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1.
Zoology (Jena) ; 148: 125958, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34399394

RESUMO

Heteropneustes fossilis is an air-breathing teleost inhabiting environments with very poor O2 conditions, and so it has evolved to cope with hypoxia. In the gills and respiratory air-sac, the sites for O2 sensing and the response to hypoxia rely on the expression of acetylcholine (Ach) acting via its nicotinic receptor (nAChR). This study examined the expression patterns of neuronal markers and some compounds in the NECs of the gills and respiratory air sac having an immunomodulatory function in mammalian lungs. Mucous cells, epithelial cells and neuroepithelial cells (NECs) were immunopositive to a variety of both neuronal markers (VAChT, nAChR, GABA-B-R1 receptor, GAD679) and the antimicrobial peptide piscidin, an evolutionary conserved humoral component of the mucosal immune system in fish. We speculate that Ach release via nAChR from mucous cells may be modulated by GABA production in the NECs and it is required for the induction of mucus production in both normoxic and hypoxic conditions. The presence of piscidin in mucous cells may act in synergy with the autocrine/paracrine signals of Ach and GABA binding to GABA B R1B receptor that may play a local immunomodulatory function in the mucous epithelia of the gills and the respiratory air sac. The potential role of the NECs in the immunobiological behaviour of the gill/air-sac is at moment a matter of speculation. The extent to which the NECs as such may participate is elusive at this stage and waits investigation.


Assuntos
Peixes-Gato/fisiologia , Brânquias/citologia , Muco/metabolismo , Células Neuroepiteliais/metabolismo , Neurotransmissores/metabolismo , Receptores de Neurotransmissores/metabolismo , Sacos Aéreos/citologia , Animais , Peixes-Gato/imunologia , Imunidade Celular , Receptores de Neurotransmissores/genética
2.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360837

RESUMO

Skin pigmentation can occur due to increased melanin, including melanocyte proliferation, melanin biosynthesis, or melanocyte migration. There are many factors that influence the melanin production process, but the role of neurotransmitters in this process is still unclear. We found that histamine and serotonin influence the different stages of melanogenesis and melanogenesis, which increase melanogenesis. Since then, several related papers have been published, and from these papers, it has been recognised that the role of neurotransmitters in skin-pigment-related diseases needs to be summarised. By introducing the role of neurotransmitters in the regulation of various pigment disorders, including vitiligo and melasma, through this review, many researchers can be expected to try to apply neurotransmitter-related agonists and antagonists as treatments for skin pigment disorders.


Assuntos
Neurotransmissores/metabolismo , Transtornos da Pigmentação/metabolismo , Receptores de Neurotransmissores/metabolismo , Pigmentação da Pele , Animais , Humanos , Melaninas/metabolismo , Melanócitos/metabolismo , Melanócitos/fisiologia , Melanose , Neurotransmissores/fisiologia , Transtornos da Pigmentação/fisiopatologia , Receptores de Neurotransmissores/fisiologia , Vitiligo
3.
Neuropeptides ; 89: 102159, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34293596

RESUMO

T cells of aged people, and of patients with either cancer or severe infections (including COVID-19), are often exhausted, senescent and dysfunctional, leading to increased susceptibilities, complications and mortality. Neurotransmitters and Neuropeptides bind their receptors in T cells, and induce multiple beneficial T cell functions. Yet, T cells of different people vary in the expression levels of Neurotransmitter and Neuropeptide receptors, and in the magnitude of the corresponding effects. Therefore, we performed an individual-based study on T cells of 3 healthy subjects, and 3 Hepatocellular Carcinoma (HCC) patients. HCC usually develops due to chronic inflammation. The inflamed liver induces reduction and inhibition of CD4+ T cells and Natural Killer (NK) cells. Immune-based therapies for HCC are urgently needed. We tested if selected Neurotransmitters and Neuropeptides decrease the key checkpoint protein PD-1 in human T cells, and increase proliferation and killing of HCC cells. First, we confirmed human T cells express all dopamine receptors (DRs), and glutamate receptors (GluRs): AMPA-GluR3, NMDA-R and mGluR. Second, we discovered that either Dopamine, Glutamate, GnRH-II, Neuropeptide Y and/or CGRP (10nM), as well as DR and GluR agonists, induced the following effects: 1. Decreased significantly both %PD-1+ T cells and PD-1 expression level per cell (up to 60% decrease, within 1 h only); 2. Increased significantly the number of T cells that proliferated in the presence of HCC cells (up to 7 fold increase), 3. Increased significantly T cell killing of HCC cells (up to 2 fold increase). 4. Few non-conventional combinations of Neurotransmitters and Neuropeptides had surprising synergistic beneficial effects. We conclude that Dopamine, Glutamate, GnRH-II, Neuropeptide Y and CGRP, alone or in combinations, can decrease % PD-1+ T cells and PD-1 expression per cell, in T cells of both healthy subjects and HCC patients, and increase their proliferation in response to HCC cells and killing of HCC cells. Yet, testing T cells of many more cancer patients is absolutely needed. Based on these findings and previous ones, we designed a novel "Personalized Adoptive Neuro-Immunotherapy", calling for validation of safety and efficacy in clinical trials.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neuropeptídeos/farmacologia , Neurotransmissores/farmacologia , Receptor de Morte Celular Programada 1/biossíntese , Receptor de Morte Celular Programada 1/genética , Linfócitos T/metabolismo , Linfócitos T CD4-Positivos/metabolismo , COVID-19/complicações , Carcinoma Hepatocelular/patologia , Dopamina/farmacologia , Agonistas de Dopamina/farmacologia , Humanos , Imunoterapia , Células Matadoras Naturais/metabolismo , Neoplasias Hepáticas/patologia , Receptores de Glutamato/efeitos dos fármacos , Receptores de Neuropeptídeos/metabolismo , Receptores de Neurotransmissores/metabolismo
4.
Int J Mol Sci ; 22(12)2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205261

RESUMO

The amyloid ß peptide (Aß) is a central player in the neuropathology of Alzheimer's disease (AD). The alteration of Aß homeostasis may impact the fine-tuning of cell signaling from the very beginning of the disease, when amyloid plaque is not deposited yet. For this reason, primary culture of rat cortical neurons was exposed to Aß25-35, a non-oligomerizable form of Aß. Cell viability, metabotropic glutamate receptors (mGluR) and adenosine receptors (AR) expression and signalling were assessed. Aß25-35 increased mGluR density and affinity, mainly due to a higher gene expression and protein presence of Group I mGluR (mGluR1 and mGluR5) in the membrane of cortical neurons. Intriguingly, the main effector of group I mGluR, the phospholipase C ß1 isoform, was less responsive. Also, the inhibitory action of group II and group III mGluR on adenylate cyclase (AC) activity was unaltered or increased, respectively. Interestingly, pre-treatment of cortical neurons with an antagonist of group I mGluR reduced the Aß25-35-induced cell death. Besides, Aß25-35 increased the density of A1R and A2AR, along with an increase in their gene expression. However, while A1R-mediated AC inhibition was increased, the A2AR-mediated stimulation of AC remained unchanged. Therefore, one of the early events that takes place after Aß25-35 exposure is the up-regulation of adenosine A1R, A2AR, and group I mGluR, and the different impacts on their corresponding signaling pathways. These results emphasize the importance of deciphering the early events and the possible involvement of metabotropic glutamate and adenosine receptors in AD physiopathology.


Assuntos
Doença de Alzheimer/etiologia , Peptídeos beta-Amiloides/toxicidade , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/toxicidade , Receptores de Neurotransmissores/metabolismo , Adenosina/metabolismo , Doença de Alzheimer/metabolismo , Animais , Córtex Cerebral , Feminino , Neurônios/metabolismo , Fosfolipase C beta/metabolismo , Gravidez , Ratos , Ratos Wistar , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo , Receptores de Glutamato/metabolismo , Transdução de Sinais
5.
Cells ; 10(5)2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067760

RESUMO

Schizophrenia is a common debilitating disease characterized by continuous or relapsing episodes of psychosis. Although the molecular mechanisms underlying this psychiatric illness remain incompletely understood, a growing body of clinical, pharmacological, and genetic evidence suggests that G protein-coupled receptors (GPCRs) play a critical role in disease development, progression, and treatment. This pivotal role is further highlighted by the fact that GPCRs are the most common targets for antipsychotic drugs. The GPCRs activation evokes slow synaptic transmission through several downstream pathways, many of them engaging intracellular Ca2+ mobilization. Dysfunctions of the neurotransmitter systems involving the action of GPCRs in the frontal and limbic-related regions are likely to underly the complex picture that includes the whole spectrum of positive and negative schizophrenia symptoms. Therefore, the progress in our understanding of GPCRs function in the control of brain cognitive functions is expected to open new avenues for selective drug development. In this paper, we review and synthesize the recent data regarding the contribution of neurotransmitter-GPCRs signaling to schizophrenia symptomology.


Assuntos
Encéfalo/metabolismo , Sinalização do Cálcio , Receptores de Quimiocinas/metabolismo , Receptores de Neurotransmissores/metabolismo , Esquizofrenia/metabolismo , Psicologia do Esquizofrênico , Transmissão Sináptica , Animais , Antipsicóticos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Sinalização do Cálcio/efeitos dos fármacos , Humanos , Neurotransmissores/uso terapêutico , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Neurotransmissores/antagonistas & inibidores , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Transmissão Sináptica/efeitos dos fármacos
6.
Toxicol Lett ; 349: 69-83, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34126181

RESUMO

Exposure to sterigmatocystin (STC) raises concerns on developmental neurological disorders. The present study investigated the effects of maternal oral STC exposure on postnatal hippocampal neurogenesis of offspring in rats. Dams were exposed to STC (1.7, 5.0, and 15.0 ppm in diet) from gestational day 6 until day 21 post-delivery (weaning), and offspring were maintained without STC exposure until adulthood on postnatal day (PND) 77, in accordance with OECD chemical testing guideline Test No. 426. On PND 21, 15.0-ppm STC decreased type-3 neural progenitor cell numbers in the subgranular zone (SGZ) due to suppressed proliferation. Increased γ-H2AX-immunoreactive (+) cell numbers in the SGZ and Ercc1 upregulation and Brip1 downregulation in the dentate gyrus suggested induction of DNA double-strand breaks in SGZ cells. Upregulation of Apex1 and Ogg1 and downregulation of antioxidant genes downstream of NRF2-Keap1 signaling suggested induction of oxidative DNA damage. Increased p21WAF1/CIP1+ SGZ cell numbers and suppressed cholinergic signaling through CHRNB2-containing receptors in GABAergic interneurons suggested potential neurogenesis suppression mechanisms. Multiple mechanisms involving N-methyl-d-aspartate (NMDA) receptor-mediated glutamatergic signaling and various GABAergic interneuron subpopulations, including CHRNA7-expressing somatostatin+ interneurons activated by BDNF-TrkB signaling, may be involved in ameliorating the neurogenesis. Upregulation of Arc, Ptgs2, and genes encoding NMDA receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors suggested synaptic plasticity facilitation. On PND 77, ARC+ granule cells decreased, and Nos2 was upregulated following 15.0 ppm STC exposure, suggesting oxidative stress-mediated synaptic plasticity suppression. Inverse pattern in gene expression changes in vesicular glutamate transporter isoforms, Slc17a7 and Slc17a6, from weaning might also be responsible for the synaptic plasticity suppression. The no-observed-adverse-effect level of maternal oral STC exposure for offspring neurogenesis was determined to be 5.0 ppm, translating to 0.34-0.85 mg/kg body weight/day.


Assuntos
Proliferação de Células/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Esterigmatocistina/toxicidade , Animais , Apoptose/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla , Giro Denteado/metabolismo , Giro Denteado/patologia , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Nível de Efeito Adverso não Observado , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores de Neurotransmissores/genética , Receptores de Neurotransmissores/metabolismo , Desmame
7.
PLoS One ; 16(4): e0250232, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33857254

RESUMO

Neuromedin U (NMU), a highly conserved peptide in mammals, is involved in a wide variety of physiological processes, including impairment of pancreatic ß-cell function via induction of mitochondrial dysfunction and endoplasmic reticulum (ER) stress, ultimately suppressing insulin secretion. NMU has two receptors, NMU receptor 1 (NMUR1) and NMUR2, both of which are G-protein-coupled receptors (GPCRs). Only NMUR1 is expressed in mouse islets and ß cell-derived MIN6-K8 cells. The molecular mechanisms underlying the insulinostatic action mediated by NMUR1 in ß cells have yet to be elucidated. In this study, we explored the molecular mechanism driving impairment of insulin secretion in ß cells by the NMU-NMUR1 axis. Pretreatment with the Gαi/o inhibitor Bordetella pertussis toxin (PTX), but not the Gαq inhibitor YM254890, abolished NMU-induced suppression of glucose-stimulated insulin secretion and calcium response in ß cells. Knockdown of Gαi2 and Gαo in ß cells counteracted NMU-induced suppression of insulin secretion and gene alterations related to mitochondrial fusion (Mfn1, Mfn2), fission (Fis1, Drp1), mitophagy (Pink1, Park2), mitochondrial dynamics (Pgc-1α, Nrf1, and Tfam), ER stress (Chop, Atp2a3, Ryr2, and Itpr2), intracellular ATP level, and mitochondrial membrane potential. NMU decreased forskolin-stimulated intracellular cAMP in both mouse and human islets. We concluded that NMUR1 coupled to PTX-sensitive Gαi2 and Gαo proteins in ß cells reduced intracellular Ca2+ influx and cAMP level, thereby causing ß-cell dysfunction and impairment. These results highlight a novel signaling mechanism of NMU and provide valuable insights into the further investigation of NMU functions in ß-cell biology.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Proteínas de Ligação ao GTP/metabolismo , Glucose/farmacologia , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Neuropeptídeos/farmacologia , Receptores de Neurotransmissores/metabolismo , Animais , Linhagem Celular , Humanos , Células Secretoras de Insulina/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos
8.
J Adv Res ; 29: 67-81, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33842006

RESUMO

Introduction: The tear proteomics and neuromediators are associated with clinical dry eye parameters following refractive surgery. Purpose: To investigate and compare the tear proteomic and neuromediator profiles following small incision lenticule extraction (SMILE) versus laser-assisted in-situ keratomileusis (LASIK). Methods: In this randomized controlled trial with paired-eye design, 70 patients were randomized to receive SMILE in one eye and LASIK in the other eye. Tear samples were collected preoperatively, and 1 week, 1, 3, 6 and 12 months postoperatively, and were examined for protein concentration changes using sequential window acquisition of all theoretical fragment ion mass spectrometry (SWATH-MS). The data were analyzed with DAVID Bioinformatics Resources for enriched gene ontology terms and over-represented pathways. Tear neuromediators levels were correlated with clinical parameters. Results: Post-SMILE eyes had significantly better Oxford staining scores and tear break-up time (TBUT) than post-LASIK eyes at 1 and 3 months, respectively. Tear substance P and nerve growth factor levels were significantly higher in the LASIK group for 3 months and 1 year, respectively. SMILE and LASIK shared some similar biological responses postoperatively, but there was significant up-regulation in leukocyte migration and wound healing at 1 week, humoral immune response and apoptosis at 1 month, negative regulation of endopeptidase activity at 3 to 6 months, and extracellular structure organization at 1 year in the post-LASIK eyes. Tear mucin-like protein 1 and substance P levels were significantly correlated with TBUT (r = -0.47, r = -0.49, respectively). Conclusion: Significant differences in the tear neuromediators and proteomics were observed between SMILE and LASIK, even though clinical dry eye signs have subsided and became comparable between 2 procedures.


Assuntos
Cirurgia da Córnea a Laser/métodos , Ceratomileuse Assistida por Excimer Laser In Situ/métodos , Miopia/cirurgia , Proteômica/métodos , Receptores de Neurotransmissores/metabolismo , Ferida Cirúrgica/metabolismo , Adulto , Córnea/inervação , Córnea/metabolismo , Síndromes do Olho Seco/metabolismo , Endopeptidases/metabolismo , Feminino , Humanos , Lasers de Excimer/uso terapêutico , Masculino , Mucinas/metabolismo , Fatores de Crescimento Neural/metabolismo , Período Pós-Operatório , Lágrimas/metabolismo , Cicatrização , Adulto Jovem
9.
Int J Mol Sci ; 22(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805468

RESUMO

The aim of this study was to investigate the effect of Lactobacillus brevis-fermented γ-aminobutyric acid (LB-GABA) on sleep behaviors in invertebrate and vertebrate models. In Drosophila melanogaster, LB-GABA-treated group showed an 8-9%-longer sleep duration than normal group did. LB-GABA-treated group also showed a 46.7% lower level of nighttime activity with a longer (11%) sleep duration under caffeine-induced arousal conditions. The LB-GABA-mediated inhibition of activity was confirmed as a reduction of total movement of flies using a video tracking system. In the pentobarbital-induced sleep test in mice, LB-GABA (100 mg/kg) shortened the time of onset of sleep by 32.2% and extended sleeping time by 59%. In addition, mRNA and protein level of GABAergic/Serotonergic neurotransmitters were upregulated following treatment with LB-GABA (2.0%). In particular, intestine- and brain-derived GABAA protein levels were increased by sevenfold and fivefold, respectively. The electroencephalography (EEG) analysis in rats showed that LB-GABA significantly increased non-rapid eye movement (NREM) (53%) with the increase in theta (θ, 59%) and delta (δ, 63%) waves, leading to longer sleep time (35%), under caffeine-induced insomnia conditions. LB-GABA showed a dose-dependent agonist activity on human GABAA receptor with a half-maximal effective concentration (EC50) of 3.44 µg/mL in human embryonic kidney 293 (HEK293) cells.


Assuntos
Sono/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologia , Animais , Cafeína/farmacologia , Proteínas de Drosophila/genética , Drosophila melanogaster , Eletroencefalografia , Fermentação , Agonistas de Receptores de GABA-A/farmacologia , Células HEK293 , Humanos , Hipnóticos e Sedativos/farmacologia , Lactobacillus brevis/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Neurotransmissores/metabolismo , Pentobarbital/farmacologia , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Receptores de Neurotransmissores/genética , Receptores de Neurotransmissores/metabolismo , Sono/fisiologia , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Ácido gama-Aminobutírico/metabolismo
10.
Nat Commun ; 12(1): 1451, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33649316

RESUMO

Proprioceptive feedback mainly derives from groups Ia and II muscle spindle (MS) afferents and group Ib Golgi tendon organ (GTO) afferents, but the molecular correlates of these three afferent subtypes remain unknown. We performed single cell RNA sequencing of genetically identified adult proprioceptors and uncovered five molecularly distinct neuronal clusters. Validation of cluster-specific transcripts in dorsal root ganglia and skeletal muscle demonstrates that two of these clusters correspond to group Ia MS afferents and group Ib GTO afferent proprioceptors, respectively, and suggest that the remaining clusters could represent group II MS afferents. Lineage analysis between proprioceptor transcriptomes at different developmental stages provides evidence that proprioceptor subtype identities emerge late in development. Together, our data provide comprehensive molecular signatures for groups Ia and II MS afferents and group Ib GTO afferents, enabling genetic interrogation of the role of individual proprioceptor subtypes in regulating motor output.


Assuntos
Mecanorreceptores/metabolismo , Fusos Musculares/metabolismo , Neurônios Aferentes/metabolismo , Animais , Calbindina 2/metabolismo , Fenômenos Eletrofisiológicos , Canais Iônicos/metabolismo , Camundongos Transgênicos , Neurônios/metabolismo , Propriocepção , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Neurotransmissores/metabolismo , Reprodutibilidade dos Testes , Análise de Sequência de RNA , Análise de Célula Única , Transcriptoma/genética
11.
Neuroscience ; 461: 180-193, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33647379

RESUMO

Glutamate (Glu) is known as the main excitatory neurotransmitter in the central nervous system. It can trigger a series of processes ranging from synaptic plasticity to neurophysiological regulation. To carry out its functions, Glu acts via interaction with its cognate receptors, which are ligand-dependent. Glutamatergic receptors include ionotropic and metabotropic categories. The first allows the passage of ions through the postsynaptic membrane, while the metabotropic subtype activates signaling cascades through second messengers. It is well known that an excess of extracellular Glu concentration induces overstimulation of ionotropic glutamatergic receptors (iGluRs), causing the excitotoxicity phenomenon that leads to neuronal damage and cell death. Excitotoxicity plays a crucial role in different brain pathologies such as brain strokes, epilepsy and neurodegenerative disorders. However, until now, there are no effective neuroprotective compounds to prevent or rescue neurons from excitotoxicity. Thus, the continuous elucidation of the molecular mechanisms underlying excitotoxicity in order to prevent damage or neuronal death is necessary. Therefore, the aim of this review was to summarize the current knowledge regarding iGluRs, while describing their structures and molecular mechanisms of action, including their role in excitotoxicity, as well as the current strategies to reduce excitotoxic damage. Particularly, strategies mediated by prolactin, a somatotropin family-related hormone that displays a significant neuroprotective effect against both Glu and kainic acid-induced excitotoxicity in the hippocampus, are described. Finally, the role of prolactin as a possible molecule in the treatment of excitotoxicity in neurological diseases is discussed.


Assuntos
Fármacos Neuroprotetores , Prolactina , Ácido Glutâmico/toxicidade , Neurônios , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Receptores de Neurotransmissores
12.
Reprod Biol Endocrinol ; 19(1): 25, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33602248

RESUMO

BACKGROUND: Accumulating data indicate that sensory nerve derived neuropeptides such as substance P and calcitonin gene related-protein (CGRP) can accelerate the progression of endometriosis via their respective receptors, so can agonists to their respective receptors receptor 1 (NK1R), receptor activity modifying protein 1 (RAMP-1) and calcitonin receptor-like receptor (CRLR). Adrenergic ß2 receptor (ADRB2) agonists also can facilitate lesional progression. In contrast, women with endometriosis appear to have depressed vagal activity, concordant with reduced expression of α7 nicotinic acetylcholine receptor (α7nAChR). The roles of these receptors in adenomyosis are completely unknown. METHODS: Adenomyotic tissue samples from 30 women with adenomyosis and control endometrial tissue samples from 24 women without adenomyosis were collected and subjected to immunohistochemistry analysis of RAMP1, CRLR, NK1R, ADRB2 and α7nAChR, along with their demographic and clinical information. The extent of tissue fibrosis was evaluated by Masson trichrome staining. RESULTS: We found that the staining levels of NK1R, CRLR, RAMP1 and ADRB2 were all significantly elevated in adenomyotic lesions as compared with control endometrium. In contrast, α7nAChR staining levels were significantly reduced. The severity of dysmenorrhea correlated positively with lesional ADRB2 staining levels. CONCLUSIONS: Our results suggest that SP, CGRP and noradrenaline may promote, while acetylcholine may stall, the progression of adenomyosis through their respective receptors on adenomyotic lesions. Additionally, through the activation of the hypothalamic-pituitary-adrenal (HPA)-sympatho-adrenal-medullary (SAM) axes and the lesional overexpression of ADRB2, adenomyosis-associated dysmenorrhea and adenomyotic lesions may be mutually promotional, forming a viscous feed-forward cycle.


Assuntos
Adenomiose/etiologia , Neuropeptídeos/fisiologia , Receptores de Neurotransmissores/fisiologia , Adenomiose/metabolismo , Adenomiose/patologia , Adulto , Proteína Semelhante a Receptor de Calcitonina/metabolismo , Estudos de Casos e Controles , China , Endométrio/metabolismo , Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neuropeptídeos/metabolismo , Proteína 1 Modificadora da Atividade de Receptores/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Receptores de Neurotransmissores/metabolismo , Transdução de Sinais , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
13.
Epilepsia ; 62(3): 659-670, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33570167

RESUMO

OBJECTIVE: One third of epilepsy patients do not become seizure-free using conventional medication. Therefore, there is a need for alternative treatments. Preclinical research using designer receptors exclusively activated by designer drugs (DREADDs) has demonstrated initial success in suppressing epileptic activity. Here, we evaluated whether long-term chemogenetic seizure suppression could be obtained in the intraperitoneal kainic acid rat model of temporal lobe epilepsy, when DREADDs were selectively expressed in excitatory hippocampal neurons. METHODS: Epileptic male Sprague Dawley rats received unilateral hippocampal injections of adeno-associated viral vector encoding the inhibitory DREADD hM4D(Gi), preceded by a cell-specific promotor targeting excitatory neurons. The effect of clozapine-mediated DREADD activation on dentate gyrus evoked potentials and spontaneous electrographic seizures was evaluated. Animals were systemically treated with single (.1 mg/kg/24 h) or repeated (.1 mg/kg/6 h) injections of clozapine. In addition, long-term continuous release of clozapine and olanzapine (2.8 mg/kg/7 days) using implantable minipumps was evaluated. All treatments were administered during the chronic epileptic phase and between 1.5 and 13.5 months after viral transduction. RESULTS: In the DREADD group, dentate gyrus evoked potentials were inhibited after clozapine treatment. Only in DREADD-expressing animals, clozapine reduced seizure frequency during the first 6 h postinjection. When administered repeatedly, seizures were suppressed during the entire day. Long-term treatment with clozapine and olanzapine both resulted in significant seizure-suppressing effects for multiple days. Histological analysis revealed DREADD expression in both hippocampi and some cortical regions. However, lesions were also detected at the site of vector injection. SIGNIFICANCE: This study shows that inhibition of the hippocampus using chemogenetics results in potent seizure-suppressing effects in the intraperitoneal kainic acid rat model, even 1 year after viral transduction. Despite a need for further optimization, chemogenetic neuromodulation represents a promising treatment prospect for temporal lobe epilepsy.


Assuntos
Anticonvulsivantes/uso terapêutico , Clozapina/uso terapêutico , Epilepsia do Lobo Temporal/tratamento farmacológico , Olanzapina/uso terapêutico , Receptores de Neurotransmissores/genética , Animais , Giro Denteado/efeitos dos fármacos , Giro Denteado/fisiopatologia , Modelos Animais de Doenças , Potenciais Evocados/fisiologia , Quinases de Receptores Acoplados a Proteína G/efeitos dos fármacos , Quinases de Receptores Acoplados a Proteína G/genética , Edição de Genes/métodos , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Neurotransmissores/efeitos dos fármacos , Convulsões/prevenção & controle
14.
Neuroimage ; 231: 117843, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33577936

RESUMO

The macaque monkey inferior parietal lobe (IPL) is a structurally heterogeneous brain region, although the number of areas it contains and the anatomical/functional relationship of identified subdivisions remains controversial. Neurotransmitter receptor distribution patterns not only reveal the position of the cortical borders, but also segregate areas associated to different functional systems. Thus we carried out a multimodal quantitative analysis of the cyto- and receptor architecture of the macaque IPL to determine the number and extent of distinct areas it encompasses. We identified four areas on the IPL convexity arranged in a caudo-rostral sequence, as well as two areas in the parietal operculum, which we projected onto the Yerkes19 surface. We found rostral areas to have relatively smaller receptor fingerprints than the caudal ones, which is in an agreement with the functional gradient along the caudo-rostral axis described in previous studies. The hierarchical analysis segregated IPL areas into two clusters: the caudal one, contains areas involved in multisensory integration and visual-motor functions, and rostral cluster, encompasses areas active during motor planning and action-related functions. The results of the present study provide novel insights into clarifying the homologies between human and macaque IPL areas. The ensuing 3D map of the macaque IPL, and the receptor fingerprints are made publicly available to the neuroscientific community via the Human Brain Project and BALSA repositories for future cyto- and/or receptor architectonically driven analyses of functional imaging studies in non-human primates.


Assuntos
Rede Nervosa/citologia , Rede Nervosa/fisiologia , Lobo Parietal/citologia , Lobo Parietal/fisiologia , Receptores de Neurotransmissores/fisiologia , Animais , Autorradiografia/métodos , Macaca fascicularis , Macaca mulatta , Masculino , Análise Multivariada , Rede Nervosa/química , Lobo Parietal/química , Receptores de Neurotransmissores/análise
16.
J Neurophysiol ; 125(3): 699-719, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33427575

RESUMO

Breathing is regulated by a host of arousal and sleep-wake state-dependent neuromodulators to maintain respiratory homeostasis. Modulators such as acetylcholine, norepinephrine, histamine, serotonin (5-HT), adenosine triphosphate (ATP), substance P, somatostatin, bombesin, orexin, and leptin can serve complementary or off-setting functions depending on the target cell type and signaling mechanisms engaged. Abnormalities in any of these modulatory mechanisms can destabilize breathing, suggesting that modulatory mechanisms are not overly redundant but rather work in concert to maintain stable respiratory output. The present review focuses on the modulation of a specific cluster of neurons located in the ventral medullary surface, named retrotrapezoid nucleus, that are activated by changes in tissue CO2/H+ and regulate several aspects of breathing, including inspiration and active expiration.


Assuntos
Células Quimiorreceptoras/fisiologia , Bulbo/fisiologia , Receptores de Neurotransmissores/fisiologia , Mecânica Respiratória/fisiologia , Trifosfato de Adenosina/fisiologia , Animais , Neurônios Colinérgicos/fisiologia , Humanos , Bulbo/citologia , Receptores Purinérgicos/fisiologia , Respiração , Neurônios Serotoninérgicos/fisiologia
17.
J Formos Med Assoc ; 120(6): 1305-1313, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33472764

RESUMO

BACKGROUND/PURPOSE: To investigate the effects of simulated childbirth on the gene expression of parasympathetic muscarinic, purinergic (P2X), and neurokinin receptors of lower urinary tract in rats. METHODS: In all, twenty-four primiparous pregnant Sprague-Dawley female rats were equally divided into three groups: (1). Control group; 8 rats, (2) intra-vaginal balloon dilation for 2 h group; 8 rats, (3) and for 4 h group; 8 rats. After balloon dilatation for 4 months, all rats were sacrificed. We analyzed the gene expression of parasympathetic muscarinic, purinergic (P2X), and neurokinin receptors by real-time quantitative PCR (q-PCR). We quantified pro-inflammatory cytokines of TNF-α and IL-6 by Enzyme-linked immunosorbent assays (ELISA). The urodynamic parameters and micturition frequency by cystometry (CMG) were recorded. RESULTS: Our results showed that the balloon dilation significantly increased micturition frequency and modified peak micturition pressure compare to those in the control groups. Balloon dilation significantly decreased voiding interval and bladder volume compared to those in the control groups. Gene expressions of M3 muscarinic, P2X3 purinergic receptors, and significantly increased following balloon dilation for 2 hours and 4 hours than those in the control group. In addition, we found that NK1R and NK3R receptors were significantly decreased after balloon dilation compare to control group. The marked increase of TNF-α and IL-6 were also seen in the 2 balloon groups. CONCLUSION: The results of our study suggested that birth trauma may impair the function of urinary tract, this being partly related to the changes in the gene expression of the neurotransmitter receptors of the lower urinary tract.


Assuntos
Bexiga Urinária , Urodinâmica , Animais , Feminino , Expressão Gênica , Gravidez , Ratos , Ratos Sprague-Dawley , Receptores de Neurotransmissores , Micção
18.
Proc Natl Acad Sci U S A ; 118(3)2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33452137

RESUMO

Transmitter receptors constitute a key component of the molecular machinery for intercellular communication in the brain. Recent efforts have mapped the density of diverse transmitter receptors across the human cerebral cortex with an unprecedented level of detail. Here, we distill these observations into key organizational principles. We demonstrate that receptor densities form a natural axis in the human cerebral cortex, reflecting decreases in differentiation at the level of laminar organization and a sensory-to-association axis at the functional level. Along this natural axis, key organizational principles are discerned: progressive molecular diversity (increase of the diversity of receptor density); excitation/inhibition (increase of the ratio of excitatory-to-inhibitory receptor density); and mirrored, orderly changes of the density of ionotropic and metabotropic receptors. The uncovered natural axis formed by the distribution of receptors aligns with the axis that is formed by other dimensions of cortical organization, such as the myelo- and cytoarchitectonic levels. Therefore, the uncovered natural axis constitutes a unifying organizational feature linking multiple dimensions of the cerebral cortex, thus bringing order to the heterogeneity of cortical organization.


Assuntos
Encéfalo/metabolismo , Comunicação Celular/genética , Córtex Cerebral/metabolismo , Receptores de Neurotransmissores/genética , Autorradiografia , Encéfalo/diagnóstico por imagem , Encéfalo/ultraestrutura , Mapeamento Encefálico , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/ultraestrutura , Humanos , Receptores de AMPA/genética , Receptores de AMPA/isolamento & purificação , Receptores de GABA-A/genética , Receptores de GABA-A/isolamento & purificação , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/isolamento & purificação , Receptores de Neurotransmissores/química , Receptores de Neurotransmissores/classificação , Receptores de Neurotransmissores/ultraestrutura
19.
Mol Biol Evol ; 38(3): 735-744, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32986821

RESUMO

The origin of nervous systems is a main theme in biology and its mechanisms are largely underlied by synaptic neurotransmission. One problem to explain synapse establishment is that synaptic orthologs are present in multiple aneural organisms. We questioned how the interactions among these elements evolved and to what extent it relates to our understanding of the nervous systems complexity. We identified the human neurotransmission gene network based on genes present in GABAergic, glutamatergic, serotonergic, dopaminergic, and cholinergic systems. The network comprises 321 human genes, 83 of which act exclusively in the nervous system. We reconstructed the evolutionary scenario of synapse emergence by looking for synaptic orthologs in 476 eukaryotes. The Human-Cnidaria common ancestor displayed a massive emergence of neuroexclusive genes, mainly ionotropic receptors, which might have been crucial to the evolution of synapses. Very few synaptic genes had their origin after the Human-Cnidaria common ancestor. We also identified a higher abundance of synaptic proteins in vertebrates, which suggests an increase in the synaptic network complexity of those organisms.


Assuntos
Evolução Biológica , Receptores de Neurotransmissores/genética , Sinapses/genética , Transmissão Sináptica/genética , Animais , Cnidários/genética , Redes Reguladoras de Genes , Humanos
20.
Life Sci ; 265: 118826, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33259863

RESUMO

Epilepsy is a neurologicaldisorder characterized by persistent predisposition to recurrent seizurescaused by abnormal neuronal activity in the brain. Epileptic seizures maydevelop due to a relative imbalance of excitatory and inhibitory neurotransmitters. Expressional alterations of receptors and ion channelsactivated by neurotransmitters can lead to epilepsy pathogenesis. AIMS: In this updated comprehensive review, we discuss the emerging implication of mutations in neurotransmitter-mediated receptors and ion channels. We aim to provide critical findings of the current literature about the role of neurotransmitters in epilepsy. MATERIALS AND METHODS: A comprehensive literature review was conducted to identify and critically evaluate studies analyzing the possible relationship between epilepsy and neurotransmitters. The PubMed database was searched for related research articles. KEY FINDINGS: Glutamate and gamma-aminobutyric acid (GABA) are the main neurotransmitters playing a critical role in the pathophysiology of this balance, and irreversible neuronal damage may occur as a result of abnormal changes in these molecules. Acetylcholine (ACh), the main stimulant of the autonomic nervous system, mediates signal transmission through cholinergic and nicotinic receptors. Accumulating evidence indicates that dysfunction of nicotinic ACh receptors, which are widely expressed in hippocampal and cortical neurons, may be significantly implicated in the pathogenesis of epilepsy. The dopamine-norepinephrine-epinephrine cycle activates hormonal and neuronal pathways; serotonin, norepinephrine, histamine, and melatonin can act as both hormones and neurotransmitters. Recent reports have demonstrated that nitric oxide mediates cognitive and memory-related functions via stimulating neuronal transmission. SIGNIFICANCE: The elucidation of the role of the main mediators and receptors in epilepsy is crucial for developing new diagnostic and therapeutic approaches.


Assuntos
Epilepsia/fisiopatologia , Neurotransmissores/metabolismo , Receptores de Neurotransmissores/genética , Acetilcolina/metabolismo , Animais , Epilepsia/genética , Ácido Glutâmico/metabolismo , Humanos , Mutação , Óxido Nítrico , Ácido gama-Aminobutírico/metabolismo
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