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1.
Biochemistry (Mosc) ; 85(Suppl 1): S108-S130, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32087056

RESUMO

It had been commonly believed for a long time, that once established, degeneration of the central nervous system (CNS) is irreparable, and that adult person merely cannot restore dead or injured neurons. The existence of stem cells (SCs) in the mature brain, an organ with minimal regenerative ability, had been ignored for many years. Currently accepted that specific structures of the adult brain contain neural SCs (NSCs) that can self-renew and generate terminally differentiated brain cells, including neurons and glia. However, their contribution to the regulation of brain activity and brain regeneration in natural aging and pathology is still a subject of ongoing studies. Since the 1970s, when Fuad Lechin suggested the existence of repair mechanisms in the brain, new exhilarating data from scientists around the world have expanded our knowledge on the mechanisms implicated in the generation of various cell phenotypes supporting the brain, regulation of brain activity by these newly generated cells, and participation of SCs in brain homeostasis and regeneration. The prospects of the SC research are truthfully infinite and hitherto challenging to forecast. Once researchers resolve the issues regarding SC expansion and maintenance, the implementation of the SC-based platform could help to treat tissues and organs impaired or damaged in many devastating human diseases. Over the past 10 years, the number of studies on SCs has increased exponentially, and we have already become witnesses of crucial discoveries in SC biology. Comprehension of the mechanisms of neurogenesis regulation is essential for the development of new therapeutic approaches for currently incurable neurodegenerative diseases and neuroblastomas. In this review, we present the latest achievements in this fast-moving field and discuss essential aspects of NSC biology, including SC regulation by hormones, neurotransmitters, and transcription factors, along with the achievements of genetic and chemical reprogramming for the safe use of SCs in vitro and in vivo.


Assuntos
Envelhecimento/metabolismo , Regeneração Nervosa/fisiologia , Células-Tronco Neurais/metabolismo , Doenças Neurodegenerativas/terapia , Adulto , Animais , Transplante de Células/efeitos adversos , Transplante de Células/métodos , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Epigênese Genética , Hormônios/metabolismo , Hormônios/farmacologia , Humanos , Células-Tronco Pluripotentes Induzidas/transplante , Doenças Neurodegenerativas/metabolismo , Neurogênese , Neurotransmissores/metabolismo , Neurotransmissores/farmacologia , Fatores de Transcrição/metabolismo
2.
Nat Rev Gastroenterol Hepatol ; 17(3): 184-192, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32071420

RESUMO

Gut-brain dysregulation has been recognized by the scientific community as being crucial to the understanding of chronic gastrointestinal conditions, and this has translated into the practice of a newly established discipline, psychogastroenterology. Along with psychotherapy, antidepressants (a subtype of central neuromodulators) have been proposed as treatments for gut-brain disorders that might benefit both psychological and gastrointestinal health. Antidepressants have been found to be effective for the treatment of comorbid anxiety and depression, pain and impaired sleep. Although the efficacy of antidepressants is well established in disorders of gut-brain interaction (DGBI), evidence is only now emerging in IBD. This Perspective discusses the use of antidepressants in DGBI and IBD, focusing on how what we have learnt about the role of antidepressants in DGBI could be applied to help optimize the management of IBD.


Assuntos
Antidepressivos/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Antidepressivos/efeitos adversos , Antidepressivos/farmacologia , Encéfalo/fisiopatologia , Dor Crônica/tratamento farmacológico , Comorbidade , Humanos , Doenças Inflamatórias Intestinais/fisiopatologia , Doenças Inflamatórias Intestinais/psicologia , Neurotransmissores/farmacologia , Neurotransmissores/uso terapêutico , Medição de Risco/métodos , Transtornos do Sono-Vigília/tratamento farmacológico
3.
Toxicol Lett ; 321: 21-31, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31830555

RESUMO

Nerve agents inhibit acetylcholinesterase (AChE), leading to a build-up of acetylcholine (ACh) and overstimulation at cholinergic synapses. Current post-exposure nerve agent treatment includes atropine to treat overstimulation at muscarinic synapses, a benzodiazepine anti-convulsant, and an oxime to restore the function of AChE. Aside from the oxime, the components do not act directly to reduce the overstimulation at nicotinic synapses. The false transmitters acetylmonoethylcholine (AMECh) and acetyldiethylcholine (ADECh) are analogs of ACh, synthesised similarly at synapses. AMECh and ADECh are partial agonists, with reduced activity compared to ACh, so it was hypothesised the false transmitters could reduce overstimulation. Synthetic routes to AMECh and ADECh, and their precursors, monoethylcholine (MECh) and diethylcholine (DECh), were devised, allowing them to be produced easily on a laboratory-scale. The mechanism of action of the false transmitters was investigated in vitro. AMECh acted as a partial agonist at human muscarinic (M1 and M3) and muscle-type nicotinic receptors, and ADECh was a partial agonist only at certain muscarinic subtypes. Their precursors acted as antagonists at muscle-type nicotinic, but not muscarinic receptors. Administration of MECh and DECh improved neuromuscular function in the soman-exposed guinea-pig hemi-diaphragm preparation. False transmitters may therefore help reduce nerve agent induced overstimulation at cholinergic synapses.


Assuntos
Acetilcolina/análogos & derivados , Antídotos/farmacologia , Colina/análogos & derivados , Inibidores da Colinesterase/envenenamento , Diafragma/inervação , Agentes Neurotóxicos/envenenamento , Neurotransmissores/farmacologia , Intoxicação por Organofosfatos/tratamento farmacológico , Soman/envenenamento , Sinapses/efeitos dos fármacos , Acetilcolina/síntese química , Acetilcolina/metabolismo , Acetilcolina/farmacologia , Acetilcolinesterase/metabolismo , Animais , Antídotos/síntese química , Células CHO , Linhagem Celular Tumoral , Colina/síntese química , Colina/farmacologia , Cricetulus , Agonismo Parcial de Drogas , Cobaias , Humanos , Masculino , Neurotransmissores/síntese química , Intoxicação por Organofosfatos/enzimologia , Intoxicação por Organofosfatos/fisiopatologia , Receptores Colinérgicos/efeitos dos fármacos , Receptores Colinérgicos/genética , Receptores Colinérgicos/metabolismo , Sinapses/enzimologia
4.
Phys Chem Chem Phys ; 21(41): 22700-22703, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31579899

RESUMO

We use cold ion spectroscopy and quantum-chemical computations to solve the structures of opioid peptides enkephalins in the gas phase. The derived structural parameters clearly correlate with the known pharmacological efficiency of the studied drugs, suggesting that gas-phase methods, perhaps, can be used for predicting the relative potency of ligand drugs that target the hydrophobic pockets of receptors.


Assuntos
Encefalinas/química , Gases/química , Modelos Moleculares , Análise Espectral , Encefalinas/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Neurotransmissores/química , Neurotransmissores/farmacologia , Relação Estrutura-Atividade
5.
PLoS Negl Trop Dis ; 13(8): e0007573, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31408466

RESUMO

The metacercariae of the Clonorchis sinensis liver fluke excyst in the duodenum of mammalian hosts, and the newly excysted juveniles (CsNEJs) migrate along the bile duct via bile chemotaxis. Cholic acid is a major component of bile that induces this migration. We investigated the neuronal control of chemotactic behavior of CsNEJs toward cholic acid. The migration of CsNEJs was strongly inhibited at sub-micromolar concentration by dopamine D1 (LE-300 and SKF-83566), D2 (spiramide, nemonapride, and sulpiride), and D3 (GR-103691 and NGB-2904) receptor antagonists, as well as a dopamine reuptake inhibitor (BTCP). Neuropeptides, FMRFamide, peptide YY, and neuropeptide Y were also potent inhibitors of chemotaxis. Meanwhile, serotonergic, glutamatergic, and cholinergic inhibitors did not affect chemotaxis, with the exception of fluoxetine and CNQX. Confocal immunofluorescence analysis indicated that dopaminergic and cholinergic neurons were colocalized in the somatic muscle tissues of adult C. sinensis. Our findings suggest that dopaminergic neurons and neuropeptides play a major role in the chemotactic migration of CsNEJs to bile, and their inhibitors or modulators could be utilized to prevent their migration from the bile duct.


Assuntos
Quimiotaxia/efeitos dos fármacos , Quimiotaxia/fisiologia , Clonorchis sinensis/efeitos dos fármacos , Clonorchis sinensis/fisiologia , Fasciola hepatica/efeitos dos fármacos , Neurotransmissores/farmacologia , Animais , Benzamidas/farmacologia , Compostos de Bifenilo/farmacologia , Ácido Cólico , Dopamina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , FMRFamida/farmacologia , Fluorenos/farmacologia , Neuropeptídeo Y/farmacologia , Peptídeo YY/farmacologia , Piperazinas/farmacologia , Serotoninérgicos/farmacologia , Compostos de Espiro/farmacologia , Sulpirida/farmacologia
6.
Biosens Bioelectron ; 140: 111329, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31163396

RESUMO

Lab-on-chip platforms, such as microfluidic chips and micro-electrode arrays (MEAs) are powerful tools that allow us to manipulate and study neurons in vitro. Microfluidic chips provide a controlled extracellular environment that structures neural networks and facilitates isolation and manipulation at a sub-cellular level. Furthermore, MEAs enable measurement of extracellular electrophysiological activity from single neurons to entire networks. Here, we demonstrate the design, fabrication and application of a 3-nodal microfluidic chip integrated with MEAs as a versatile study platform for neurobiology and pathophysiology. In this work, we evaluate the use of the microfluidic chip to structure a neural network into three separate nodes, interconnected through tunnels that isolate and guide axons into a channel, thus facilitating synaptic contacts between neurons originating from opposite nodes. Furthermore, we demonstrate the utility of the MEA for monitoring developing activity and intra-/inter nodal connectivity of the structured neural network. Finally, we demonstrate the versatility of the platform in two separate experiments. First, we demonstrate the ability to measure intra- and inter-nodal dynamic responses to a fluidically isolated chemical stimulation. Then, we demonstrate the feature of the microfluidic chip enabling the disruption of functional connectivity between nodes and examination of the immediate activity response of the neural network. The platform enables in vitro modelling of neural networks to study their functional connectomes in the context of neurodegenerative disease and CNS trauma, including spinal cord injury.


Assuntos
Técnicas Biossensoriais/instrumentação , Dispositivos Lab-On-A-Chip , Rede Nervosa/citologia , Rede Nervosa/efeitos dos fármacos , Neurotransmissores/farmacologia , Animais , Axotomia , Linhagem Celular , Desenho de Equipamento , Rede Nervosa/fisiologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo
7.
Nat Commun ; 10(1): 2620, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197165

RESUMO

Conventional drug screens and treatments often ignore the underlying complexity of brain network dysfunctions, resulting in suboptimal outcomes. Here we ask whether we can correct abnormal functional connectivity of the entire brain by identifying and combining multiple neuromodulators that perturb connectivity in complementary ways. Our approach avoids the combinatorial complexity of screening all drug combinations. We develop a high-speed platform capable of imaging more than 15000 neurons in 50ms to map the entire brain functional connectivity in large numbers of vertebrates under many conditions. Screening a panel of drugs in a zebrafish model of human Dravet syndrome, we show that even drugs with related mechanisms of action can modulate functional connectivity in significantly different ways. By clustering connectivity fingerprints, we algorithmically select small subsets of complementary drugs and rapidly identify combinations that are significantly more effective at correcting abnormal networks and reducing spontaneous seizures than monotherapies, while minimizing behavioral side effects. Even at low concentrations, our polytherapy performs superior to individual drugs even at highest tolerated concentrations.


Assuntos
Epilepsias Mioclônicas/tratamento farmacológico , Modelos Biológicos , Rede Nervosa/efeitos dos fármacos , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Neurotransmissores/farmacologia , Algoritmos , Animais , Animais Geneticamente Modificados , Comportamento Animal/efeitos dos fármacos , Encéfalo/citologia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Mapeamento Encefálico/métodos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/patologia , Ensaios de Triagem em Larga Escala/métodos , Humanos , Microscopia Confocal/métodos , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Neurotransmissores/uso terapêutico , Peixe-Zebra
8.
Biomed Res Int ; 2019: 8941046, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31240228

RESUMO

Chloride (Cl-) homeostasis is an essential process involved in neuronal signalling and cell survival. Inadequate regulation of intracellular Cl- interferes with synaptic signalling and is implicated in several neurological diseases. The main inhibitory neurotransmitter of the central nervous system is γ-aminobutyric acid (GABA). GABA hyperpolarises the membrane potential by activating Cl- permeable GABAA receptor channels (GABAAR). This process is reliant on Cl- extruder K+-Cl- cotransporter 2 (KCC2), which generates the neuron's inward, hyperpolarising Cl- gradient. KCC2 is encoded by the fifth member of the solute carrier 12 family (SLC12A5) and has remained a poorly understood component in the development and severity of many neurological diseases for many years. Recent advancements in next-generation sequencing and specific gene targeting, however, have indicated that loss of KCC2 activity is involved in a number of diseases including epilepsy and schizophrenia. It has also been implicated in neuropathic pain following spinal cord injury. Any variant of SLC12A5 that negatively regulates the transporter's expression may, therefore, be implicated in neurological disease. A recent whole exome study has discovered several causative mutations in patients with epilepsy. Here, we discuss the implications of KCC2 in neurological disease and consider the evolving evidence for KCC2's potential as a therapeutic target.


Assuntos
Canais de Cloreto/metabolismo , Neurônios/metabolismo , Simportadores/antagonistas & inibidores , Simportadores/metabolismo , Ácido gama-Aminobutírico/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Cloretos/metabolismo , Epilepsia/metabolismo , Marcação de Genes , Homeostase , Humanos , Potenciais da Membrana , Neuralgia/metabolismo , Neurotransmissores/farmacologia , Fosforilação , Esquizofrenia/metabolismo , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Traumatismos da Medula Espinal , Simportadores/genética
9.
ACS Appl Mater Interfaces ; 11(17): 15344-15353, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30974942

RESUMO

Myelination by oligodendrocytes (OLs) is a key developmental milestone in terms of the functions of the central nervous system (CNS). Demyelination caused by defects in OLs is a hallmark of several CNS disorders. Although a potential therapeutic strategy involves treatment with the myelin-forming cells, there is no readily available source of these cells. OLs can be differentiated from pluripotent stem cells; however, there is a lack of efficient culture systems that generate functional OLs. Here, we demonstrate biomimetic approaches to promote OL differentiation from human-induced pluripotent stem cells (iPSCs) and to enhance the maturation and myelination capabilities of iPSC-derived OL (iPSC-OL). Functionalization of culture substrates using the brain extracellular matrix (BEM) derived from decellularized human brain tissue enhanced the differentiation of iPSCs into myelin-expressing OLs. Co-culture of iPSC-OL with induced neuronal (iN) cells on BEM substrates, which closely mimics the in vivo brain microenvironment for myelinated neurons, not only enhanced myelination of iPSC-OL but also improved electrophysiological function of iN cells. BEM-functionalized aligned electrospun nanofibrous scaffolds further promoted the maturation of iPSC-OLs, enhanced the production of myelin sheath-like structures by the iPSC-OL, and enhanced the neurogenesis of iN cells. Thus, the biomimetic strategy presented here can generate functional OLs from stem cells and facilitate myelination by providing brain-specific biochemical, biophysical, and structural signals. Our system comprising stem cells and brain tissue from human sources could help in the establishment of human demyelination disease models and the development of regenerative cell therapy for myelin disorders.


Assuntos
Encéfalo/metabolismo , Matriz Extracelular/química , Bainha de Mielina/fisiologia , Diferenciação Celular , Linhagem Celular , Técnicas de Cocultura , Fenômenos Eletrofisiológicos , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Proteína Básica da Mielina/metabolismo , Nanofibras/química , Neurogênese , Neurônios/citologia , Neurônios/metabolismo , Neurotransmissores/farmacologia , Oligodendroglia/citologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo
10.
Life Sci ; 225: 98-106, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30959026

RESUMO

AIMS: Arterial insufficiency ulcers are frequent complications of peripheral artery disease and infection or long-term neglect of the ulcer can eventually lead to amputation of the affected body part. An ischemic environment, caused by interrupted blood flow, affects the supply of nutrients and elongates the inflammation period, inducing tissue degeneration. Thus, the modulation of neovascularization and inflammation could be an ideal therapeutic strategy for ischemic wound healing. This study aimed to elucidate whether systemically administered substance P (SP) could promote ischemic wound repair in mice by restoring blood perfusion and suppressing inflammation. MAIN METHODS: The effects of SP were assessed by analyzing wound size, blood flow, epidermal and dermal layer regeneration, vessel formation, and the inflammatory cytokine profiles in a hind-limb ischemia non-clinical mouse model. KEY FINDINGS: SP-treated mice exhibited dramatically rapid wound healing and restoration of blood flow within the ischemic zone, compared with saline-treated mice. Notably, SP-treated mice showed enhanced pericyte-covered vasculature compared to saline-treated mice. Moreover, anti-inflammatory effects were detected in mice in the SP-treated group, including suppression of inflammation-mediated spleen enlargement, reduction of tumor necrosis factor-alpha, and promotion of circulatory interleukin-10 levels. SIGNIFICANCE: These results suggest that SP could be a possible therapeutic candidate for patients with peripheral artery disease, including those with ischemic ulcers.


Assuntos
Modelos Animais de Doenças , Inflamação/prevenção & controle , Isquemia/complicações , Neovascularização Fisiológica/efeitos dos fármacos , Neurotransmissores/farmacologia , Substância P/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Inflamação/etiologia , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pele/efeitos dos fármacos , Pele/metabolismo
11.
Life Sci ; 224: 232-240, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30930116

RESUMO

AIMS: Opioid receptor blockers such as naloxone and naltrexone have been suggested to have a bone mass-increasing effect. However, the mechanisms at play have not been clarified. We examined the effects of naltrexone on osteoblasts and determined the expression of opioid growth factor receptor (OGFR) in osteoblasts. Naltrexone blocks the OGFR and other canonical opioid receptors. Thus, we designed experiments to clarify the effects of naltrexone on bone tissue by examining the physiological role of OGFR signaling in osteoblasts and the changes in bone structure after naltrexone systemic administration in mice. MAIN METHODS: We used mouse osteoblast-like cell line MC3T3-E1 for in vitro experiments. We cultured MC3T3-E1 cells in the presence of the OGFR agonist met-enkephalin (met-enk). Then, we measured cell proliferation activity and analyzed the expression levels of cell proliferation-related genes. For our in vivo experiments, we administered naltrexone intraperitoneally to mice daily for 28 days and administered the animals in the control group equivalent volumes of saline. After sacrificing the mice, we performed micro-computed tomography and bone morphology analyses. KEY FINDINGS: Met-enk suppressed cell proliferation in MC3T3-E1 cells. Moreover, Low dose naltrexone administration significantly increased their femoral bone mass, bone formation ratio, and osteoblast number/bone surface values when comparing the values for the same variables in the control group. SIGNIFICANCE: Our results suggest that naltrexone increases bone mass due to osteoblast number increments caused by the OGFR signaling block. Opioid receptor blockers have potential as therapeutic agents for osteoporosis as well as opioid antagonists.


Assuntos
Densidade Óssea/efeitos dos fármacos , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Osteoblastos/citologia , Receptores Opioides/química , Animais , Proliferação de Células , Células Cultivadas , Encefalina Metionina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Neurotransmissores/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Receptores Opioides/genética , Receptores Opioides/metabolismo
12.
World J Gastroenterol ; 25(10): 1185-1196, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30886502

RESUMO

There is overwhelming evidence that functional gastrointestinal disorders (FGIDs) are associated with specific mechanisms that constitute important targets for personalized treatment. There are specific mechanisms in patients presenting with functional upper gastrointestinal symptoms (UGI Sx). Among patients with UGI Sx, approximately equal proportions (25%) of patients have delayed gastric emptying (GE), reduced gastric accommodation (GA), both impaired GE and GA, or neither, presumably due to increased gastric or duodenal sensitivity. Treatments targeted to the underlying pathophysiology utilize prokinetics, gastric relaxants, or central neuromodulators. Similarly, specific mechanisms in patients presenting with functional lower gastrointestinal symptoms, especially with diarrhea or constipation, are recognized, including at least 30% of patients with functional constipation pelvic floor dyssynergia and 5% has colonic inertia (with neural or interstitial cells of Cajal loss in myenteric plexus); 25% of patients with diarrhea-predominant irritable bowel syndrome (IBSD) has evidence of bile acid diarrhea; and, depending on ethnicity, a varying proportion of patients has disaccharidase deficiency, and less often sucrose-isomaltase deficiency. Among patients with predominant pain or bloating, the role of fermentable oligosaccharides, disaccharides, monosaccharides and polyols should be considered. Personalization is applied through pharmacogenomics related to drug pharmacokinetics, specifically the role of CYP2D6, 2C19 and 3A4 in the use of drugs for treatment of patients with FGIDs. Single mutations or multiple genetic variants are relatively rare, with limited impact to date on the understanding or treatment of FGIDs. The role of mucosal gene expression in FGIDs, particularly in IBS-D, is the subject of ongoing research. In summary, the time for personalization of FGIDs, based on deep phenotyping, is here; pharmacogenomics is relevant in the use of central neuromodulators. There is still unclear impact of the role of genetics in the management of FGIDs.


Assuntos
Fármacos Gastrointestinais/farmacologia , Gastroenteropatias/tratamento farmacológico , Neurotransmissores/farmacologia , Variantes Farmacogenômicos , Medicina de Precisão/métodos , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/genética , Dissacaridases/deficiência , Dissacaridases/genética , Fármacos Gastrointestinais/uso terapêutico , Gastroenteropatias/diagnóstico , Gastroenteropatias/etiologia , Gastroenteropatias/genética , Motilidade Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/genética , Humanos , Neurotransmissores/uso terapêutico , Diafragma da Pelve/fisiopatologia , Resultado do Tratamento
13.
J Steroid Biochem Mol Biol ; 189: 195-203, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30872014

RESUMO

A broad variety of central nervous system diseases have been associated with glutamate induced excitotoxicity under pathological conditions. The neuroprotective effects of neurosteroids can combat this excitotoxicity. Herein, we have demonstrated the neuroprotective effect of novel steroidal N-methyl-D-aspartate receptor inhibitors against glutamate- or NMDA- induced excitotoxicity. Pretreatment with neurosteroids significantly reduced acute L-glutamic acid or NMDA excitotoxicity mediated by Ca2+ entry and consequent ROS (reactive oxygen species) release and caspase-3 activation. Compounds 6 (IC50 = 5.8 µM), 7 (IC50 = 12.2 µM), 9 (IC50 = 7.8 µM), 13 (IC50 = 1.1 µM) and 16 (IC50 = 8.2 µM) attenuated glutamate-induced Ca2+ entry more effectively than memantine (IC50 = 18.9 µM). Moreover, compound 13 shows comparable effect with MK-801 (IC50 = 1.2 µM) and also afforded significant protection without any adverse effect upon prolonged exposure. This drop in Ca2+ level resulted in corresponding ROS suppression and prevented glutamate-induced caspase-3 activation. Therefore, compound 13 has great potential for development into a therapeutic agent for improving glutamate-related nervous system diseases.


Assuntos
Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Neurotransmissores/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Células Cultivadas , Ácido Glutâmico/efeitos adversos , N-Metilaspartato/efeitos adversos , Neurônios/citologia , Neurônios/metabolismo , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/química , Neurotransmissores/química , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
14.
Fish Shellfish Immunol ; 88: 432-440, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30862518

RESUMO

Opioid neuropeptides are developed early in the course of a long evolutionary process. As the endogenous messengers of immune system, opioid neuropeptides participate in regulating immune response. In this study, the mechanism that Met-enkephalin (M-ENK) inhibits ROS production through Wnt/ß-catenin signaling was investigated in the ZF4 cells of zebrafish. ZF4 cells were exposed to 0, 10, 20, 40, 80, and 160 µM Met-enkephalin (M-ENK) for 24 h, and the cell viability was detected with 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. The cell viability was significantly increased by 10, 20, 40, 80, and 160 µM M-ENK. After ZF4 cells were exposed to 0, 20, 40, and 80 µM M-ENK for 24 h, the mRNA expression of Wnt10b, ß-catenin, and CCAAT/enhancer binding protein α (C/EBPα) was significantly increased by 40 and 80 µM M-ENK. However, the mRNA and protein expression of GSK-3ß was significantly decreased by 40 and 80 µM M-ENK. The protein expression of ß-catenin was significantly induced by 40 and 80 µM M-ENK, while the protein expression of p-ß-catenin was significantly decreased by 20, 40, and 80 µM M-ENK. In addition, the mRNA expression of CAT, SOD, and GSH-PX was significantly increased by 40 and 80 µM M-ENK. The levels of H2O2, ·OH, and O2·- were significantly decreased, but the activity of CAT, SOD, and GSH-PX was significantly increased by 40 and 80 µM M-ENK. The fluorescence intensity of reactive oxygen species (ROS) was decreased, and that of mitochondrial membrane potential (MMP) was increased with the increase of M-ENK concentration in ZF4 cells. The results showed that M-ENK could induce Wnt/ß-catenin signaling, which further inhibited ROS production through the induction of C/EBPα, MMP, and the activities of antioxidant enzymes.


Assuntos
Encefalina Metionina/farmacologia , Neurotransmissores/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Via de Sinalização Wnt , Peixe-Zebra , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Catalase/metabolismo , Sobrevivência Celular , Células Cultivadas , Glutationa Peroxidase/metabolismo , Peróxido de Hidrogênio/metabolismo , Potencial da Membrana Mitocondrial , Superóxido Dismutase/metabolismo , beta Catenina/metabolismo
15.
PLoS One ; 14(3): e0213721, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30865708

RESUMO

A growing body of literature has demonstrated the potential for ketamine in the treatment of major depression. Sub-anesthetic doses produce rapid and sustained changes in depressive behavior, both in patients and rodent models, associated with reorganization of glutamatergic synapses in the prefrontal cortex (PFC). While ketamine is known to regulate N-methyl-D-aspartate (NMDA) -type glutamate receptors (NMDARs), the full complement of downstream cellular consequences for ketamine administration are not well understood. Here, we combine electrophysiology with 2-photon imaging and glutamate uncaging in acute slices of mouse PFC to further examine how ketamine alters glutamatergic synaptic transmission. We find that four hours after ketamine treatment, glutamatergic synapses themselves are not significantly affected. However, levels of the neuromodulatory Regulator of G-protein Signaling (RGS4) are dramatically reduced. This loss of RGS4 activity is associated with disruption of the normal compartmentalization of synaptic neuromodulation. Thus, under control conditions, α2 adrenergic receptors and type B γ-aminobutyric acid (GABAB) receptors selectively inhibit α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) -type glutamate receptors (AMPARs) and NMDARs, respectively. After ketamine administration and reduction in RGS4 activity, this selectivity is lost, with both modulatory systems broadly inhibiting glutamatergic transmission. These results suggest a novel mechanism by which ketamine may influence synaptic signaling and provide new avenues for the exploration of therapeutics directed at treating neuropsychiatric disorders, such as depression.


Assuntos
Depressão/tratamento farmacológico , Glutamina/metabolismo , Ketamina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Antidepressivos/administração & dosagem , Antidepressivos/farmacologia , Comportamento Animal , Encéfalo/efeitos dos fármacos , Feminino , Ketamina/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , N-Metilaspartato , Neurônios/metabolismo , Neurotransmissores/administração & dosagem , Neurotransmissores/farmacologia , Receptores de AMPA/metabolismo , Receptores de GABA/metabolismo , Transdução de Sinais , Natação , Sinapses/metabolismo , Potenciais Sinápticos/efeitos dos fármacos , Gravação em Vídeo
16.
Cell ; 176(1-2): 1, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30633900

RESUMO

During the postpartum period, the brain's inhibitory GABAA receptors may not recover in time following their reduced numbers during pregnancy. This is likely the cause of postpartum depression prevalent in ∼12% of childbearing women. A new therapy for this condition consists of administering a synthetic neurosteroid during the postpartum period to alleviate the mood disorder. To view this Bench to Bedside, open or download the PDF.


Assuntos
Depressão Pós-Parto/terapia , Pregnanolona/farmacologia , Receptores de GABA-A/metabolismo , beta-Ciclodextrinas/farmacologia , Adulto , Depressão Pós-Parto/metabolismo , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/terapia , Combinação de Medicamentos , Feminino , Humanos , Transtornos do Humor , Neurotransmissores/farmacologia , Período Pós-Parto/metabolismo , Gravidez , Prevalência , Receptores de GABA-A/fisiologia
17.
Gastroenterology ; 156(5): 1483-1495.e6, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30610864

RESUMO

BACKGROUND & AIMS: The enteric nervous system (ENS) is the largest branch of the peripheral nervous system, comprising complex networks of neurons and glia, which are present throughout the gastrointestinal tract. Although development of a fully functional ENS is required for gastrointestinal motility, little is known about the ontogeny of ENS function in humans. We studied the development of neuronal subtypes and the emergence of evoked electrical activity in the developing human ENS. METHODS: Human fetal gut samples (obtained via the MRC-Wellcome Trust Human Developmental Biology Resource-UK) were characterized by immunohistochemistry, calcium imaging, RNA sequencing, and quantitative real-time polymerase chain reaction analyses. RESULTS: Human fetal colon samples have dense neuronal networks at the level of the myenteric plexus by embryonic week (EW) 12, with expression of excitatory neurotransmitter and synaptic markers. By contrast, markers of inhibitory neurotransmitters were not observed until EW14. Electrical train stimulation of internodal strands did not evoke activity in the ENS of EW12 or EW14 tissues. However, compound calcium activation was observed at EW16, which was blocked by the addition of 1 µmol/L tetrodotoxin. Expression analyses showed that this activity was coincident with increases in expression of genes encoding proteins involved in neurotransmission and action potential generation. CONCLUSIONS: In analyses of human fetal intestinal samples, we followed development of neuronal diversity, electrical excitability, and network formation in the ENS. These processes are required to establish the functional enteric circuitry. Further studies could increase our understanding of the pathogenesis of a range of congenital enteric neuropathies.


Assuntos
Colo/inervação , Sistema Nervoso Entérico/fisiologia , Potenciais Evocados , Rede Nervosa/fisiologia , Neurogênese , Neurônios/fisiologia , Sinalização do Cálcio , Colo/embriologia , Estimulação Elétrica , Sistema Nervoso Entérico/efeitos dos fármacos , Sistema Nervoso Entérico/embriologia , Potenciais Evocados/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Idade Gestacional , Humanos , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/embriologia , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Neurônios/efeitos dos fármacos , Neurotransmissores/farmacologia , Fenótipo , Gravidez , Segundo Trimestre da Gravidez , Transmissão Sináptica
18.
Cell Tissue Res ; 377(1): 45-58, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30649612

RESUMO

Studies about the pathogenesis of mood disorders have consistently shown that multiple factors, including genetic and environmental, play a crucial role on their development and neurobiology. Multiple pathological theories have been proposed, of which several ultimately affects or is a consequence of dysfunction in brain neuroplasticity and homeostatic mechanisms. However, current clinical available pharmacological intervention, which is predominantly monoamine-based, suffers from a partial and lacking response even after weeks of continuous treatment. These issues raise the need for better understanding of aetiologies and brain abnormalities in depression, as well as developing novel treatment strategies. Nitric oxide (NO) is a gaseous unconventional neurotransmitter, which regulates and governs several important physiological functions in the central nervous system, including processes, which can be associated with the development of mood disorders. This review will present general aspects of the NO system in depression, highlighting potential targets that may be utilized and further explored as novel therapeutic targets in the future pharmacotherapy of depression. In particular, the review will link the importance of neuroplasticity mechanisms governed by NO to a possible molecular basis for the antidepressant effects.


Assuntos
Antidepressivos/farmacologia , Encéfalo , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/metabolismo , Neurotransmissores/farmacologia , Óxido Nítrico/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Humanos , Camundongos , Plasticidade Neuronal , Ratos , Transdução de Sinais
19.
Glia ; 67(4): 688-702, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30485550

RESUMO

Williams-Beuren syndrome (WBS) is a microdeletion disorder with cognitive phenotype. NSUN5 gene, which encodes a cytosine-5 RNA methyltransferase, is located in WBS deletion locus. To investigate the influence of NSUN5 deletion on cognitive behaviors, we produced single-gene Nsun5 knockout (Nsun5-KO) mice. Here, we report that adult Nsun5-KO mice showed spatial cognitive deficits. Size of the brain and hippocampal structures and the number of CA1 or CA3 pyramidal cells in Nsun5-KO mice did not differ from WT mice. Basal properties of Schaffer collateral-CA1 synaptic transmission in Nsun5-KO mice were unchanged, but NMDA receptor (NMDAr)-dependent long-term potentiation (LTP) was not induced. The NMDA-evoked current in CA1 pyramidal cells was reduced in Nsun5-KO mice without the changes in expression and phosphorylation of NMDAr subunits NR2A and NR2B. Although the protein level of AMPA receptor subunit GluR2 was attenuated in Nsun5-KO mice, the AMPA-evoked current was not altered. Hippocampal immuno-staining showed the selective expression of Nsun5 in NG2 or PDGFRα labeled oligodendrocyte precursor cells (OPCs), but not in pyramidal cells or astrocytes. Analysis of RT-PCR determined the Nsun5 expression in purified populations of OPCs rather than neurons or astrocytes. The Nsun5 deficiency led to decreases in the number and neurite outgrowth of OPCs in the hippocampal CA1 and DG, with the decline in NG2 expression and OPCs proliferation. These findings indicate that the Nsun5 deletion suppresses NMDAr activity in neuronal cells probably through the disrupted development and function of OPCs, leading to deficits in NMDAr-dependent LTP and spatial cognitive abilities.


Assuntos
Transtornos Cognitivos/genética , Transtornos Cognitivos/patologia , DNA (Citosina-5-)-Metiltransferases/deficiência , Células Precursoras de Oligodendrócitos/patologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Animais , Encéfalo/citologia , Encéfalo/fisiologia , Células Cultivadas , DNA (Citosina-5-)-Metiltransferases/genética , Modelos Animais de Doenças , Ingestão de Alimentos/genética , Metabolismo Energético/genética , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/genética , Comportamento Exploratório , Feminino , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Neurotransmissores/farmacologia
20.
Behav Brain Res ; 359: 671-685, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30267715

RESUMO

Recent preclinical studies point to muscarinic and GABAB receptors as novel therapeutic targets for the treatment of schizophrenia. This study was aimed to assess the role of muscarinic and GABAB receptor interactions in animal models of schizophrenia, using positive allosteric modulators (PAMs) of GABAB receptor (GS39783), muscarinic M4 (VU0152100) and M5 (VU0238429) receptor, and partial allosteric agonist of M1 receptor (VU0357017). DOI-induced head twitches, social interaction and novel object recognition tests were used as the models of schizophrenia. Analyses of DOI-induced increases in sEPSCs (spontaneous excitatory postsynaptic currents) were performed as complementary experiments to the DOI-induced head twitch studies. Haloperidol-induced catalepsy and the rotarod test were used to examine the adverse effects of the drugs. All three activators of muscarinic receptors were active in DOI-induced head twitches. When administered together with GS39783 in subeffective doses, only the co-administration of VU0152100 and GS39783 was effective. The combination also reduced the frequency but not the amplitude of DOI-induced sEPSCs. Neither VU0357017 nor VU0238429 were active in social interaction test when given alone, and also the combination of VU0152100 and GS39783 failed to reverse MK-801-induced deficits observed in this test. All muscarinic activators when administered alone or in combination with GS39783 reversed the MK-801-induced disruption of memory in the novel object recognition test, and their actions were blocked by specific antagonists. None of the tested compounds or their combinations influenced the motor coordination of the animals. The compounds had no effect on haloperidol-induced catalepsy and did not induce catalepsy when administered alone. Pharmacokinetic analysis confirmed lack of possible drug-drug interactions after combined administration of GS39783 with VU0357017 or VU0152100; however, when the drug was co-administered with VU0238429 its ability to pass the blood-brain barrier slightly decreased, suggesting potential drug-drug interactions. Our data show that modulation of cholinergic and GABAergic systems can potentially be beneficial in the treatment of the positive and cognitive symptoms of schizophrenia without inducing the adverse effects typical for presently used antipsychotics.


Assuntos
Antipsicóticos/farmacologia , Neurotransmissores/farmacologia , Receptores de GABA-B/metabolismo , Receptores Muscarínicos/metabolismo , Esquizofrenia/tratamento farmacológico , Regulação Alostérica , Animais , Antipsicóticos/farmacocinética , Benzamidas/farmacocinética , Benzamidas/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ciclopentanos/farmacocinética , Ciclopentanos/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Indóis/farmacocinética , Indóis/farmacologia , Masculino , Camundongos , Neurotransmissores/farmacocinética , Piridinas/farmacocinética , Piridinas/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Esquizofrenia/metabolismo , Tiofenos/farmacocinética , Tiofenos/farmacologia
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