , Anorexia/patologia , Anorexia/fisiopatologia , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Grelina , Injeções Intraventriculares , Masculino , Neuropeptídeo Y/uso terapêutico , Peptídeos/uso terapêutico , Ratos , Ratos Wistar , Receptores de Melanocortina , Valores de Referência , Terceiro Ventrículo
18.
J Leukoc Biol ; 69(1): 98-104, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11200074

RESUMO

The effects of the natural and synthetic ligands for the melanocortin receptor type 3 (MC3-R) have been evaluated in a murine model of experimental gout. Systemic treatment of mice with gamma2-melanocyte-stimulating hormone (gamma2-MSH) and the synthetic agonist MTII inhibited accumulation of KC, interleukin-1 beta (IL-1beta), and PMN elicited by urate crystals in the peritoneal cavity. In vitro, macrophage (Mø) activation, determined as release of KC and IL-1beta, was inhibited by gamma2-MSH and MTII. The mixed MC3/4-R antagonist SHU9119 prevented the inhibitory actions of gamma2-MSH and MTII in vitro and in vivo, whereas the selective MC4-R antagonist HS024 was without effect. Western blotting also showed the presence of MC3-R protein on murine peritoneal Mø. Furthermore, agonism at the MC3-R evoked accumulation of cAMP within the Mø, which was inhibited by SHU9119. Thus, naturally occurring melanocortins, as well as the synthetic long-acting compound MTII, activate MC3-R on peritoneal Mø to inhibit the experimental inflammatory response.


Assuntos
Gota/tratamento farmacológico , Hormônios Estimuladores de Melanócitos/farmacologia , Hormônios Estimuladores de Melanócitos/uso terapêutico , Receptores da Corticotropina/agonistas , alfa-MSH/análogos & derivados , alfa-MSH/farmacologia , alfa-MSH/uso terapêutico , Animais , Gota/imunologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Masculino , Camundongos , Receptor Tipo 3 de Melanocortina , Receptores da Corticotropina/imunologia
19.
Curr Opin Investig Drugs ; 2(8): 1064-9, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11892914

RESUMO

Gouty arthritis is currently treated with drugs that have an array of side effects. Therefore, identification of novel endogenous targets for drug development may have beneficial properties ACTH4-10, a heptapeptide fragment derived from the hormone adrenocorticotrophin (ACTH) modulates the inflammatory response in a corticosterone-independent manner, via agonism at melanocortin type 3 receptors (MC3-R) expressed on peritoneal macrophages. MC3-R agonists inhibit cytokine formation and subsequent neutrophil migration, while antagonists abrogate these effects. Together, these data highlight MC3-R as a potential therapeutic target and suggest that small molecule agonists directed at MC3-R with more specific actions, may be potentially novel therapeutics for treating this pathology.


Assuntos
Artrite/tratamento farmacológico , Receptores da Corticotropina/agonistas , Animais , Artrite/fisiopatologia , Gota/tratamento farmacológico , Gota/fisiopatologia , Humanos , Hormônios Estimuladores de Melanócitos/uso terapêutico , Receptor Tipo 3 de Melanocortina , Receptores da Corticotropina/química , Receptores da Corticotropina/efeitos dos fármacos
20.
J Pharmacol Exp Ther ; 291(3): 1023-7, 1999 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-10565820

RESUMO

Melanocortin peptides are known to be extremely potent in causing the sustained reversal of different shock conditions, both in experimental animals and humans; the mechanism of action includes an essential brain loop. Three melanocortin receptor subtypes are expressed in brain tissue: MC(3), MC(4,) and MC(5) receptors. In a volume-controlled model of hemorrhagic shock in anesthetized rats, invariably causing the death of control animals within 30 min after saline injection, the i.v. bolus administration of the adrenocorticotropin fragment 1-24 (agonist at MC(4) and MC(5) receptors) at a dose of 160 microg/kg i.v. (54 nmol/kg) produced an almost complete and sustained restoration of cardiovascular and respiratory functions. An equimolar dose of gamma(1)-melanocyte stimulating hormone (selective agonist at MC(3) receptors) was completely ineffective. The selective antagonist at MC(4) receptors, HS014, although having no influence on cardiovascular and respiratory functions per se, dose-dependently prevented the antishock activity of adrenocorticotropin fragment 1-24, with the effect being complete either at the i.v. dose of 200 microg/kg or at the i.c.v. dose of 5 microg/rat (17-20 microg/kg). We concluded that the effect of melanocortin peptides in hemorrhagic shock is mediated by the MC(4) receptors in the brain.


Assuntos
Hormônios Estimuladores de Melanócitos/uso terapêutico , Receptores da Corticotropina/fisiologia , Choque Hemorrágico/tratamento farmacológico , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Volume Sanguíneo/fisiologia , Química Encefálica/efeitos dos fármacos , Cosintropina/farmacologia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Masculino , Peptídeos/uso terapêutico , Ratos , Ratos Wistar , Receptor Tipo 4 de Melanocortina , Receptores da Corticotropina/efeitos dos fármacos , Mecânica Respiratória/efeitos dos fármacos , Choque Hemorrágico/fisiopatologia
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