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1.
Elife ; 82019 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-31609204

RESUMO

The hippocampus, a brain region that is important for spatial navigation and episodic memory, benefits from a rich diversity of neuronal cell-types. Through the use of an intersectional genetic viral vector approach in mice, we report novel hippocampal neurons which we refer to as LINCs, as they are long-range inhibitory neuronal nitric oxide synthase (nNOS)-expressing cells. LINCs project to several extrahippocampal regions including the tenia tecta, diagonal band, and retromammillary nucleus, but also broadly target local CA1 cells. LINCs are thus both interneurons and projection neurons. LINCs display regular spiking non-pyramidal firing patterns, are primarily located in the stratum oriens or pyramidale, have sparsely spiny dendrites, and do not typically express somatostatin, VIP, or the muscarinic acetylcholine receptor M2. We further demonstrate that LINCs can strongly influence hippocampal function and oscillations, including interregional coherence. The identification and characterization of these novel cells advances our basic understanding of both hippocampal circuitry and neuronal diversity.


Assuntos
Hipocampo/citologia , Interneurônios/química , Interneurônios/citologia , Rede Nervosa/citologia , Óxido Nítrico Sintase Tipo I/análise , Potenciais de Ação , Animais , Camundongos , Receptor Muscarínico M2/análise , Somatostatina/análise , Peptídeo Intestinal Vasoativo/análise
2.
eNeuro ; 6(5)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31481397

RESUMO

Information processing in sensory cortex is highly sensitive to nonsensory variables such as anesthetic state, arousal, and task engagement. Recent work in mouse visual cortex suggests that evoked firing rates, stimulus-response mutual information, and encoding efficiency increase when animals are engaged in movement. A disinhibitory circuit appears central to this change: inhibitory neurons expressing vasoactive intestinal peptide (VIP) are activated during movement and disinhibit pyramidal cells by suppressing other inhibitory interneurons. Paradoxically, although movement activates a similar disinhibitory circuit in auditory cortex (ACtx), most ACtx studies report reduced spiking during movement. It is unclear whether the resulting changes in spike rates result in corresponding changes in stimulus-response mutual information. We examined ACtx responses evoked by tone cloud stimuli, in awake mice of both sexes, during spontaneous movement and still conditions. VIP+ cells were optogenetically activated on half of trials, permitting independent analysis of the consequences of movement and VIP activation, as well as their intersection. Movement decreased stimulus-related spike rates as well as mutual information and encoding efficiency. VIP interneuron activation tended to increase stimulus-evoked spike rates but not stimulus-response mutual information, thus reducing encoding efficiency. The intersection of movement and VIP activation was largely consistent with a linear combination of these main effects: VIP activation recovered movement-induced reduction in spike rates, but not information transfer.


Assuntos
Estimulação Acústica/métodos , Córtex Auditivo/metabolismo , Interneurônios/metabolismo , Movimento/fisiologia , Peptídeo Intestinal Vasoativo/metabolismo , Potenciais de Ação/fisiologia , Animais , Córtex Auditivo/química , Feminino , Técnicas de Introdução de Genes , Interneurônios/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Optogenética/métodos , Peptídeo Intestinal Vasoativo/análise
3.
Eur J Pharmacol ; 862: 172629, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31449808

RESUMO

Congestive cardiac failure has become one of the major health challenges of the 21st century and new therapies are needed to address this problem. The concentration of vasoactive intestinal peptide (VIP) in the heart has been shown to decrease as fibrosis (the pathology leading to heart failure) increases and to become undetectable in end stage cardiomyopathy. We sought to determine whether replenishment of myocardial VIP might treat myocardial fibrosis and therefore represent a new therapeutic target. Wistar Kyoto rats on a high (4.4%) salt diet were randomised to zero time control, 4 week infusion of VIP (5 pmol/kg/min) or vehicle control infusion. Myocardial VIP concentration was measured by radioimmunoassay, fibrosis was quantitated by computerised histomorphometry and changes in pro-fibrotic mediators were measured by quantitative rt-PCR. Myocardial VIP increased significantly in VIP treated rats compared with vehicle treated controls (P < 0.01) while fibrosis in the VIP treated rats was significantly lower than in both the zero time control (P < 0.05) and the vehicle infused control (P < 0.0005). Although all six profibrotic mediators which were measured increased over the 4 week experimental period VIP infusion only affected angiotensinogen (Agt) and angiotensin receptor type 1a (AT1a) expression. In both instances VIP caused a significant decrease in messenger rna expression (Agt P < 0.01 and At1a P < 0.01) compared with vehicle infused controls. We conclude that VIP infusion increased myocardial VIP concentration and was able to reverse existing myocardial fibrosis suggesting a possible therapeutic role for a VIP based therapy in cardiac failure.


Assuntos
Cardiomiopatias/tratamento farmacológico , Miocárdio/patologia , Peptídeo Intestinal Vasoativo/administração & dosagem , Angiotensinogênio/análise , Angiotensinogênio/metabolismo , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Cardiomiopatias/diagnóstico , Cardiomiopatias/etiologia , Modelos Animais de Doenças , Fibrose , Humanos , Infusões Intravenosas , Masculino , Miocárdio/metabolismo , Ratos , Ratos Endogâmicos WKY , Receptor Tipo 1 de Angiotensina/análise , Receptor Tipo 1 de Angiotensina/metabolismo , Sódio na Dieta/efeitos adversos , Peptídeo Intestinal Vasoativo/análise , Peptídeo Intestinal Vasoativo/metabolismo
4.
Elife ; 82019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-30998185

RESUMO

Located in the midbrain, the inferior colliculus (IC) is the hub of the central auditory system. Although the IC plays important roles in speech processing, sound localization, and other auditory computations, the organization of the IC microcircuitry remains largely unknown. Using a multifaceted approach in mice, we have identified vasoactive intestinal peptide (VIP) neurons as a novel class of IC principal neurons. VIP neurons are glutamatergic stellate cells with sustained firing patterns. Their extensive axons project to long-range targets including the auditory thalamus, auditory brainstem, superior colliculus, and periaqueductal gray. Using optogenetic circuit mapping, we found that VIP neurons integrate input from the contralateral IC and the dorsal cochlear nucleus. The dorsal cochlear nucleus also drove feedforward inhibition to VIP neurons, indicating that inhibitory circuits within the IC shape the temporal integration of ascending inputs. Thus, VIP neurons are well-positioned to influence auditory computations in a number of brain regions.


Assuntos
Colículos Inferiores/anatomia & histologia , Colículos Inferiores/fisiologia , Rede Nervosa/anatomia & histologia , Neurônios/química , Neurônios/fisiologia , Peptídeo Intestinal Vasoativo/análise , Animais , Núcleo Coclear/anatomia & histologia , Camundongos , Técnicas de Rastreamento Neuroanatômico , Neurônios/classificação , Optogenética
5.
Neurotoxicology ; 69: 47-59, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30222996

RESUMO

Acrylamide is one of the food toxins to which the human body is exposed. Although researchers' interest in acrylamide has been growing in recent years, the knowledge of its effect on the gastrointestinal tract, especially on intramural neurons which form the enteric nervous system is scarce. The aim of this experiment was to determine the influence of acrylamide, administered at doses equivalent to the human tolerable daily intake (TDI, 0.5 µg/kg b.w./day) and ten times higher than the TDI (5 µg/kg b.w./day), on the distribution of vasoactive intestinal peptide (VIP), substance P (SP), and calcitonin gene related peptide (CGRP) in intramural neurons of the domestic pig stomach. Using double immunofluorescent labelling we revealed that the ENS neurons underwent adaptive changes in response to the supplementation of acrylamide, which manifested themselves as increased expression of VIP, SP and CGRP, both in intramural neurons and by an increase in the nerve density in submucous and muscular layers in the porcine stomach. These substances take part in defensive reactions of neurons and transmission of sensory reactions may play an important role in protecting the stomach against the harmful effect of acrylamide. Moreover, it has been shown that acrylamide induces a significant response of ENS neurons even in TDI dose, which suggests that it is not neutral to the body. These findings may be the basis for further toxicological studies addressing the question if currently permitted minimal content of acrylamide in the food does jeopardize the health of human consumers?


Assuntos
Acrilamida/toxicidade , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Mucosa Gástrica/metabolismo , Neurônios/metabolismo , Substância P/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo , Acrilamida/administração & dosagem , Animais , Peptídeo Relacionado com Gene de Calcitonina/análise , Relação Dose-Resposta a Droga , Mucosa Gástrica/química , Mucosa Gástrica/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Distribuição Aleatória , Estômago/química , Estômago/efeitos dos fármacos , Substância P/análise , Suínos , Peptídeo Intestinal Vasoativo/análise
6.
Anat Histol Embryol ; 47(6): 517-526, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30105873

RESUMO

The gastrointestinal (GI) tract is innervated by nerve processes derived from the intramural enteric neurons and neurons localized outside the digestive tract. This study analysed the neurochemical characterization of nerves in the wall of the porcine oesophagus using single immunofluorescence technique. Immunoreactivity to vesicular acetylcholine transporter (VAChT), neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), somatostatin (SOM), galanin (GAL), neuronal isoform of nitric oxide synthase (nNOS), substance P (SP), leucine enkephalin (LENK), calcitonin gene-related peptide (CGRP) or dopamine beta-hydroxylase (DBH) was investigated in intramuscular and intramucosal nerves of the cervical, thoracic and abdominal oesophagus. The results indicate that all of the substances studied were present in the oesophageal nerves. The density of particular populations of fibres depended on the segment of the oesophagus. The most numerous were fibres immunoreactive to VIP in the longitudinal and circular muscle layers of the abdominal oesophagus: The number of these fibres amounted to 16.4 ± 0.8 and 18.1 ± 3.1, respectively. In turn, the least numerous were CGRP-positive fibres, which were present only in the circular muscle layer of the cervical oesophagus and mucosal layer of the abdominal oesophagus in the number of 0.3 ± 0. The obtained results show that nerves in the porcine oesophageal wall are very diverse in their neurochemical coding, and differences between particular parts of the oesophagus suggest that organization of the innervation clearly depends on the fragment of this organ.


Assuntos
Sistema Nervoso Entérico/química , Esôfago/inervação , Imunofluorescência/veterinária , Fibras Nervosas/química , Neuropeptídeos/análise , Animais , Peptídeo Relacionado com Gene de Calcitonina/análise , Dopamina beta-Hidroxilase/análise , Encefalina Leucina/análise , Feminino , Galanina/análise , Neuropeptídeo Y/análise , Óxido Nítrico Sintase Tipo I/análise , Somatostatina/análise , Substância P/análise , Suínos , Peptídeo Intestinal Vasoativo/análise , Proteínas Vesiculares de Transporte de Acetilcolina/análise
7.
Chin Med J (Engl) ; 131(16): 1964-1968, 2018 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-30082528

RESUMO

Background: Previous studies demonstrate that eccrine sweat glands are innervated by both cholinergic and adrenergic nerves. However, it is still unknown whether the secretory coils and ducts of eccrine sweat glands are equally innervated by the sympathetic nerve fibers. To well understand the mechanisms on sweat secretion and reabsorption, the differential innervation of secretory coils and ducts in human eccrine sweat glands was investigated in the study. Methods: From June 2016 to June 2017, six human skins were fixed, paraffin-embedded, and cut into 5 µm-thick sections, followed by costaining for nerve fiber markers protein gene product 9.5 (PGP 9.5), tyrosine hydroxylase (TH) and vasoactive intestinal peptide (VIP), and eccrine sweat gland markers K7, S100P, and K14 by combining standard immunofluorescence with tyramide signal amplification (IF-TSA). Stained sections were observed under the microscope, photographed, and analyzed. Results: The fluorescent signals of PGP 9.5, TH, and VIP were easily visualized, by IF-TSA, as circular patterns surrounding eccrine sweat glands, but only PGP 9.5 could be observed by standard IF. The IF-TSA method is more sensitivity than standard IF in detecting antigens expressed at low levels. PGP 9.5, TH, and VIP appeared primarily surrounding the secretory coils and sparsely surrounding the sweat ducts. Conclusion: Sweat secretion is mainly controlled by autonomic nerves whereas sweat reabsorption is less affected by nerve activity.


Assuntos
Glândulas Écrinas/inervação , Fibras Nervosas , Glândulas Sudoríparas/inervação , Imunofluorescência , Humanos , Peptídeo Intestinal Vasoativo/análise
8.
J Neurosci ; 38(31): 6983-7003, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29954847

RESUMO

In cortical structures, principal cell activity is tightly regulated by different GABAergic interneurons (INs). Among these INs are vasoactive intestinal polypeptide-expressing (VIP+) INs, which innervate preferentially other INs, providing a structural basis for temporal disinhibition of principal cells. However, relatively little is known about VIP+ INs in the amygdaloid basolateral complex (BLA). In this study, we report that VIP+ INs have a variable density in the distinct subdivisions of the mouse BLA. Based on different anatomical, neurochemical, and electrophysiological criteria, VIP+ INs could be identified as IN-selective INs (IS-INs) and basket cells expressing CB1 cannabinoid receptors. Whole-cell recordings of VIP+ IS-INs revealed three different spiking patterns, none of which was associated with the expression of calretinin. Genetic targeting combined with optogenetics and in vitro recordings enabled us to identify several types of BLA INs innervated by VIP+ INs, including other IS-INs, basket and neurogliaform cells. Moreover, light stimulation of VIP+ basket cell axon terminals, characterized by CB1 sensitivity, evoked IPSPs in ∼20% of principal neurons. Finally, we show that VIP+ INs receive a dense innervation from both GABAergic inputs (although only 10% from other VIP+ INs) and distinct glutamatergic inputs, identified by their expression of different vesicular glutamate transporters.In conclusion, our study provides a wide-range analysis of single-cell properties of VIP+ INs in the mouse BLA and of their intrinsic and extrinsic connectivity. Our results reinforce the evidence that VIP+ INs are structurally and functionally heterogeneous and that this heterogeneity could mediate different roles in amygdala-dependent functions.SIGNIFICANCE STATEMENT We provide the first comprehensive analysis of the distribution of vasoactive intestinal polypeptide-expressing (VIP+) interneurons (INs) across the entire mouse amygdaloid basolateral complex (BLA), as well as of their morphological and physiological properties. VIP+ INs in the neocortex preferentially target other INs to form a disinhibitory network that facilitates principal cell firing. Our study is the first to demonstrate the presence of such a disinhibitory circuitry in the BLA. We observed structural and functional heterogeneity of these INs and characterized their input/output connectivity. We also identified several types of BLA INs that, when inhibited, may provide a temporal window for principal cell firing and facilitate associative plasticity, e.g., in fear learning.


Assuntos
Complexo Nuclear Basolateral da Amígdala/citologia , Interneurônios/fisiologia , Peptídeo Intestinal Vasoativo/análise , Potenciais de Ação , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Contagem de Células , Conectoma , Cruzamentos Genéticos , Genes Reporter , Ácido Glutâmico/metabolismo , Potenciais Pós-Sinápticos Inibidores/efeitos da radiação , Interneurônios/química , Interneurônios/classificação , Interneurônios/efeitos da radiação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Optogenética , Técnicas de Patch-Clamp , Terminações Pré-Sinápticas/ultraestrutura , Receptor CB1 de Canabinoide/análise , Proteínas Vesiculares de Transporte de Glutamato/metabolismo , Ácido gama-Aminobutírico/metabolismo
9.
BMC Urol ; 18(1): 47, 2018 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-29789007

RESUMO

BACKGROUND: Although the pelvic autonomic plexus branches are considered to be a mixture of sympathetic and parasympathetic nerves, little is known regarding the composite fibers of the pelvic plexus branches. This study aimed to investigate the immunohistochemical features of sympathetic and parasympathetic nerves in the pelvic autonomic plexus branches. METHODS: Using 10 donated elderly male cadavers, the detailed topohistology of nerve fibers at and around the bladder, seminal vesicle, prostate, and rectum was examined. Neuronal nitric oxide synthase (nNOS) and vasoactive intestinal polypeptide (VIP) were used as parasympathetic nerve markers; tyrosine hydroxylase (TH) was used as a sympathetic nerve marker. The myenteric plexus of the colon was utilized as a positive control. RESULTS: Most nerve fibers in the bladder, seminal vesicle, prostate, and rectum were both nNOS- and TH-positive. Thus, pelvic plexus branches were classified into two types: 1) triple-positive mixed nerves (nNOS+, VIP+, TH+, thick myelinated fibers + or -) and 2) double-positive mixed nerves (nNOS+, VIP-, TH+, thick myelinated fibers + or -). Notably, triple-positive nerves were localized within the posterosuperior part of the plexus (near the rectum) and travelled anteroinferiorly toward the posterolateral corner of the prostate. The posteriorly and inferiorly located nerves were predominantly composed of parasympathetic, rather than sympathetic, fibers. In contrast, nerve fibers within and along the bladder and seminal vesicle contained either no or few VIP-positive nerves. These superiorly located nerves were characterized by clear sympathetic nerve dominance. CONCLUSIONS: The nerves of the pelvic plexus branches were clearly classified into nerves around the bladder and seminal vesicle (VIP-negative) and nerves around the prostate (VIP-positive). Although nNOS- and VIP-positive nerve fibers are candidate cavernous nerves, cavernous nerve identity cannot be definitively concluded for these nerves in the periprostatic region.


Assuntos
Plexo Hipogástrico/química , Fibras Nervosas/química , Próstata/química , Reto/química , Glândulas Seminais/química , Bexiga Urinária/química , Idoso , Idoso de 80 Anos ou mais , Cadáver , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo I/análise , Próstata/inervação , Reto/inervação , Glândulas Seminais/inervação , Bexiga Urinária/inervação , Peptídeo Intestinal Vasoativo/análise
10.
Proc Natl Acad Sci U S A ; 115(16): 4276-4281, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29610316

RESUMO

Endogenous circadian clocks control 24-h physiological and behavioral rhythms in mammals. Here, we report a real-time in vivo fluorescence recording system that enables long-term monitoring of circadian rhythms in the brains of freely moving mice. With a designed reporter of circadian clock gene expression, we tracked robust Cry1 transcription reporter rhythms in the suprachiasmatic nucleus (SCN) of WT, Cry1-/- , and Cry2-/- mice in LD (12 h light, 12 h dark) and DD (constant darkness) conditions and verified that signals remained stable for over 6 mo. Further, we recorded Cry1 transcriptional rhythms in the subparaventricular zone (SPZ) and hippocampal CA1/2 regions of WT mice housed under LD and DD conditions. By using a Cre-loxP system, we recorded Per2 and Cry1 transcription rhythms specifically in vasoactive intestinal peptide (VIP) neurons of the SCN. Finally, we demonstrated the dynamics of Per2 and Cry1 transcriptional rhythms in SCN VIP neurons following an 8-h phase advance in the light/dark cycle.


Assuntos
Ritmo Circadiano/fisiologia , Criptocromos/biossíntese , Tecnologia de Fibra Óptica/métodos , Fluorometria/métodos , Neurônios/metabolismo , Proteínas Circadianas Period/biossíntese , Núcleo Supraquiasmático/metabolismo , Animais , Proteínas de Bactérias/análise , Proteínas de Bactérias/genética , Região CA1 Hipocampal/metabolismo , Região CA2 Hipocampal/metabolismo , Células Cultivadas , Ritmo Circadiano/genética , Criptocromos/deficiência , Criptocromos/genética , Dependovirus/genética , Tecnologia de Fibra Óptica/instrumentação , Fluorometria/instrumentação , Genes Reporter , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Hipotálamo Anterior/metabolismo , Estudos Longitudinais , Proteínas Luminescentes/análise , Proteínas Luminescentes/genética , Camundongos , Camundongos Endogâmicos C57BL , Movimento , Neurônios/química , Neurônios/classificação , Fibras Ópticas , Especificidade de Órgãos , Proteínas Circadianas Period/genética , Fotoperíodo , Núcleo Supraquiasmático/citologia , Transcrição Genética , Peptídeo Intestinal Vasoativo/análise
11.
J Headache Pain ; 19(1): 21, 2018 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-29523978

RESUMO

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide implicated in a wide range of functions, such as nociception and in primary headaches. Regarding its localization, PACAP has been observed in the sensory trigeminal ganglion (TG), in the parasympathetic sphenopalatine (SPG) and otic ganglia (OTG), and in the brainstem trigeminocervical complex. Immunohistochemistry has shown PACAP-38 in numerous cell bodies of SPG/OTG, co-stored with vasoactive intestinal peptide (VIP), nitric oxide synthase (NOS) and, to a minor degree, with choline acetyltransferase. PACAP has in addition been found in a subpopulation of calcitonin gene-related peptide (CGRP)-immunoreactive cells in the trigeminal system. The PACAP/VIP receptors (PAC1, VPAC1, and VPAC2) are present in sensory neurons and in vascular smooth muscle related to the trigeminovascular system. It is postulated that PACAP is involved in nociception. In support, abolishment of PACAP synthesis or reception leads to diminished pain responses, whereas systemic PACAP-38 infusion triggers pain behavior in animals and delayed migraine-like attacks in migraine patients without marked vasodilatory effects. In addition, increased plasma levels have been documented in acute migraine attacks and in cluster headache, in accordance with findings in experimental models of trigeminal activation. This suggest that the activation of the trigeminal system may result in elevated venous levels of PACAP, a change that can be reduced when headache is treated. The data presented in this review indicate that PACAP and its receptors may be promising targets for migraine therapeutics.


Assuntos
Transtornos da Cefaleia Primários/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Animais , Gânglios Parassimpáticos/química , Gânglios Parassimpáticos/metabolismo , Transtornos da Cefaleia Primários/diagnóstico , Transtornos da Cefaleia Primários/terapia , Humanos , Neurônios Aferentes/química , Neurônios Aferentes/metabolismo , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/análise , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/análise , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/metabolismo , Gânglio Trigeminal/química , Gânglio Trigeminal/metabolismo , Peptídeo Intestinal Vasoativo/análise , Peptídeo Intestinal Vasoativo/metabolismo
13.
Zhongguo Zhen Jiu ; 37(2): 125-129, 2017 Feb 12.
Artigo em Chinês | MEDLINE | ID: mdl-29231472

RESUMO

OBJECTIVE: To compare the efficacy between acupuncture with smoothing liver and regulating qi and lactulose for post-stroke slow transit constipation(STC) and to explore the mechanism. METHODS: Sixty patients were randomized into an acupuncture group and a medication group,30 cases in each one. Based on the comprehensive stroke unit care,acupuncture with smoothing liver and regulating qi was used at Danzhong(CV 17),Qihai(CV 6),Tianshu(ST 25),Neiguan(PC 6),Gongsun(SP 4) and Taichong(LR 3) in the acupuncture group,once a day. Lactulose oral liquid was taken at a draught in the morning in the medication group,20 to 30 mL a time,once a day. The study period was 11 weeks,including 1-week baseline evaluation,6-week treatment and 4-week follow-up. We recorded the time of the first independent defecation,constipation symptom score,and gastrointestinal hormone level,including somatostatin(SS),motilin(MTL),P substance(SP) and vasoactive intestinal peptide(VIP). Also,the side effects were recorded at any time. RESULTS: The time of the first independent defecation was (30.18±16.14) h in the acupuncture group,which was significantly different from (43.22±28.42) h in the medication group(P<0.05). The constipation scores after 6-week treatment and at follow-up were lower than those before treatment in the two groups (all P<0.05),with better results in the acupuncture group(both P<0.05). MTL and SP increased,as well as SS and VIP decreased after treatment in the two groups(all P<0.05). The changes were better in the acupuncture group(all P<0.05). The side effect was not observed in the two groups. CONCLUSIONS: Acupuncture with smoothing liver and regulating qi achieves better effect than lactulose for post-stroke STC in terms of efficacy onset,extent,and long term. The mechanism may relate to increasing excitatory regulatory peptide and reducing inhibitory regulatory peptide.


Assuntos
Terapia por Acupuntura/métodos , Constipação Intestinal/terapia , Fármacos Gastrointestinais/administração & dosagem , Lactulose/administração & dosagem , Fígado , Qi , Acidente Vascular Cerebral/complicações , Pontos de Acupuntura , Constipação Intestinal/etiologia , Humanos , Motilina/análise , Somatostatina/análise , Substância P/análise , Resultado do Tratamento , Peptídeo Intestinal Vasoativo/análise
14.
Chin J Physiol ; 60(4): 215-225, 2017 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-28847141

RESUMO

The plasmalemmal Na⁺/Ca²âº changer (NCX) regulates intracellular Ca²âº by exchanging 3 Na⁺ for 1 Ca²âº in either the Ca²âº exit or Ca²âº entry mode. All three NCX isoforms NCX1, NCX2, and NCX3 are expressed in the rat brain, with isoform-specific differential distribution. In the central clock of suprachiasmatic nucleus (SCN), intracellular Ca²âº controls the circadian release of major neuropeptides, which are the arginine vasopressin (AVP), vasoactive intestinal peptide (VIP) and gastrin releasing peptide (GRP), and the NCX, most likely NCX1, rapidly clears depolarization-induced somatic Ca²âº influx. However, the role of NCX2 in the SCN remains unknown. This study aimed to investigate the colocalization of NCX2 with neuropeptides and daily expression profiles of NCX2 in mRNA and protein levels. Consistent with the restricted distribution of NCX2 in the retinorecipient ventral SCN, the immunostaining results showed colocalization of NCX2 with VIP, GRP and VIP/GRP in the ventral SCN, but not with AVP in the dorsal SCN, or markers for astrocyte and major input pathways. Importantly, the presynaptic marker Bassoon was found to colocalize with NCX2/GRP and NCX2/ VIP, indicating localization of both VIP/NCX2 and GRP/NCX2 at the presynaptic sites. Furthermore, real-time PCR and western blotting revealed no day-night difference in NCX2 mRNA and protein levels, in contrast to a robust circadian rhythm in the expression of clock genes Per1 and Per2. Together the results suggest a role of NCX2 in the regulation of the release of VIP and GRP.


Assuntos
Relógios Circadianos/fisiologia , Neuropeptídeos/análise , Trocador de Sódio e Cálcio/análise , Núcleo Supraquiasmático/química , Animais , Cálcio/metabolismo , Peptídeo Liberador de Gastrina/análise , Peptídeo Liberador de Gastrina/genética , Neuropeptídeos/genética , RNA Mensageiro/análise , Ratos , Trocador de Sódio e Cálcio/genética , Peptídeo Intestinal Vasoativo/análise , Peptídeo Intestinal Vasoativo/genética
15.
Curr Med Chem ; 24(33): 3649-3665, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28707585

RESUMO

BACKGROUND: Migraine is a primary headache disorder. Despite numerous studies conducted with the aim to understand the pathophysiology of migraine, several aspects are still unclear. The trigeminovascular system plays a key role. Neurogenic inflammation is presumed to be an important factor in migraine pathophysiology, mediated by the activation of primary neurons, leading to the release of various pro-inflammatory neuropeptides and neurotransmitters such as Calcitonin Gene-Related Peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP). Nitric oxide (NO), Pituitary adenylate cyclase-activating polypeptide (PACAP) and Glutamate (Glu) also play an important role in the modulation of inflammatory mechanisms. OBJECTIVE: To review the literature focusing on novel therapeutic targets in migraine, related to neurogenic inflammation. METHOD: A systematic literature search in the database of PUBMED was conducted regarding therapeutic strategies in migraine, focusing on substances and cytokines released during neurogenic inflammation, published until January 2017. RESULTS: Ongoing phase III clinical studies with monoclonal antibodies against CGRP and CGRP receptors offer promising novel aspects for migraine treatment. Preclinical and clinical studies targeting SP and nitric oxide synthase (NOS) were all terminated with no significant results compared to placebo. New promising therapeutic goal could be PACAP and its receptor (PAC1), and kynurenic acid (KYNA) analogues. CONCLUSION: Current migraine treatment offers pain relief only for a small proportion of migraine patients and might not be adequate for patients with cardiovascular comorbidity due to side effects. Better understanding of migraine pathophysiology might, therefore, lead to novel therapeutic lines both in migraine attack treatment and prophylaxis.


Assuntos
Descoberta de Drogas , Transtornos de Enxaqueca/tratamento farmacológico , Inflamação Neurogênica/tratamento farmacológico , Animais , Peptídeo Relacionado com Gene de Calcitonina/análise , Peptídeo Relacionado com Gene de Calcitonina/imunologia , Descoberta de Drogas/métodos , Humanos , Ácido Cinurênico/análise , Ácido Cinurênico/imunologia , Transtornos de Enxaqueca/imunologia , Transtornos de Enxaqueca/patologia , Terapia de Alvo Molecular/métodos , Inflamação Neurogênica/imunologia , Inflamação Neurogênica/patologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/análise , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/imunologia , Substância P/análise , Substância P/imunologia , Peptídeo Intestinal Vasoativo/análise , Peptídeo Intestinal Vasoativo/imunologia
16.
J Comp Neurol ; 525(10): 2394-2410, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28324630

RESUMO

The vagina is innervated by a complex arrangement of sensory, sympathetic, and parasympathetic nerve fibers that contain classical transmitters plus an array of neuropeptides and enzymes known to regulate diverse processes including blood flow and nociception. The neurochemical characteristics and distributions of peptide-containing nerves in the mouse vagina are unknown. This study used multiple labeling immunohistochemistry, confocal maging and analysis to investigate the presence and colocalization of the peptides vasoactive intestinal polypeptide (VIP), calcitonin-gene related peptide (CGRP), substance P (SP), neuropeptide tyrosine (NPY), and the nitric oxide synthesizing enzyme neuronal nitric oxide synthase (nNOS) in nerve fibers of the murine vaginal wall. We compared cervical and vulvar areas of the vagina in young nullipara and older multipara C57Bl/6 mice, and identified differences including that small ganglia were restricted to cervical segments, epithelial fibers were mainly present in vulvar segments and most nerve fibers were found in the lamina propria of the cervical region of the vagina, where a higher number of fibers containing immunoreactivity for VIP, CGRP, SP, or nNOS were found. Two populations of VIP-containing fibers were identified: fibers containing CGRP and fibers containing VIP but not CGRP. Differences between young and older mice were present in multiple layers of the vaginal wall, with older mice showing overall loss of innervation of epithelium of the proximal vagina and reduced proportions of VIP, CGRP, and SP containing nerve fibers in the distal epithelium. The distal vagina also showed increased vascularization and perivascular fibers containing NPY. Immunolabeling of ganglia associated with the vagina indicated the likely origin of some peptidergic fibers. Our results reveal regional differences and age- or parity-related changes in innervation of the mouse vagina, effecting the distribution of neuropeptides with diverse roles in function of the female genital tract.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/análise , Fibras Nervosas/química , Neuropeptídeo Y/análise , Substância P/análise , Vagina/química , Peptídeo Intestinal Vasoativo/análise , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Fibras Nervosas/metabolismo , Neuropeptídeo Y/metabolismo , Óxido Nítrico Sintase Tipo I/análise , Óxido Nítrico Sintase Tipo I/metabolismo , Substância P/metabolismo , Vagina/citologia , Vagina/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo
17.
Surg Radiol Anat ; 39(5): 477-484, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28130613

RESUMO

PURPOSE: To describe and discuss the normal anatomy and function of enteric neurons in the esophagus of aged individuals. METHOD: We examined ganglion cells in esophagus specimens obtained from 15 elderly cadavers without any macroscopic pathology in the mediastinum and abdomen. Neuronal nitric oxide synthase and vasoactive intestinal polypeptide were used as parasympathetic nerve markers, and tyrosine hydroxylase as a sympathetic nerve marker. RESULTS: The thoracic and abdominal esophagus contained a well-developed myenteric nerve plexus (S100 protein-positive area) in the intermuscular layer: 0.02-0.03 mm2 per 1-mm length of the circular esophageal wall. The cervical esophagus usually contained no ganglion cells. The number of parasympathetic ganglion cells was maximal in the upper or middle thoracic esophagus (mean 18-23 cells per section), whereas sympathetic cells were considerably less numerous at any sites (mean 1-3 cells). CONCLUSION: In comparison with previous data from elderly cadavers, the esophagus carried much fewer ganglion cells than the intestine and colon; sympathetic cells were particular less numerous. Esophageal smooth muscle exhibits a unique mode of peristalsis characterized by a rebound contraction with a long latency after stimulation. This type of peristalsis appears to be regulated by inhibitory, nNOS-positive nerves with a sparse distribution, which seems to account for the long-span peristalsis unique to the esophagus. The extreme sparsity of ganglion cells in the cervical esophagus suggests that enteric neuron-integrated peristalsis, like that in the intestine and colon, is unlikely. Surgical treatment of the esophagus is likely to change or impair these unique features.


Assuntos
Esôfago/inervação , Imuno-Histoquímica/métodos , Plexo Mientérico/anatomia & histologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Cadáver , Humanos , Masculino , Neurônios , Óxido Nítrico Sintase Tipo I/análise , Tirosina 3-Mono-Oxigenase/análise , Peptídeo Intestinal Vasoativo/análise
18.
J Neurosci ; 35(37): 12869-89, 2015 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-26377473

RESUMO

UNLABELLED: Neurogliaform (RELN+) and bipolar (VIP+) GABAergic interneurons of the mammalian cerebral cortex provide critical inhibition locally within the superficial layers. While these subtypes are known to originate from the embryonic caudal ganglionic eminence (CGE), the specific genetic programs that direct their positioning, maturation, and integration into the cortical network have not been elucidated. Here, we report that in mice expression of the transcription factor Prox1 is selectively maintained in postmitotic CGE-derived cortical interneuron precursors and that loss of Prox1 impairs the integration of these cells into superficial layers. Moreover, Prox1 differentially regulates the postnatal maturation of each specific subtype originating from the CGE (RELN, Calb2/VIP, and VIP). Interestingly, Prox1 promotes the maturation of CGE-derived interneuron subtypes through intrinsic differentiation programs that operate in tandem with extrinsically driven neuronal activity-dependent pathways. Thus Prox1 represents the first identified transcription factor specifically required for the embryonic and postnatal acquisition of CGE-derived cortical interneuron properties. SIGNIFICANCE STATEMENT: Despite the recognition that 30% of GABAergic cortical interneurons originate from the caudal ganglionic eminence (CGE), to date, a specific transcriptional program that selectively regulates the development of these populations has not yet been identified. Moreover, while CGE-derived interneurons display unique patterns of tangential and radial migration and preferentially populate the superficial layers of the cortex, identification of a molecular program that controls these events is lacking.Here, we demonstrate that the homeodomain transcription factor Prox1 is expressed in postmitotic CGE-derived cortical interneuron precursors and is maintained into adulthood. We found that Prox1 function is differentially required during both embryonic and postnatal stages of development to direct the migration, differentiation, circuit integration, and maintenance programs within distinct subtypes of CGE-derived interneurons.


Assuntos
Córtex Cerebral/citologia , Neurônios GABAérgicos/citologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/fisiologia , Interneurônios/citologia , Proteínas do Tecido Nervoso/fisiologia , Neurogênese/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Biomarcadores , Calbindina 2/análise , Moléculas de Adesão Celular Neuronais/análise , Linhagem da Célula , Movimento Celular , Córtex Cerebral/embriologia , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/patologia , Proteínas da Matriz Extracelular/análise , Neurônios GABAérgicos/metabolismo , Perfilação da Expressão Gênica , Interneurônios/classificação , Interneurônios/metabolismo , Camundongos , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Serina Endopeptidases/análise , Proteínas Supressoras de Tumor/deficiência , Peptídeo Intestinal Vasoativo/análise
19.
World J Gastroenterol ; 21(25): 7929-32, 2015 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-26167095

RESUMO

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Diarrheal NB is quite rare and is not easy to diagnose in the early stage. Six cases of diarrheal NB in our hospital treated from 1996 to 2006 were retrospectively analyzed, including characteristics such as electrolyte imbalance, pathologic features, vasoactive intestinal peptide (VIP) immunohistochemical staining results, treatment, and prognosis. All patients were boys with 3-8 loose or watery stools each day and routine fecal tests were normal. Abdominal tumors were identified by B-ultrasound. Drugs were ineffective. Three patients underwent surgery, and the remaining three patients received surgery and chemotherapy. Diarrhea stopped after treatment in five patients. Two patients died due to intractable hypokalemia. The tumor was located in the adrenal gland in four patients, in the upper retroperitoneum in one patient, and in the presacral area in one patient. Pathologic findings were NB and ganglioneuroblastoma. Five patients were at clinical stage I-II, and one was at stage III. Four patients survived (followed-up for 6 mo to 4 years). Immunohistochemical staining for VIP was positive. Refractory diarrhea is a paraneoplastic syndrome of NB and is rare. Patients aged 1-3 years who present with chronic intractable diarrhea should be followed closely. Intractable diarrhea, hypokalemia, and dysplasia are the initial clinical manifestations. Increased VIP is characteristic of this disease. Potassium supplementation plays a vital role in the treatment procedure, especially preoperatively. The prognosis of diarrheal NB is good following appropriate treatment.


Assuntos
Neoplasias das Glândulas Suprarrenais/complicações , Diarreia/etiologia , Neuroblastoma/complicações , Síndromes Paraneoplásicas/etiologia , Neoplasias Retroperitoneais/complicações , Neoplasias das Glândulas Suprarrenais/química , Neoplasias das Glândulas Suprarrenais/mortalidade , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/terapia , Biomarcadores Tumorais/análise , Biópsia , Pré-Escolar , Diarreia/diagnóstico , Diarreia/mortalidade , Diarreia/terapia , Humanos , Hipopotassemia/etiologia , Imuno-Histoquímica , Lactente , Masculino , Estadiamento de Neoplasias , Neuroblastoma/química , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Neuroblastoma/terapia , Síndromes Paraneoplásicas/mortalidade , Síndromes Paraneoplásicas/patologia , Síndromes Paraneoplásicas/terapia , Neoplasias Retroperitoneais/química , Neoplasias Retroperitoneais/patologia , Neoplasias Retroperitoneais/terapia , Estudos Retrospectivos , Resultado do Tratamento , Peptídeo Intestinal Vasoativo/análise
20.
Urology ; 85(4): 964.e1-6, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25704994

RESUMO

OBJECTIVE: To investigate the expression and distribution of phosphodiesterase (PDE) isoenzymes PDE1A, PDE2A, PDE4A, PDE4B, and PDE5A in human urethral tissue. METHODS: Specimens of penile urethra were obtained from male subjects who had undergone male-to-female sex reassignment surgery. Using immunohistochemistry (immunofluorescence), the occurrence of PDE1A, PDE2A, PDE4A, PDE4B, and PDE5A, the neuronal nitric oxide synthase, calcitonin gene-related peptide, and vasoactive intestinal polypeptide was examined in urethral sections. Cytosolic supernatants prepared from isolated human urethral tissue were subjected to Western blot analysis using specific anti-PDE antibodies. RESULTS: Immunosignals specific for PDE1A, 4A, 4B, and 5A were observed in the urethral smooth musculature. The smooth muscle bundles were seen innervated by slender nerve fibers, characterized by the expression of the neuronal nitric oxide synthase, calcitonin gene-related peptide, and vasoactive intestinal polypeptide. The expression of the PDE isoenzymes mentioned was confirmed by Western blotting. CONCLUSION: The results provide evidence for a significance of both the cyclic adenosine monophosphate and cyclic guanosine monophosphate signaling in the control of human urethral smooth muscle. The selective inhibition of PDE isoenzymes might represent a pharmacologic option to influence the function of smooth musculature in the human outflow region.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/análise , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/análise , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/análise , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/análise , Músculo Liso/enzimologia , Uretra/enzimologia , Western Blotting , Peptídeo Relacionado com Gene de Calcitonina/análise , Humanos , Imuno-Histoquímica , Isoenzimas/análise , Isoenzimas/metabolismo , Masculino , Pessoa de Meia-Idade , Músculo Liso/inervação , Óxido Nítrico Sintase Tipo I/análise , Transdução de Sinais , Peptídeo Intestinal Vasoativo/análise
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