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1.
Postepy Biochem ; 66(3): 205-212, 2020 09 30.
Artigo em Polonês | MEDLINE | ID: mdl-33315318

RESUMO

It has been found that in brain areas responsible for controlling appetite brain-derived neurotrophic factor (BDNF) and TrkB receptor expression are also present. In addition to involvement in neurogenesis, neuroprotection and synaptic plasticity, BDNF has anorexigenic activity. Decreasing of BDNF levels in the brain causes uncontrolled food intake, in turn, administration of BDNF to the central nervous system (CNS) leads to weight loss in animals. BDNF may participate with other factors such as leptin, insulin, cholecystokinin or corticotropin in the regulation of food intake. In addition, BDNF can affect glucose metabolism. It was found that peripheral BDNF level is lower in anorexia compared to healthy people. Moreover, BDNF levels tend to return to basal value when body weight normalizes. The mutation in the BDNF gene could also be important in the pathogenesis of obesity, although data on the blood concentration of this neurotrophin in obese are ambiguous.


Assuntos
Regulação do Apetite , Fator Neurotrófico Derivado do Encéfalo , Animais , Peso Corporal , Fator Neurotrófico Derivado do Encéfalo/genética , Humanos , Obesidade/genética , Receptor trkB/metabolismo
2.
Proc Natl Acad Sci U S A ; 117(35): 21667-21672, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32817534

RESUMO

Extensive pharmacologic, genetic, and epigenetic research has linked the glucocorticoid receptor (GR) to memory processes, and to risk and symptoms of posttraumatic stress disorder (PTSD). In the present study we investigated the epigenetic pattern of 12 genes involved in the regulation of GR signaling in two African populations of heavily traumatized individuals: Survivors of the rebel war in northern Uganda (n = 463) and survivors of the Rwandan genocide (n = 350). The strongest link between regional methylation and PTSD risk and symptoms was observed for NTRK2, which encodes the transmembrane receptor tropomyosin-related kinase B, binds the brain-derived neurotrophic factor, and has been shown to play an important role in memory formation. NTRK2 methylation was not related to trauma load, suggesting that methylation differences preexisted the trauma. Because NTRK2 methylation differences were predominantly associated with memory-related PTSD symptoms, and because they seem to precede traumatic events, we next investigated the relationship between NTRK2 methylation and memory in a sample of nontraumatized individuals (n = 568). We found that NTRK2 methylation was negatively associated with recognition memory performance. Furthermore, fMRI analyses revealed NTRK2 methylation-dependent differences in brain network activity related to recognition memory. The present study demonstrates that NTRK2 is epigenetically linked to memory functions in nontraumatized subjects and to PTSD risk and symptoms in traumatized populations.


Assuntos
Glicoproteínas de Membrana/genética , Receptor trkB/genética , Transtornos de Estresse Pós-Traumáticos/genética , Adulto , Idoso , Encéfalo/metabolismo , Metilação de DNA/genética , Epigênese Genética/genética , Feminino , Glucocorticoides/metabolismo , Humanos , Masculino , Glicoproteínas de Membrana/metabolismo , Memória/fisiologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Receptor trkB/metabolismo , Receptores de Glucocorticoides/metabolismo , Fatores de Risco , Ruanda/epidemiologia , Transtornos de Estresse Pós-Traumáticos/metabolismo , Sobreviventes , Uganda/epidemiologia
3.
Nat Commun ; 11(1): 3935, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769979

RESUMO

GABAA/glycine-mediated neuronal inhibition critically depends on intracellular chloride (Cl-) concentration which is mainly regulated by the K+-Cl- co-transporter 2 (KCC2) in the adult central nervous system (CNS). KCC2 heterogeneity thus affects information processing across CNS areas. Here, we uncover a gradient in Cl- extrusion capacity across the superficial dorsal horn (SDH) of the spinal cord (laminae I-II: LI-LII), which remains concealed under low Cl- load. Under high Cl- load or heightened synaptic drive, lower Cl- extrusion is unveiled in LI, as expected from the gradient in KCC2 expression found across the SDH. Blocking TrkB receptors increases KCC2 in LI, pointing to differential constitutive TrkB activation across laminae. Higher Cl- lability in LI results in rapidly collapsing inhibition, and a form of activity-dependent synaptic plasticity expressed as a continuous facilitation of excitatory responses. The higher metaplasticity in LI as compared to LII differentially affects sensitization to thermal and mechanical input. Thus, inconspicuous heterogeneity of Cl- extrusion across laminae critically shapes plasticity for selective nociceptive modalities.


Assuntos
Sensibilização do Sistema Nervoso Central/fisiologia , Cloretos/metabolismo , Plasticidade Neuronal/fisiologia , Nociceptividade/fisiologia , Células do Corno Posterior/fisiologia , Animais , Células Cultivadas , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/metabolismo , Camundongos , Modelos Neurológicos , Optogenética , Cultura Primária de Células , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Ratos , Receptor trkB/antagonistas & inibidores , Receptor trkB/metabolismo , Simportadores/metabolismo
4.
Life Sci ; 258: 118107, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32682919

RESUMO

Cognitive impairment has been widely recognized as a common symptom of chronic stress. Ginsenoside Rd (GRd), the major active compound in Panax ginseng, was previously reported in various neurological researches. However, little research is available regarding on the effect of GRd on cognitive improvement in mice subjected to chronic stress. In the present study, we investigated the neuroprotective effects of GRd in chronic restraint stress (CRS)-induced cognitive deficits and explored the potential mechanism in male C57BL/6J mice. Our results demonstrated that oral administration of GRd for 28 days markedly increased the spontaneous alternation in Y-maze and the relative discrimination index in novel object or location recognition tests following CRS. Additionally, GRd treatment considerably increased the antioxidant enzymes activities in the hippocampus. The expression levels of hippocampus and serum inflammation factors in the CRS groups were also counter-regulated by GRd treatment. Meanwhile, GRd treatment could reverse CRS-induced the decrease in phosphorylated phosphoinositide 3-kinase (PI3K), camp-reflecting element binding protein (CREB), brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) expression in the hippocampus. These findings provided evidences that GRd improves cognitive impairment in CRS mice by mitigating oxidative stress and inflammation, while upregulating the hippocampal BDNF-mediated CREB signaling pathway.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Ginsenosídeos/uso terapêutico , Restrição Física , Transdução de Sinais , Estresse Psicológico/tratamento farmacológico , Animais , Doença Crônica , Disfunção Cognitiva/sangue , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Ginsenosídeos/química , Ginsenosídeos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Inflamação/sangue , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Receptor trkB/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/sangue , Estresse Psicológico/fisiopatologia
5.
Life Sci ; 256: 117892, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32502538

RESUMO

BACKGROUND: Organophosphorus pesticides exert their toxic effects mainly by the inhibition of acetylcholinesterase (AChE), which is related to emotional disorders, such as depression. Atropine-oximes therapy is commonly used; however, the efficacy of oximes in the reactivation of AChE has been inconsistent. The objective of this study was to investigate the possible neuroprotective effect of (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one (Cℓ-HIN), a compound that combines the isatin and oxime functional groups, in rats exposed to malathion. The effect of Cℓ-HIN on the AChE activity and the BDNF-Trkß pathway in the prefrontal cortex of malathion-exposed rats were tested. METHODS: Wistar male rats were co-treated with Cℓ-HIN [50 mg/kg (p.o.) (3 mL/kg)] and/or malathion [250 mg/kg (i.p.) (5 mL/kg)] and performed behavioral tests twelve hours after these exposures. RESULTS: The Cℓ-HIN reversed the increased immobility time in the forced swimming test and the decreased grooming time in the splash test induced by malathion, but any significant difference was observed in locomotion analysis. These results demonstrate the antidepressant-like effect of Cℓ-HIN. The cortical AChE activity was reactivated by Cℓ-HIN in rats exposed to malathion. Malathion induced an increase in Trkß and a decrease in BDNF levels in the prefrontal cortex of rats, which were avoided by Cℓ-HIN. CONCLUSION: These findings support the hypothesis that Cℓ-HIN is an AChE reactivator with antidepressant-like properties, which is related to the improvement of BDNF-Trkß signaling after acute exposure to malathion in rats. Thus, the results allow suggesting the potential use of Cℓ-HIN as an oxime-based therapy against the neurotoxic effects of malathion.


Assuntos
Acetilcolinesterase/metabolismo , Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Indóis/farmacologia , Malation/toxicidade , Oxindois/farmacologia , Receptor trkB/metabolismo , Transdução de Sinais , Animais , Antidepressivos/administração & dosagem , Antidepressivos/química , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Indóis/administração & dosagem , Indóis/química , Indóis/uso terapêutico , Masculino , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Oxindois/administração & dosagem , Oxindois/química , Oxindois/uso terapêutico , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
6.
Nat Commun ; 11(1): 2977, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532995

RESUMO

Independent scientific achievements have led to the discovery of aberrant splicing patterns in oncogenesis, while more recent advances have uncovered novel gene fusions involving neurotrophic tyrosine receptor kinases (NTRKs) in gliomas. The exploration of NTRK splice variants in normal and neoplastic brain provides an intersection of these two rapidly evolving fields. Tropomyosin receptor kinase B (TrkB), encoded NTRK2, is known for critical roles in neuronal survival, differentiation, molecular properties associated with memory, and exhibits intricate splicing patterns and post-translational modifications. Here, we show a role for a truncated NTRK2 splice variant, TrkB.T1, in human glioma. TrkB.T1 enhances PDGF-driven gliomas in vivo, augments PDGF-induced Akt and STAT3 signaling in vitro, while next generation sequencing broadly implicates TrkB.T1 in the PI3K signaling cascades in a ligand-independent fashion. These TrkB.T1 findings highlight the importance of expanding upon whole gene and gene fusion analyses to include splice variants in basic and translational neuro-oncology research.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Glicoproteínas de Membrana/genética , Oncogenes/genética , Isoformas de RNA/genética , Processamento de RNA , Receptor trkB/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Células Cultivadas , Perfilação da Expressão Gênica , Ontologia Genética , Glioma/metabolismo , Glioma/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Glicoproteínas de Membrana/metabolismo , Camundongos , Células NIH 3T3 , Células-Tronco Neurais/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Isoformas de RNA/metabolismo , Receptor trkB/metabolismo , Transdução de Sinais/genética
7.
Exerc Sport Sci Rev ; 48(3): 125-132, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32412926

RESUMO

Acute intermittent hypoxia (AIH) and task-specific training (TST) synergistically improve motor function after spinal cord injury; however, mechanisms underlying this synergistic relation are unknown. We propose a hypothetical working model of neural network and cellular elements to explain AIH-TST synergy. Our goal is to forecast experiments necessary to advance our understanding and optimize the neurotherapeutic potential of AIH-TST.


Assuntos
Terapia por Exercício/métodos , Neurônios Motores/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/reabilitação , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Humanos , Hipóxia/fisiopatologia , Glicoproteínas de Membrana/metabolismo , Plasticidade Neuronal , Receptor trkB/metabolismo , Medula Espinal/metabolismo
8.
Adv Exp Med Biol ; 1195: 33, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468455

RESUMO

Autophagy is crucial for neuronal integrity. Loss of key autophagic components leads to progressive neurodegeneration and structural defects in neuronal synapses. However, the molecular mechanisms regulating autophagy in the brain remain elusive. Similarly, while it is widely accepted that protein turnover is required for synaptic plasticity, the contribution of autophagy to the degradation of synaptic proteins is unknown. We find that BDNF signaling via the tropomyosin receptor kinase B (TrkB) and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway suppresses autophagy in vivo. Autophagy is differentially regulated by fasting, in different brain regions. Suppression of autophagy is required for BDNF-induced synaptic plasticity and for memory enhancement, under conditions of nutritional stress. BDNF signaling suppresses autophagy in the forebrain of adult mice. Indeed, BDNF ablation in the neural lineage causes uncontrolled increase in autophagy. In turn, increased autophagy mediates the synaptic defects caused by BDNF deficiency. Thus, fasting suppresses autophagy in regions of the mouse forebrain, thereby promoting synaptic remodeling and memory through a BDNF-regulated mechanism. We identify three key remodelers of postsynaptic densities as cargo of autophagy. Our results establish autophagy as a pivotal component of BDNF signaling, which is essential for BDNF-induced synaptic plasticity. This molecular mechanism underlies behavioral adaptations that increase fitness in times of scarcity.


Assuntos
Autofagia/fisiologia , Encéfalo/metabolismo , Animais , Encéfalo/citologia , Plasticidade Neuronal , Fosfatidilinositol 3-Quinases/metabolismo , Receptor trkB/metabolismo , Sinapses
9.
Nat Commun ; 11(1): 1950, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327658

RESUMO

BDNF signaling in hypothalamic circuitries regulates mammalian food intake. However, whether BDNF exerts metabolic effects on peripheral organs is currently unknown. Here, we show that the BDNF receptor TrkB.T1 is expressed by pancreatic ß-cells where it regulates insulin release. Mice lacking TrkB.T1 show impaired glucose tolerance and insulin secretion. ß-cell BDNF-TrkB.T1 signaling triggers calcium release from intracellular stores, increasing glucose-induced insulin secretion. Additionally, BDNF is secreted by skeletal muscle and muscle-specific BDNF knockout phenocopies the ß-cell TrkB.T1 deletion metabolic impairments. The finding that BDNF is also secreted by differentiated human muscle cells and induces insulin secretion in human islets via TrkB.T1 identifies a new regulatory function of BDNF on metabolism that is independent of CNS activity. Our data suggest that muscle-derived BDNF may be a key factor mediating increased glucose metabolism in response to exercise, with implications for the treatment of diabetes and related metabolic diseases.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Cálcio/metabolismo , Células Cultivadas , Glucose/metabolismo , Intolerância à Glucose , Humanos , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Knockout , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptor trkB/química , Receptor trkB/genética , Receptor trkB/metabolismo , Transdução de Sinais
10.
Vascul Pharmacol ; 128-129: 106674, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32179157

RESUMO

Most of what is known on vascular brain-derived neurotrophic factor (BDNF) derived from experiments on cultured endothelial cells. Therefore, the present study compared BDNF levels/localization in artery (aorta) vs vein (vena cava) from a same territory in rats either sedentary (SED) or exposed to treadmill exercise (EX) as a mean to stimulate endogenous endothelial nitric oxide (NO) production. In SED rats, for both artery and vein, BDNF was strongly expressed by endothelial cells, while only a faint and scattered expression was observed throughout the media. Endothelial and muscular BDNF staining as vascular BDNF protein levels were however higher in artery than in vein, while BDNF mRNA levels did not differ between vessels. Irrespective of the vessels, EX resulted in an increase (+50%) in BDNF protein levels with no change in BDNF mRNA levels, a selective endothelial BDNF overexpression (x4) and an increase in vascular levels of tropomyosin related kinase B receptors (TrkB) phosphorylated at tyrosine 816 (p-TrkBTyr816). Endothelial expressions of BDNF and p-TrkBTyr816 were positively associated when SED and EX rats were simultaneously examined. The results incite to consider endothelial BDNF as a full and NO-dependent endothelium-derived factor that exerts autocrine effects.


Assuntos
Aorta Abdominal/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Células Endoteliais/metabolismo , Vasodilatação , Veias Cavas/metabolismo , Animais , Comunicação Autócrina , Fator Neurotrófico Derivado do Encéfalo/genética , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação , Esforço Físico , Ratos Wistar , Receptor trkB/metabolismo , Comportamento Sedentário , Transdução de Sinais
11.
Biomed Res Int ; 2020: 6734048, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32149119

RESUMO

Retinoic acid- (RA-) triggered neuroblastoma cell lines are widely used cell modules of neuronal differentiation in neurodegenerative disease studies, but the gene regulatory mechanism underlying differentiation is unclear now. In this study, system biological analysis was performed on public microarray data from three neuroblastoma cell lines (SK-N-SH, SH-SY5Y-A, and SH-SY5Y-E) to explore the potential molecular processes of all-trans retinoic acid- (ATRA-) triggered differentiation. RT-qPCR, functional genomics analysis, western blotting, chromatin immunoprecipitation (ChIP), and homologous sequence analysis were further performed to validate the gene regulation processes and identify the RA response element in a specific gene. The potential disturbed biological pathways (111 functional GO terms in 14 interactive functional groups) and gene regulatory network (10 regulators and 71 regulated genes) in neuroblastoma differentiation were obtained. 15 of the 71 regulated genes are neuronal projection-related. Among them, NTRK2 is the only one that was dramatically upregulated in the RT-qPCR test that we performed on ATRA-treated SH-SY5Y-A cells. We further found that the overexpression of the NTRK2 gene can trigger differentiation-like changes in SH-SY5Y-A cells. Functional genomic analysis and western blotting assay suggested that, in neuroblastoma cells, ATRA may directly regulate the NTRK2 gene by activating the RA receptor (RAR) that binds in its promoter region. A novel RA response DNA element in the NTRK2 gene was then identified by bioinformatics analysis and chromatin immunoprecipitation (ChIP) assay. The novel element is sequence conservation and position variation among different species. Our study systematically provided the potential regulatory information of ATRA-triggered neuroblastoma differentiation, and in the NTRK2 gene, we identified a novel RA response DNA element, which may contribute to the differentiation in a human-specific manner.


Assuntos
Regulação da Expressão Gênica , Glicoproteínas de Membrana/genética , Neuroblastoma/genética , Neuroblastoma/metabolismo , Receptor trkB/genética , Tretinoína/metabolismo , Sítios de Ligação , Diferenciação Celular , Linhagem Celular Tumoral , Redes Reguladoras de Genes , Humanos , Glicoproteínas de Membrana/metabolismo , Neuritos/metabolismo , Receptor trkB/metabolismo , Receptores do Ácido Retinoico/metabolismo , Transcriptoma
12.
Food Funct ; 11(2): 1729-1739, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32043504

RESUMO

Our previous study showed that EPA-enriched ethanolamine plasmalogen (EPA-pPE) exerted more significant effects than EPA-enriched phosphatidylethanolamine (EPA-PE) in improving learning and memory deficit. However, the results of the mechanism study were not consistent with the improved cognitive function, which suggested that other signaling pathways might be involved. In the present study, primary cultured hippocampal neurons and cognitive deficiency rats were used to compare the effects of EPA-pPE and EPA-PE on brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element-binding protein (CREB) signaling and neuronal apoptosis. The in vitro experiment showed that both EPA-pPE and EPA-PE could relieve cell death and improve the cellular morphology of neurons via upregulating anti-apoptotic proteins and downregulating pro-apoptotic proteins. The in vivo experiment showed that EPA-pPE exerted more significant effects than EPA-PE in improving the number of neuronal Nissl bodies, increasing the branching of dendrites and dendritic spine density in cortical neurons, as well as improving the expression of synaptic vesicle-related proteins synaptophysin (SYN) and PSD95 via BDNF/TrkB/CREB signaling. These results indicated that EPA-pPE exerted neuroprotection at least partly through inhibiting neuronal apoptosis and enhancing the BDNF/TrkB/CREB pathway, which suggests that EPA-enriched plasmalogen can be explored as a potential therapeutic agent in long-term Alzheimer's disease therapy.


Assuntos
Apoptose/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ácido Eicosapentaenoico/farmacologia , Fosfatidiletanolaminas/farmacologia , Plasmalogênios/farmacologia , Animais , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipocampo/citologia , Masculino , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor trkB/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
Biol Sex Differ ; 11(1): 8, 2020 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-32087746

RESUMO

Depression and anxiety are more common among females than males and represent a leading cause of disease-related disability in women. Since the dopamine D1-D2 heteromer is involved in depression- and anxiety-like behavior, the possibility that the receptor complex may have a role in mediating sex differences in such behaviors and related biochemical signaling was explored.In non-human primate caudate nucleus and in rat striatum, females expressed higher density of D1-D2 heteromer complexes and a greater number of D1-D2 expressing neurons compared to males. In rat, the sex difference in D1-D2 expression levels occurred even though D1 receptor expression was lower in female than in male with no difference in D2 receptor expression. In behavioral tests, female rats showed faster latency to depressive-like behavior and a greater susceptibility to the pro-depressive and anxiogenic-like effects of D1-D2 heteromer activation by low doses of SKF 83959, all of which were ameliorated by the selective heteromer disrupting peptide, TAT-D1. The sex difference observed in the anxiety test correlated with differences in low-frequency delta and theta oscillations in the nucleus accumbens. Analysis of signaling pathways revealed that the sex difference in D1-D2 heteromer expression led to differences in basal and heteromer-stimulated activities of two important signaling pathways, BDNF/TrkB and Akt/GSK3/ß-catenin.These results suggest that the higher D1-D2 heteromer expression in female may significantly increase predisposition to depressive-like and anxiety-like behavior in female animals.


Assuntos
Ansiedade/metabolismo , Núcleo Caudado/metabolismo , Depressão/metabolismo , Núcleo Accumbens/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Caracteres Sexuais , Transdução de Sinais , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/administração & dosagem , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/análogos & derivados , Animais , Ansiedade/fisiopatologia , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Núcleo Caudado/efeitos dos fármacos , Chlorocebus aethiops , Depressão/fisiopatologia , Feminino , Quinase 3 da Glicogênio Sintase/metabolismo , Masculino , Núcleo Accumbens/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Receptor trkB/metabolismo , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Transdução de Sinais/efeitos dos fármacos , beta Catenina/metabolismo
14.
Nat Commun ; 11(1): 869, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054836

RESUMO

Spinal disinhibition has been hypothesized to underlie pain hypersensitivity in neuropathic pain. Apparently contradictory mechanisms have been reported, raising questions on the best target to produce analgesia. Here, we show that nerve injury is associated with a reduction in the number of inhibitory synapses in the spinal dorsal horn. Paradoxically, this is accompanied by a BDNF-TrkB-mediated upregulation of synaptic GABAARs and by an α1-to-α2GABAAR subunit switch, providing a mechanistic rationale for the analgesic action of the α2,3GABAAR benzodiazepine-site ligand L838,417 after nerve injury. Yet, we demonstrate that impaired Cl- extrusion underlies the failure of L838,417 to induce analgesia at high doses due to a resulting collapse in Cl- gradient, dramatically limiting the benzodiazepine therapeutic window. In turn, enhancing KCC2 activity not only potentiated L838,417-induced analgesia, it rescued its analgesic potential at high doses, revealing a novel strategy for analgesia in pathological pain, by combined targeting of the appropriate GABAAR-subtypes and restoring Cl- homeostasis.


Assuntos
Analgésicos/farmacologia , Cloretos/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/fisiopatologia , Receptores de GABA-A/fisiologia , Analgesia/métodos , Analgésicos/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Fluorbenzenos/metabolismo , Fluorbenzenos/farmacologia , Agonistas de Receptores de GABA-A/farmacologia , Transporte de Íons/efeitos dos fármacos , Ligantes , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Ratos , Ratos Sprague-Dawley , Receptor trkB/metabolismo , Simportadores/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Triazóis/metabolismo , Triazóis/farmacologia
15.
Int J Mol Sci ; 21(3)2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31979374

RESUMO

The neurotrophic tropomyosin receptor kinase (NTRK) genes (NTRK1, NTRK2, and NTRK3) code for three transmembrane high-affinity tyrosine-kinase receptors for nerve growth factors (TRK-A, TRK-B, and TRK-C) which are mainly involved in nervous system development. Loss of function alterations in these genes can lead to nervous system development problems; conversely, activating alterations harbor oncogenic potential, promoting cell proliferation/survival and tumorigenesis. Chromosomal rearrangements are the most clinically relevant alterations of pathological NTRK activation, leading to constitutionally active chimeric receptors. NTRK fusions have been detected with extremely variable frequencies in many pediatric and adult cancer types, including central nervous system (CNS) tumors. These alterations can be detected by different laboratory assays (e.g., immunohistochemistry, FISH, sequencing), but each of these approaches has specific advantages and limitations which must be taken into account for an appropriate use in diagnostics or research. Moreover, therapeutic targeting of this molecular marker recently showed extreme efficacy. Considering the overall lack of effective treatments for brain neoplasms, it is expected that detection of NTRK fusions will soon become a mainstay in the diagnostic assessment of CNS tumors, and thus in-depth knowledge regarding this topic is warranted.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/metabolismo , Fusão Gênica , Glicoproteínas de Membrana/genética , Inibidores de Proteínas Quinases/uso terapêutico , Receptor trkA/genética , Receptor trkB/genética , Receptor trkC/genética , Animais , Biomarcadores Tumorais/genética , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Humanos , Glicoproteínas de Membrana/metabolismo , Medicina de Precisão , Receptor trkA/metabolismo , Receptor trkB/metabolismo , Receptor trkC/metabolismo , Transdução de Sinais/genética
16.
J Mol Biol ; 432(4): 815-827, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31962123

RESUMO

Optogenetic activation of receptors has advantages compared with chemical or ligand treatment because of its high spatial and temporal precision. Especially in the brain, the use of a genetically encoded light-tunable receptor is superior to direct infusion or systemic drug treatment. We applied light-activatable TrkB receptors in the mouse brain with reduced basal activity by incorporating Cry2PHR mutant, Opto-cytTrkB(E281A). Upon AAV mediated gene delivery, this form was expressed at sufficient levels in the mouse hippocampus (HPC) and medial entorhinal cortex (MEC) retaining normal canonical signal transduction by the blue light stimulus, even by delivery of noninvasive LED light on the mouse head. Within target cells, where its expression was driven by a cell type-specific promoter, Opto-cytTrkB(E281A)-mediated TrkB signaling could be controlled by adjusting light-stimulating conditions. We further demonstrated that Opto-cytTrkB(E281A) could locally induce TrkB signaling in axon terminals in the MEC-HPC. In summary, Opto-cytTrkB(E281A) will be useful for elucidating time- and region-specific roles of TrkB signaling ranging from cellular function to neural circuit mechanisms.


Assuntos
Hipocampo/metabolismo , Receptor trkB/metabolismo , Animais , Axônios/metabolismo , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Córtex Entorrinal/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Optogenética , Regiões Promotoras Genéticas/genética , Regiões Promotoras Genéticas/fisiologia , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Receptor trkB/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
17.
Int J Mol Sci ; 21(3)2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31991770

RESUMO

Dietary fats and sugars were identified as risk factors for overweight and neurodegeneration, especially in middle-age, an earlier stage of the aging process. Therefore, our aim was to study the metabolic response of both white adipose tissue and brain in middle aged rats fed a typical Western diet (high in saturated fats and fructose, HFF) and verify whether a similarity exists between the two tissues. Specific cyto/adipokines (tumor necrosis factor alpha (TNF-α), adiponectin), critical obesity-inflammatory markers (haptoglobin, lipocalin), and insulin signaling or survival protein network (insulin receptor substrate 1 (IRS), Akt, Erk) were quantified in epididymal white adipose tissue (e-WAT), hippocampus, and frontal cortex. We found a significant increase of TNF-α in both e-WAT and hippocampus of HFF rats, while the expression of haptoglobin and lipocalin was differently affected in the various tissues. Interestingly, adiponectin amount was found significantly reduced in e-WAT, hippocampus, and frontal cortex of HFF rats. Insulin signaling was impaired by HFF diet in e-WAT but not in brain. The above changes were associated with the decrease in brain derived neurotrophic factor (BDNF) and synaptotagmin I and the increase in post-synaptic protein PSD-95 in HFF rats. Overall, our investigation supports for the first time similarities in the response of adipose tissue and brain to Western diet.


Assuntos
Tecido Adiposo/metabolismo , Encéfalo/metabolismo , Dieta Ocidental , Metabolismo Energético , Adipócitos/metabolismo , Animais , Biomarcadores , Citocinas/sangue , Citocinas/metabolismo , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Insulina/metabolismo , Masculino , Modelos Biológicos , Especificidade de Órgãos , Ratos , Receptor trkB/metabolismo , Transdução de Sinais
18.
Exp Neurol ; 327: 113215, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31991126

RESUMO

Neurogenic differentiation 1 (NeuroD1) is mainlyexpressed in developing neurons where it plays critical roles in neuronal maturation and neurite elongation. The potential role and mechanism of NeuroD1 in adult axonal regeneration is not clear. The present study used synapsin (SYN) Cre and AAV9-Flex vectors to conditionally overexpress NeuroD1 in adult spinal neurons and found that NeuroD1 overexpression significantly accelerated axonal regeneration and functional recovery after sciatic nerve injury. Further in vitro and in vivo experiments suggested that the mechanism of NeuroD1 promotion on axonal regeneration was related to its regulation of the expression of neurotrophin BDNF and its receptor TrkB as well as a microtubule severing protein spastin.


Assuntos
Axônios/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Regeneração Nervosa/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Nervo Isquiático/lesões , Nervos Espinhais/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Feminino , Camundongos , Atividade Motora/fisiologia , Proteínas do Tecido Nervoso/genética , Traumatismos dos Nervos Periféricos/fisiopatologia , Receptor trkB/metabolismo , Recuperação de Função Fisiológica/fisiologia
19.
Proc Natl Acad Sci U S A ; 117(4): 2170-2179, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31932427

RESUMO

Tuberous Sclerosis Complex (TSC) is a rare genetic disease that manifests with early symptoms, including cortical malformations, childhood epilepsy, and TSC-associated neuropsychiatric disorders (TANDs). Cortical malformations arise during embryonic development and have been linked to childhood epilepsy before, but the underlying mechanisms of this relationship remain insufficiently understood. Zebrafish have emerged as a convenient model to study elementary neurodevelopment; however, without in-depth functional analysis, the Tsc2-deficient zebrafish line cannot be used for studies of TANDs or new drug screening. In this study, we found that the lack of Tsc2 in zebrafish resulted in heterotopias and hyperactivation of the mTorC1 pathway in pallial regions, which are homologous to the mammalian cortex. We observed commissural thinning that was responsible for brain dysconnectivity, recapitulating TSC pathology in human patients. The lack of Tsc2 also delayed axonal development and caused aberrant tract fasciculation, corresponding to the abnormal expression of genes involved in axon navigation. The mutants underwent epileptogenesis that resulted in nonmotor seizures and exhibited increased anxiety-like behavior. We further mapped discrete parameters of locomotor activity to epilepsy-like and anxiety-like behaviors, which were rescued by reducing tyrosine receptor kinase B (TrkB) signaling. Moreover, in contrast to treatment with vigabatrin and rapamycin, TrkB inhibition rescued brain dysconnectivity and anxiety-like behavior. These data reveal that commissural thinning results in the aberrant regulation of anxiety, providing a mechanistic link between brain anatomy and human TANDs. Our findings also implicate TrkB signaling in the complex pathology of TSC and reveal a therapeutic target.


Assuntos
Ansiedade/metabolismo , Epilepsia/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Receptor trkB/metabolismo , Esclerose Tuberosa/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Ansiedade/genética , Ansiedade/psicologia , Modelos Animais de Doenças , Epilepsia/genética , Epilepsia/psicologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Receptor trkB/genética , Convulsões/genética , Convulsões/metabolismo , Convulsões/psicologia , Esclerose Tuberosa/genética , Esclerose Tuberosa/psicologia , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
20.
Am J Surg Pathol ; 44(2): 162-173, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31567189

RESUMO

This study was undertaken to determine the frequency, and the clinicopathologic and genetic features, of colon cancers driven by neurotrophic receptor tyrosine kinase (NTRK) gene fusions. Of the 7008 tumors screened for NTRK expression using a pan-Trk antibody, 16 (0.23%) had Trk immunoreactivity. ArcherDx assay detected TPM3-NTRK1 (n=9), LMNA-NTRK1 (n=3), TPR-NTRK1 (n=2) and EML4-NTRK3 (n=1) fusion transcripts in 15 cases with sufficient RNA quality. Patients were predominantly women (median age: 63 y). The tumors involved the right (n=12) and left colon unequally and were either stage T3 (n=12) or T4. Local lymph node and distant metastases were seen at presentation in 6 and 1 patients, respectively. Lymphovascular invasion was present in all cases. Histologically, tumors showed moderate to poor (n=11) differentiation with a partly or entirely solid pattern (n=5) and mucinous component (n=10), including 1 case with sheets of signet ring cells. DNA mismatch repair-deficient phenotype was seen in 13 cases. Tumor-infiltrating CD4/CD8 lymphocytes were prominent in 9 cases. Programmed death-ligand 1 positive tumor-infiltrating immune cells and focal tumor cell positivity were seen in the majority of cases. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 cases. No mutations in BRAF, RAS, and PIK3CA were identified. However, other genes of the PI3K-AKT/MTOR pathway were mutated. In several cases, components of Wnt/ß-catenin (APC, AMER1, CTNNB1), p53, and TGFß (ACVR2A, TGFBR2) pathways were mutated. However, no SMAD4 mutations were found. Two tumors harbored FBXW7 tumor suppressor gene mutations. NTRK fusion tumors constitute a distinct but rare subgroup of colorectal carcinomas.


Assuntos
Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/genética , Proteínas de Fusão Oncogênica/genética , Receptores Proteína Tirosina Quinases/genética , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/patologia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fusão Oncogênica , Proteínas de Fusão Oncogênica/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptor trkA/genética , Receptor trkA/metabolismo , Receptor trkB/genética , Receptor trkB/metabolismo , Receptor trkC/genética , Receptor trkC/metabolismo
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