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2.
Am J Pathol ; 189(12): 2487-2502, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31541644

RESUMO

Lymphedema is a chronic condition caused by disruption of lymphatic vessels, which often occurs after invasive surgery. Calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide produced by alternative splicing of the primary transcript of the calcitonin/CGRP gene (Calca). CGRP was initially identified as a neuropeptide released primarily from sensory nerves and involved in regulating pathophysiological nociceptive pain. However, recent studies have shown CGRP is also released from a variety of other cells and possesses multiple functions. In this study, CGRP knockout (-/-) mice were used to show the actions of endogenous CGRP in postoperative lymphedema. After generating a mouse postoperative tail lymphedema model, the edema was observed to be more severe in CGRP-/- mice than in wild-type mice. Numbers of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1)-positive lymphatic capillaries were decreased and lymphatic capillary formation-related factors were down-regulated in CGRP-/- mice. In addition, accumulation of M2 but not M1 macrophages was selectively reduced in the edematous tissue of CGRP-/- mice. Selective depletion of M2 macrophages decreased lymphatic capillary formation and worsened lymphedema in wild-type mice but not CGRP-/- mice, where numbers of M2 macrophages were already diminished. These findings suggest that endogenous CGRP acts to ameliorate postoperative lymphedema by enhancing lymphatic capillary formation and that M2 macrophages play critical roles. CGRP may be a useful therapeutic target for the treatment of postoperative lymphedema.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Modelos Animais de Doenças , Linfangiogênese , Vasos Linfáticos/patologia , Linfedema/patologia , Macrófagos/patologia , Complicações Pós-Operatórias , Animais , Vasos Linfáticos/metabolismo , Linfedema/etiologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
3.
Am J Physiol Renal Physiol ; 317(4): F1010-F1021, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31390233

RESUMO

Glucagon-like peptide-1 (GLP-1), an incretin hormone, has diuretic and natriuretic effects. The present study was designed to explore the possible underlying mechanisms for the diuretic and natriuretic effects of GLP-1 via renal nerves in rats. Immunohistochemistry revealed that GLP-1 receptors were avidly expressed in the pelvic wall, the wall being adjacent to afferent renal nerves immunoreactive to calcitonin gene-related peptide, which is the dominant neurotransmitter for renal afferents. GLP-1 (3 µM) infused into the left renal pelvis increased ipsilateral afferent renal nerve activity (110.0 ± 15.6% of basal value). Intravenous infusion of GLP-1 (1 µg·kg-1·min-1) for 30 min increased renal sympathetic nerve activity (RSNA). After the distal end of the renal nerve was cut to eliminate the afferent signal, the increase in efferent renal nerve activity during intravenous infusion of GLP-1 was diminished compared with the increase in total RSNA (17.0 ± 9.0% vs. 68.1 ± 20.0% of the basal value). Diuretic and natriuretic responses to intravenous infusion of GLP-1 were enhanced by total renal denervation (T-RDN) with acute surgical cutting of the renal nerves. Selective afferent renal nerve denervation (A-RDN) was performed by bilateral perivascular application of capsaicin on the renal nerves. Similar to T-RDN, A-RDN enhanced diuretic and natriuretic responses to GLP-1. Urine flow and Na+ excretion responses to GLP-1 were not significantly different between T-RDN and A-RDN groups. These results indicate that the diuretic and natriuretic effects of GLP-1 are partly governed via activation of afferent renal nerves by GLP-1 acting on sensory nerve fibers within the pelvis of the kidney.


Assuntos
Vias Aferentes/efeitos dos fármacos , Diurese/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Rim/efeitos dos fármacos , Rim/inervação , Natriurese/efeitos dos fármacos , Animais , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Denervação , Peptídeo 1 Semelhante ao Glucagon/biossíntese , Receptor do Peptídeo Semelhante ao Glucagon 1/biossíntese , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/imunologia , Células HEK293 , Humanos , Pelve Renal/efeitos dos fármacos , Pelve Renal/inervação , Masculino , Ratos , Ratos Sprague-Dawley , Circulação Renal/efeitos dos fármacos , Sódio/urina , Sistema Nervoso Simpático/efeitos dos fármacos , Urodinâmica/efeitos dos fármacos
4.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 33(4): 511-515, 2019 Apr 15.
Artigo em Chinês | MEDLINE | ID: mdl-30983204

RESUMO

Objective: To summarize the research progress on the calcitonin gene-related peptide (CGRP) and receptor activator of nuclear factor κB (RANK)/receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) system during bone reconstruction to provide theoretical basis for further research on the prevention and treatment of bone-related diseases. Methods: The relevant research results at home and abroad in recent years were analyzed and summarized. Results: CGRP and RANK/RANKL/OPG system play important regulatory roles in the bone reconstruction. Conclusion: At present, the research on the mechanism of CGRP and RANK/RANKL/OPG system in bone reconstruction is insufficient. Therefore, it is necessary to study further on the process and interrelation of CGRP and RANK/RANKL/OPG system in bone reconstruction to confirm their mechanism, which will bring new ideas and methods for the treatment of bone related diseases in clinic.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Osteoprotegerina , Ligante RANK , Receptor Ativador de Fator Nuclear kappa-B , Remodelação Óssea/fisiologia , Calcitonina , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Proteínas de Transporte , Glicoproteínas , Glicoproteínas de Membrana , NF-kappa B/fisiologia , Osteoprotegerina/fisiologia , Ligante RANK/fisiologia , Receptor Ativador de Fator Nuclear kappa-B/fisiologia , Receptores Citoplasmáticos e Nucleares
5.
Handb Exp Pharmacol ; 255: 131-140, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30879200

RESUMO

Increasing knowledge about the role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology has led to the development of antibodies against this peptide or its receptor. However, CGRP is widely expressed throughout the body, participating not only in pathophysiological conditions but also in several physiological processes and homeostatic responses during pathophysiological events. Therefore, in this chapter, the risks of long-term blockade of the CGRP pathway will be discussed, with focus on the cardiovascular system, as this peptide has been described to have a protective role during ischemic events, and migraine patients present a higher risk of stroke and myocardial infarction.


Assuntos
Doenças Cardiovasculares , Sistema Cardiovascular , Calcitonina , Peptídeo Relacionado com Gene de Calcitonina/genética , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Sistema Cardiovascular/fisiopatologia , Humanos , Fatores de Risco
6.
J Headache Pain ; 20(1): 27, 2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30866804

RESUMO

Calcitonin gene-related peptide (CGRP) is a neuropeptide with a pivotal role in the pathophysiology of migraine. Blockade of CGRP is a new therapeutic target for patients with migraine. CGRP and its receptors are distributed not only in the central and peripheral nervous system but also in the cardiovascular system, both in blood vessels and in the heart. We reviewed the current evidence on the role of CGRP in the cardiovascular system in order to understand the possible short- and long-term effect of CGRP blockade with monoclonal antibodies in migraineurs.In physiological conditions, CGRP has important vasodilating effects and is thought to protect organs from ischemia. Despite the aforementioned cardiovascular implication, preventive treatment with CGRP antibodies has shown no relevant cardiovascular side effects. Results from long-term trials and from real life are now needed.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Transtornos de Enxaqueca/tratamento farmacológico , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Sistema Cardiovascular/fisiopatologia , Humanos , Transtornos de Enxaqueca/etiologia , Transtornos de Enxaqueca/fisiopatologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/fisiologia , Fatores Sexuais , Vasodilatação/fisiologia
7.
J Cereb Blood Flow Metab ; 39(4): 690-703, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29297736

RESUMO

Calcitonin gene-related peptide (CGRP) can cause migraines, yet it is also a potent vasodilator that protects against hypertension. Given the emerging role of CGRP-targeted antibodies for migraine prevention, an important question is whether the protective actions of CGRP are mediated by vascular or neural CGRP receptors. To address this, we have characterized the cardiovascular phenotype of transgenic nestin/hRAMP1 mice that have selective elevation of a CGRP receptor subunit in the nervous system, human receptor activity-modifying protein 1 (hRAMP1). Nestin/hRAMP1 mice had relatively little hRAMP1 RNA in blood vessels and intravenous injection of CGRP caused a similar blood pressure decrease in transgenic and control mice. At baseline, nestin/hRAMP1 mice exhibited similar mean arterial pressure, heart rate, baroreflex sensitivity, and sympathetic vasomotor tone as control mice. We previously reported that expression of hRAMP1 in all tissues favorably improved autonomic regulation and attenuated hypertension induced by angiotensin II (Ang II). Similarly, in nestin/hRAMP1 mice, hypertension caused by Ang II or phenylephrine was greatly attenuated, and associated autonomic dysregulation and increased sympathetic vasomotor tone were diminished or abolished. We conclude that increased expression of neuronal CGRP receptors is sufficient to induce a protective change in cardiovascular autonomic regulation with implications for migraine therapy.


Assuntos
Doenças do Sistema Nervoso Autônomo/prevenção & controle , Hipertensão/prevenção & controle , Sistema Nervoso/química , Proteína 1 Modificadora da Atividade de Receptores/metabolismo , Animais , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Humanos , Camundongos , Camundongos Transgênicos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo
8.
J Cereb Blood Flow Metab ; 39(4): 573-594, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-28948863

RESUMO

Vascular theories of migraine and cluster headache have dominated for many years the pathobiological concept of these disorders. This view is supported by observations that trigeminal activation induces a vascular response and that several vasodilating molecules trigger acute attacks of migraine and cluster headache in susceptible individuals. Over the past 30 years, this rationale has been questioned as it became clear that the actions of some of these molecules, in particular, calcitonin gene-related peptide and pituitary adenylate cyclase-activating peptide, extend far beyond the vasoactive effects, as they possess the ability to modulate nociceptive neuronal activity in several key regions of the trigeminovascular system. These findings have shifted our understanding of these disorders to a primarily neuronal origin with the vascular manifestations being the consequence rather than the origin of trigeminal activation. Nevertheless, the neurovascular component, or coupling, seems to be far more complex than initially thought, being involved in several accompanying features. The review will discuss in detail the anatomical basis and the functional role of the neurovascular mechanisms relevant to migraine and cluster headache.


Assuntos
Cefaleia Histamínica/fisiopatologia , Transtornos de Enxaqueca/fisiopatologia , Acoplamento Neurovascular/fisiologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Humanos , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/fisiologia , Núcleos do Trigêmeo
9.
Endocrine ; 63(2): 193-203, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30306319

RESUMO

PURPOSE: Calcitonin gene-related peptide (CGRP) is a neuropeptide widely distributed in the central and peripheral nervous systems, which is known as a potent vasodilator. Postmenopausal women who experience hot flushes have high levels of plasma CGRP, suggesting its involvement in menopausal vasomotor symptoms. METHODS: In this review, we describe the biochemical aspects of CGRP and its effects associated with deficiencies of sexual hormones on skin temperature, vasodilatation, and sweating as well as the possible peripheral and central mechanisms involved in these events. RESULTS: Several studies have shown that the effects of CGRP on increasing skin temperature and inducing vasodilatation are potentiated by a deficiency of sex hormones, a common condition of postmenopausal women. Additionally, the medial preoptic area of the hypothalamus, involved in thermoregulation, contains over 25-fold more CGRP-immunoreactive cells in female rodents compared with male rodents, reinforcing the role of female sex hormones on the action of CGRP. Some studies suggest that ovarian hormone deficiency decreases circulating endogenous CGRP, inducing an upregulation of CGRP receptors. Consequently, the high CGRP receptor density, especially in blood vessels, amplifies the stimulatory effects of this neuropeptide to raise skin temperature in postmenopausal women during hot flushes. CONCLUSIONS: The duration of the perception of each hot flush in a woman is brief, while local reddening after intradermal administration of α-CGRP persists for 1 to 6 h. This contrast remains unclear.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Fogachos/etiologia , Menopausa/fisiologia , Sistema Vasomotor/fisiopatologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/sangue , Feminino , Fogachos/sangue , Fogachos/fisiopatologia , Humanos , Masculino , Menopausa/sangue , Roedores , Vasodilatação/fisiologia
10.
Sci Rep ; 8(1): 17001, 2018 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-30451912

RESUMO

Calcitonin (CT) plays an important role in calcium homeostasis, and its precursor, proCT, is positively associated with the body mass index in the general human population. However, the physiological role of endogenous CT in the regulation of metabolism remains unclear. Knockout mice with gene-targeted deletion of exon 4 of Calca (CT KO) were generated by targeted modification in embryonic stem cells. Male mice were used in all experiments and were fed a slightly higher fat diet than the standard diet. The CT KO mice did not exhibit any abnormal findings in appearance, but exhibited weight loss from 15 months old, i.e., significantly decreased liver, adipose tissue, and kidney weights, compared with wild-type control mice. Furthermore, CT KO mice exhibited significantly decreased fat contents in the liver, lipid droplets in adipose tissues, serum glucose, and lipid levels, and significantly increased insulin sensitivity and serum adiponectin levels. CT significantly promoted 3T3-L1 adipocyte differentiation and suppressed adiponectin release. These results suggested that CT gene deletion prevents obesity, hyperglycemia, and hyperlipidemia in aged male mice. This is the first definitive evidence that CT may contribute to glucose and lipid metabolism in aged male mice, possibly via decreased adiponectin secretion from adipocytes.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Calcitonina/metabolismo , Dieta Hiperlipídica/efeitos adversos , Glucose/metabolismo , Lipídeos/análise , Fígado/metabolismo , Obesidade/metabolismo , Adiponectina/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Animais , Composição Corporal , Feminino , Resistência à Insulina , Fígado/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/patologia
11.
Headache ; 58(10): 1689-1696, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30426478

RESUMO

BACKGROUND: Migraine impacts more than 36 million people in the United States and 1 billion people worldwide. Despite the increasing availability of acute and preventive therapies, there is still tremendous unmet need. Potential treatments in development include monoclonal antibodies (mAbs). Appropriate use of these "biologic" treatments will necessitate an understanding of the aspects that distinguish them from traditional medications. AIM: Many drug classes are prescribed for migraine treatment, but all have limitations. Recently, calcitonin gene-related peptide (CGRP) activity has shown a significant promise as a target for preventive therapy. In this review, we provide an overview of the potential role of CGRP mAbs in migraine, with a focus on their design, pharmacokinetics, safety, and immunogenicity. CONCLUSIONS: The CGRP mAbs are an innovative new therapy for migraine and address the need for effective and tolerable preventive options. MAbs, including those that target CGRP or its receptor, bind to a target with high specificity and affinity and lead to few off-target adverse effects, although mechanism-based adverse reactions may occur. Unlike other therapeutic antibodies used to treat neurologic disease, CGRP mAbs do not have a target within the immune system and have been designed to avoid altering the immune system. The safety and efficacy of mAbs against CGRP or its receptors are being investigated in clinical development programs, and the first of these therapies has received regulatory approval in the United States.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Transtornos de Enxaqueca/prevenção & controle , Anticorpos Anti-Idiotípicos/biossíntese , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Peptídeo Relacionado com Gene de Calcitonina/imunologia , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/efeitos adversos , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/fisiopatologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/imunologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/fisiologia
12.
Headache ; 58(10): 1658-1669, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30324723

Assuntos
Anticorpos Monoclonais/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Transtornos de Enxaqueca/prevenção & controle , Guias de Prática Clínica como Assunto , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/imunologia , Adolescente , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Tamanho Corporal , Peptídeo Relacionado com Gene de Calcitonina/imunologia , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/administração & dosagem , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/efeitos adversos , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/imunologia , Criança , Ensaios Clínicos como Assunto , Cefaleia Histamínica/prevenção & controle , Contraindicações de Medicamentos , Relação Dose-Resposta a Droga , Relação Dose-Resposta Imunológica , Feminino , Acesso aos Serviços de Saúde , Humanos , Masculino , Seleção de Pacientes , Cefaleia Pós-Traumática/prevenção & controle , Gravidez , Complicações na Gravidez/tratamento farmacológico
13.
PLoS Pathog ; 14(9): e1007279, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30180210

RESUMO

The digestive tract is the first organ affected by the ingestion of foodborne bacteria. While commensal bacteria become resident, opportunistic or virulent bacteria are eliminated from the gut by the local innate immune system. Here we characterize a new mechanism of defense, independent of the immune system, in Drosophila melanogaster. We observed strong contractions of longitudinal visceral muscle fibers for the first 2 hours following bacterial ingestion. We showed that these visceral muscle contractions are induced by immune reactive oxygen species (ROS) that accumulate in the lumen and depend on the ROS-sensing TRPA1 receptor. We then demonstrate that both ROS and TRPA1 are required in a subset of anterior enteroendocrine cells for the release of the DH31 neuropeptide which activates its receptor in the neighboring visceral muscles. The resulting contractions of the visceral muscles favors quick expulsion of the bacteria, limiting their presence in the gut. Our results unveil a precocious mechanism of defense against ingested opportunistic bacteria, whether they are Gram-positive like Bacillus thuringiensis or Gram-negative like Erwinia carotovora carotovora. Finally, we found that the human homolog of DH31, CGRP, has a conserved function in Drosophila.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Proteínas de Drosophila/fisiologia , Microbioma Gastrointestinal/fisiologia , Trato Gastrointestinal/microbiologia , Trato Gastrointestinal/fisiologia , Hormônios de Inseto/fisiologia , Animais , Animais Geneticamente Modificados , Bacillus thuringiensis/patogenicidade , Drosophila melanogaster/genética , Drosophila melanogaster/microbiologia , Drosophila melanogaster/fisiologia , Feminino , Microbiologia de Alimentos , Doenças Transmitidas por Alimentos/microbiologia , Doenças Transmitidas por Alimentos/fisiopatologia , Humanos , Imunidade Inata , Canais Iônicos , Lactobacillus plantarum/patogenicidade , Contração Muscular/fisiologia , Infecções Oportunistas/microbiologia , Infecções Oportunistas/fisiopatologia , Infecções Oportunistas/prevenção & controle , Pectobacterium carotovorum/patogenicidade , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Canal de Cátion TRPA1/fisiologia
14.
PLoS One ; 13(9): e0203215, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30260982

RESUMO

Nerve terminals of primary sensory neurons are influenced by their environment through target derived trophic factors, like nerve growth factor (NGF) or glial cell line-derived neurotrophic factor (GDNF). In mice, subpopulations of DRG neurons express receptors either for NGF or GDNF and therefore differentially respond to these neurotrophic factors. We probed neurite endings from porcine DRG neurons cultured in either NGF or GDNF and examined their shape, elongation and stimulus-evoked CGRP release. A compartmentalized culture system was employed allowing spatial separation of outgrown neurites from their somata and use of different growth factors in the compartments. We show that neurites of GDNF cultured somata extend into lateral compartments without added growth factor, unlike neurites of NGF cultured ones. Neurites of NGF cultured somata extend not only into NGF- but also into GDNF-containing compartments. GDNF at the site of terminals of NGF responsive somata led to a strong neurite arborization and formation of large growth cones, compared to neurites in medium with NGF. Functionally, we could detect evoked CGRP release from as few as 7 outgrown neurites per compartment and calculated release per mm neurite length. CGRP release was detected both in neurites from NGF and GDNF cultured somata, suggesting that also the latter ones are peptidergic in pig. When neurites of NGF cultured somata were grown in GDNF, capsaicin evoked a lower CGRP release than high potassium, compared to those grown in NGF. Our experiments demonstrate that the compartmented culture chamber can be a suitable model to assess neurite properties from trophic factor specific primary sensory neurons. With this model, insights into mechanisms of gain or loss of function of specific nociceptive neurites may be achieved.


Assuntos
Gânglios Espinais/citologia , Gânglios Espinais/fisiologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/fisiologia , Fator de Crescimento Neural/fisiologia , Neuritos/fisiologia , Neuritos/ultraestrutura , Animais , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Capsaicina/farmacologia , Técnicas de Cultura de Células/instrumentação , Células Cultivadas , Gânglios Espinais/efeitos dos fármacos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/administração & dosagem , Técnicas In Vitro , Camundongos , Modelos Neurológicos , Fator de Crescimento Neural/administração & dosagem , Neuritos/efeitos dos fármacos , Potássio/farmacologia , Sus scrofa , Canais de Cátion TRPV/metabolismo
15.
Yakugaku Zasshi ; 138(8): 1119-1126, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-30068853

RESUMO

Calcitonin gene-related peptide (CGRP) plays an important role in several physiological processes such as vasodilation, cardiovascular homeostasis and transmission of pain. Here we report the generation of a transgenic mouse overexpressing αCGRP and the impact of this on baseline physiological responses. αCGRP transgenic mice displayed significantly increased αCGRP mRNA levels in the kidney, heart and hippocampus. To assess cardiovascular physiology, we measured arterial pressure using a tail cuff system. Heart rate, systolic pressure, mean arterial pressure and diastolic pressure were significantly lower in αCGRP transgenic mice than wild-type mice. To assess pain, a hot plate test was performed and the latency of response was used as an indicator of supraspinal response. In addition, a tail immersion test was performed to assess thermal nociception. A significant increase in latency was observed in the αCGRP transgenic mice when compared with wild-type mice in both tests. These results suggest that αCGRP overexpression causes an increase in thermal reaction and downregulation of the cardiovascular system, presumably due in increased levels of αCGRP.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/genética , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Camundongos Transgênicos/genética , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Fenômenos Fisiológicos Cardiovasculares , Regulação para Baixo , Expressão Gênica , Hipotensão , Masculino , Nociceptividade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
16.
Curr Neurol Neurosci Rep ; 18(9): 62, 2018 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-30058044

RESUMO

PURPOSE OF REVIEW: To provide an updated overview of Photophobia with a particular focus on photophobia related to migraine. RECENT FINDINGS: Melanopsin-containing photoreceptors called intrinsically photosensitive retinal ganglion cells (ipRGCs) have been identified in the retina and explain the rational for photophobia in individuals who are blind. Photophobia, a sensory disturbance provoked by light, is a common neurological and ophthalmological symptom. Migraine, a common neurological condition, is pathognomonic of photophobia; however, other primary headache conditions, traumatic brain injury, and impairment of the optic pathway can cause photophobia. In addition, anterior and posterior segment ocular pathology, medications, and psychiatric conditions can result in photophobia. At least 2 (possibly three) distinct neural pathways are involved in photophobia. Some of the basic science regarding these pathways is discussed in this review including the role of calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide. Management of photophobia includes treatment of the underlying etiology and conservative strategies such as wearing sunglasses.


Assuntos
Fotofobia/diagnóstico , Fotofobia/fisiopatologia , Animais , Lesões Encefálicas Traumáticas/diagnóstico , Lesões Encefálicas Traumáticas/fisiopatologia , Lesões Encefálicas Traumáticas/terapia , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Humanos , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/fisiopatologia , Transtornos de Enxaqueca/terapia , Fotofobia/terapia , Células Ganglionares da Retina/fisiologia , Opsinas de Bastonetes/fisiologia
17.
J Clin Invest ; 128(7): 2774-2786, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29634489

RESUMO

Activation of non-neuronal microglia is thought to play a causal role in spinal processing of neuropathic pain. To specifically investigate microglia-mediated effects in a model of neuropathic pain and overcome the methodological limitations of previous approaches exploring microglia function upon nerve injury, we selectively ablated resident microglia by intracerebroventricular ganciclovir infusion into male CD11b-HSVTK-transgenic mice, which was followed by a rapid, complete, and persistent (23 weeks) repopulation of the CNS by peripheral myeloid cells. In repopulated mice that underwent sciatic nerve injury, we observed a normal response to mechanical stimuli, but an absence of thermal hypersensitivity ipsilateral to the injured nerve. Furthermore, we found that neuronal expression of calcitonin gene-related peptide (CGRP), which is a marker of neurons essential for heat responses, was diminished in the dorsal horn of the spinal cord in repopulated mice. These findings identify distinct mechanisms for heat and mechanical hypersensitivity and highlight a crucial contribution of CNS myeloid cells in the facilitation of noxious heat.


Assuntos
Sistema Nervoso Central/patologia , Sistema Nervoso Central/fisiopatologia , Hiperalgesia/patologia , Hiperalgesia/fisiopatologia , Células Mieloides/patologia , Células Mieloides/fisiologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Temperatura Alta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/citologia , Microglia/fisiologia , Neuralgia/patologia , Neuralgia/fisiopatologia , Fragmentos de Peptídeos/fisiologia , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Nervos Periféricos/patologia , Nervos Periféricos/fisiopatologia , Corno Dorsal da Medula Espinal/patologia , Corno Dorsal da Medula Espinal/fisiopatologia
18.
J Struct Biol ; 203(1): 27-36, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29501724

RESUMO

The Calcitonin-gene related peptide (CGRP) family is a group of peptide hormones, which consists of IAPP, calcitonin, adrenomedullin, intermedin, αCGRP and ßCGRP. IAPP and calcitonin have been extensively associated with the formation of amyloid fibrils, causing Type 2 Diabetes and Medullary Thyroid Carcinoma, respectively. In contrast, the potential amyloidogenic properties of αCGRP still remain unexplored, although experimental trials have indicated its presence in deposits, associated with the aforementioned disorders. Therefore, in this work, we investigated the amyloidogenic profile of αCGRP, a 37-residue-long peptide hormone, utilizing both biophysical experimental techniques and Molecular Dynamics simulations. These efforts unravel a novel amyloidogenic member of the CGRP family and provide insights into the mechanism underlying the αCGRP polymerization.


Assuntos
Proteínas Amiloidogênicas/química , Peptídeo Relacionado com Gene de Calcitonina/química , Proteínas Amiloidogênicas/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Humanos , Simulação de Dinâmica Molecular , Difração de Raios X
19.
Cell Mol Biol Lett ; 23: 4, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29416550

RESUMO

Background: Calcitonin gene-related peptide (CGRP) can protect against hyperoxia-induced lung injury, making the upregulation of CGRP a potential therapeutic approach for this type of injury. However, the effects of CGRP on the Wnt7b/ß-catenin signaling pathway are unclear. In this study, we investigated the roles of CGRP and the Wnt7b/ß-catenin signaling pathway in hyperoxia-induced lung injury. Methods: Premature Sprague Dawley (SD) rats were exposed to 21, 40, 60 and 95% oxygen for 3, 7 and 14 days. The animals' body weights, survival rates and endogenous CGRP levels were measured. Lung samples were harvested for histological analyses and measurements of malondialdehyde (MDA) concentration and total antioxidant capacity (TAOC). We also assessed the MDA concentration and TAOC in the lung tissues after administration of 200 nmol/kg CGRP8-37 (a CGRP antagonist). Finally, alveolar epithelial type II (AEC II) cells were isolated from premature rats, exposed to 21 or 95% oxygen for 3, 7 and 14 days, and treated with 10- 8 mol/l exogenous CGRP. The protein expressions of Wnt7b and ß-catenin were assessed using western blotting, and TCF and c-myc mRNA expressions were assessed using qPCR. Results: Rats exposed to 60 and 95% oxygen had significantly lower body weights and survival rates than the 21 and 40% groups, and the decrease was time dependent. Endogenous CGRP was elevated in the lung tissues of premature rats exposed to 95% oxygen. CGRP8-37 induced apparent inflammation in the lung tissue and alveolar structural remodeling. In addition, the expression levels of Wnt7b and ß-catenin were markedly increased after exposure for 3 days. They peaked at 7 days, then declined at 14 days. The levels of TCF/c-myc in AEC II cells increased significantly after CGRP treatment when compared with cells that had only undergone hyperoxia. Conclusions: CGRP protected against hyperoxia-induced lung injury in premature rats. This process involves the Wnt7b/ß-catenin signaling pathway.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Lesão Pulmonar/metabolismo , Via de Sinalização Wnt , Animais , Animais Recém-Nascidos , Antioxidantes/análise , Peso Corporal , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Células Cultivadas , Hiperóxia/complicações , Pulmão/química , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/etiologia , Lesão Pulmonar/patologia , Malondialdeído/análise , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ratos , Ratos Sprague-Dawley , Análise de Sobrevida , Fatores de Transcrição TCF/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
20.
J Invest Dermatol ; 138(3): 688-696, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29054601

RESUMO

Sensing environmental temperature is a key factor allowing individuals to maintain thermal homeostasis via thermoregulatory mechanisms, including changes to skin blood flow. Among transient receptor potential channels, transient receptor potential vanilloid 3 (TRPV3) is a heat-activated cation channel highly expressed in keratinocytes. However, the role of TRPV3 in triggering heat-evoked cutaneous vasodilation is unknown. Using a murine in vivo model of local acute environmental heat exposure in the skin, we show that TRPV3 is involved in the local thermoregulatory control of skin blood flow by initiating the release of calcitonin gene-related peptide and nitric oxide in response to local heating of the skin. In addition to their contribution in local heat-evoked vasodilation, TRPV3, calcitonin gene-related peptide, and nitric oxide also contribute to internal body temperature stability during passive whole-body heating. This study provides in vivo demonstration of the role of TRPV3 as a strong modulator of cutaneous vascular thermoregulatory mechanisms.


Assuntos
Regulação da Temperatura Corporal/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Canais de Cátion TRPV/fisiologia , Vasodilatação/fisiologia , Animais , Temperatura Alta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/biossíntese , Pele/irrigação sanguínea
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