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1.
Toxicol Lett ; 320: 95-102, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760062

RESUMO

Exposure to organic solvent in industry, including n-hexane is correlated with central-peripheral axonopathy, which is mediated by its active metabolite, 2,5-hexanedione (HD). However, the underlying mechanism is still largely unknown. Recently identified microRNAs (miRNAs) may play important roles in toxicant exposure and in the process of toxicant-induced neuropathys. To examine the role of miRNAs in HD-induced toxicity, neuropathic animal model was successfully built. miRNA microarray analysis revealed 105 differentially expressed miRNAs after HD exposure. Bioinformatics analysis showed that "Axon" and "Neurotrophin Signaling Pathway" was the top significant GO term and pathway, respectively. 7 miRNAs both related to "Axon" and "Neurotrophin Signaling Pathway" were screened out and further confirmed by Real-Time PCR. Correspondingly, the deregulation expression levels of proteins of four target genes (GSK3ß, Map3k1, BDNF and MAP1B) were further confirmed via western blot, verifying the results of gene target analysis. Taken together, our results showed that the axon-related miRNAs to be associated with MAP1B or neurotrophin signal pathways changed in nerve tissues following HD exposure. These miRNAs may play important roles in HD-induced neurotoxicity.


Assuntos
Axônios/efeitos dos fármacos , Hexanonas/toxicidade , MicroRNAs/metabolismo , Síndromes Neurotóxicas/etiologia , Nervo Isquiático/efeitos dos fármacos , Solventes/toxicidade , Medula Espinal/efeitos dos fármacos , Animais , Axônios/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Bases de Dados Genéticas , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , MAP Quinase Quinase Quinase 1/genética , MAP Quinase Quinase Quinase 1/metabolismo , Masculino , MicroRNAs/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Ratos Sprague-Dawley , Nervo Isquiático/metabolismo , Transdução de Sinais , Medula Espinal/metabolismo , Transcriptoma
2.
Artigo em Russo | MEDLINE | ID: mdl-31851173

RESUMO

AIM: To study an effect of cabergoline on dopamine and noradrenaline concentration and BDNF mRNA level in the rat midbrain and hypothalamus. MATERIAL AND METHODS: Twenty adult male Wistar rats were used in a single treatment paradigm: animals of the treatment group (n=10) received cabergoline (i.p., 0.5 mg/kg) and the control group (n=10) received an equivalent volume of the solvent. Quantitative analysis for the dopamine (DA) and noradrenaline (NA) was carried out using high-performance liquid chromatography (HPLC) coupled with electrochemical detection. BDNF mRNA levels were studied using quantitative RT-PCR. RESULTS AND CONCLUSION: Cabergoline significantly increases NA concentration in the midbrain 24 hours after injection: 639.2±64.5 ng/g in the treatment group versus 398.0±66.0 ng/g in the control group (p<0.05), while mean content of DA is not significantly changed (211.4±16.3 ng/g vs 169.7±54.6 ng/g, respectively). Cabergoline does not affect hypothalamic DA and NA levels. The drug increases BDNF mRNA levels by 2-times in the midbrain, but not in the hypothalamus, 24 hours after injection.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Cabergolina , Catecolaminas , Receptores de Dopamina D2 , Animais , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cabergolina/farmacologia , Catecolaminas/metabolismo , Ergolinas , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , RNA Mensageiro , Ratos , Ratos Wistar , Receptores de Dopamina D2/agonistas
3.
Adv Exp Med Biol ; 1185: 451-455, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884653

RESUMO

Physical exercise is protective in rodent models of retinal injury and disease. Data suggest that this is in part mediated by brain-derived neurotrophic factor (BDNF) signal transduction. It has been hypothesized that exercised-induced neuroprotection may be mediated by increases in circulating lactate that in turn alter BDNF secretion. We therefore tested whether mice undergoing a treadmill running regimen previously shown to be protective in a mouse model of retinal degeneration (RD) have increased serum levels of lactate. Lactate levels in exercised and non-exercised mice were statistically indistinguishable. A role for circulating lactate in exercise-induced retinal protection is unsupported.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ácido Láctico/sangue , Neuroproteção , Condicionamento Físico Animal , Degeneração Retiniana/prevenção & controle , Animais , Camundongos , Retina , Transdução de Sinais
4.
Biochemistry (Mosc) ; 84(11): 1306-1328, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31760920

RESUMO

Focal brain injuries (in particular, stroke and traumatic brain injury) induce with high probability the development of delayed (months, years) cognitive and depressive disturbances which are frequently comorbid. The association of these complications with hippocampal alterations (in spite of the lack of a primary injury of this structure), as well as the lack of a clear dependence between the probability of depression and dementia development and primary damage severity and localization served as the basis for a new hypothesis on the distant hippocampal damage as a key link in the pathogenesis of cognitive and psychiatric disturbances. According to this hypothesis, the excess of corticosteroids secreted after a focal brain damage, in particular in patients with abnormal stress-response due to hypothalamic-pituitary-adrenal axis (HPAA) dysfunction, interacts with corticosteroid receptors in the hippocampus inducing signaling pathways which stimulate neuroinflammation and subsequent events including disturbances in neurogenesis and hippocampal neurodegeneration. In this article, the molecular and cellular mechanisms associated with the regulatory role of the HPAA and multiple functions of brain corticosteroid receptors in the hippocampus are analyzed. Functional and structural damage to the hippocampus, a brain region selectively vulnerable to external factors and responding to them by increased cytokine secretion, forms the basis for cognitive function disturbances and psychopathology development. This concept is confirmed by our own experimental data, results of other groups and by prospective clinical studies of post-stroke complications. Clinically relevant biochemical approaches to predict the risks and probability of post-stroke/post-trauma cognitive and depressive disturbances are suggested using the evaluation of biochemical markers of patients' individual stress-response. Pathogenetically justified ways for preventing these consequences of focal brain damage are proposed by targeting key molecular mechanisms underlying hippocampal dysfunction.


Assuntos
Lesões Encefálicas/patologia , Hipocampo/metabolismo , Animais , Lesões Encefálicas/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citocinas/metabolismo , Humanos , Estresse Oxidativo , Sistema Hipófise-Suprarrenal , Receptores de Esteroides/metabolismo
5.
Comput Biol Chem ; 83: 107153, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31751881

RESUMO

Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor with various roles in the central nervous system neurogenesis, neuroprotection, and axonal guide. By attaching to Tropomyosin receptor kinase B (TrkB) receptor, this protein triggers downstream signaling pathways which lead to cellular growth, proliferation, survival, and neuroplasticity. Deregulation at mRNA level is involved in various central nervous system disorders including, Huntington, Alzheimer's, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis diseases. Considering the importance of BDNF functions, deciphering the regulatory mechanisms controlling BDNF expression level could pave the way to develop more accurate and efficient treatments for neurological diseases. Among different regulatory systems, microRNAs (miRNAs) play prominent roles by targeting genes 3' untranslated regions. In this study, 127 validated and bioinformatic-predicted miRNAs with potentially regulatory roles in BDNF expression were analyzed. Various aspects of miRNAsö possible functions were assessed by bioinformatic online tools to find their potential regulatory functions in signaling pathways, neurological disorders, expression of transcription factors and miRNAs sponge. Analyzed data led to introduce 5 newly reported miRNAs that could regulate BDNF expression level. Finally, high throughput sequencing data from different brain regions and neurological disorders were analyzed to measure correlation of candidate miRNAs with BDNF level in experimental studies. In this study, a list of novel miRNAs with possible regulatory roles in BDNF expression level involving in different neurological disorders was introduced.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Simulação por Computador , MicroRNAs/metabolismo , Doenças Neurodegenerativas/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Perfilação da Expressão Gênica , Humanos , MicroRNAs/genética
6.
Anticancer Res ; 39(11): 5933-5942, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704818

RESUMO

BACKGROUND/AIM: Perineural invasion (PNI) is a significant pathological feature in head and neck cancer. The molecular mechanisms of PNI are poorly understood. Contrary to the previous belief that cancer cells invade nerves, recent studies have shown that Schwann cells (SC) can dedifferentiate, intercalate between cancer cells, and promote cancer dispersion. Communication between cells through brain-derived neurotrophic factor (BDNF) activation of its receptor tropomyosin receptor kinase B (TRKB) may contribute to these cellular events. We aimed to determine the effect of TRKB inhibitor ANA-12 on the direction of cell migration and degree of SC-induced oral cancer cell dispersion. MATERIALS AND METHODS: Cell migration and dispersion assays were performed in vitro using murine SC and oral carcinoma cell lines. Assays were performed with and without ANA-12. RESULTS: Although SCs preferentially migrated towards cancer cells in control medium, there was minimal SC-associated cancer cell dispersion. In contrast, treatment with ANA-12 reduced migration of SCs and cancer cells towards each other and initiated more SC-associated cancer cell dispersion. CONCLUSION: This pilot study shows that BDNF-TRKB signaling may have a role in regulating interactions between SC and oral cancer cells that affect cell migration, intercalation, and cancer cell dispersion. Further research into these interactions may provide important clues about the molecular and cellular mechanisms of PNI.


Assuntos
Azepinas/farmacologia , Benzamidas/farmacologia , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Carcinoma de Células Escamosas/patologia , Glicoproteínas de Membrana/antagonistas & inibidores , Neoplasias Bucais/patologia , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Receptor trkB/antagonistas & inibidores , Células de Schwann/patologia , Animais , Apoptose , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Movimento Celular , Proliferação de Células , Técnicas de Cocultura , Humanos , Técnicas In Vitro , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Projetos Piloto , Receptor trkB/metabolismo , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Células Tumorais Cultivadas
7.
Nat Commun ; 10(1): 4799, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641124

RESUMO

Metabolic diseases harm brain health and cognitive functions, but whether maternal metabolic unbalance may affect brain plasticity of next generations is still unclear. Here, we demonstrate that maternal high fat diet (HFD)-dependent insulin resistance multigenerationally impairs synaptic plasticity, learning and memory. HFD downregulates BDNF and insulin signaling in maternal tissues and epigenetically inhibits BDNF expression in both germline and hippocampus of progeny. Notably, exposure of the HFD offspring to novel enriched environment restores Bdnf epigenetic activation in the male germline and counteracts the transmission of cognitive impairment to the next generations. BDNF administration to HFD-fed mothers or preserved insulin sensitivity in HFD-fed p66Shc KO mice also prevents the intergenerational transmission of brain damage to the progeny. Collectively, our data suggest that maternal diet multigenerationally impacts on descendants' brain health via gametic mechanisms susceptible to lifestyle.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Aprendizagem/fisiologia , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Epigênese Genética , Feminino , Proteína Forkhead Box O3/metabolismo , Regulação da Expressão Gênica , Hipocampo/fisiopatologia , Histona Desacetilase 2/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovário/metabolismo , Sirtuína 2/metabolismo , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/genética
8.
Planta Med ; 85(17): 1363-1373, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31618776

RESUMO

Lespedeza bicolor, a traditional herbal medicine widely used in Australia, North America, and Eastern Asia, has various therapeutic effects on inflammation, nephritis, hyperpigmentation, and diuresis. In this study, to evaluate the effects of L. bicolor on cognitive function, we examined whether L. bicolor improved amyloid beta-induced memory impairment and assessed the possible mechanisms in mice. Catechin, rutin, daidzein, luteolin, naringenin, and genistein were identified in the powdered extract of L. bicolor by HPCL-DAD analyses. In behavioral experiments, L. bicolor (25 and 50 mg/kg, p. o.) significantly improved amyloid beta25 - 35 (6 nmol, intracerebroventricular)-induced cognitive dysfunction in the Y-maze, novel recognition, and passive avoidance tests. Our molecular studies showed L. bicolor (25 and 50 mg/kg, p. o.) significantly recovered the reduced glutathione content as well as increased thiobarbituric acid reactive substance and acetylcholinesterase activities in the hippocampus. Furthermore, we found that L. bicolor significantly increased the expression of brain-derived neurotrophic factor, and phospho-Akt, extracellular signal-regulated kinase, and cAMP response element binding caused by amyloid beta25 - 35 in the hippocampus. In conclusion, L. bicolor exerts a potent memory-enhancing effect on cognitive dysfunction induced by amyloid beta25 - 35 in mice.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Lespedeza/química , Transtornos da Memória/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Peptídeos beta-Amiloides , Animais , Cognição/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Transtornos da Memória/induzido quimicamente , Camundongos , Fragmentos de Peptídeos , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima
9.
Neurochem Res ; 44(11): 2590-2605, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31560103

RESUMO

Increased number of newly-born neurons produced at latent stage after status epilepticus (SE) contribute to aberrant rewiring of hippocampus and are hypothesized to promote epileptogenesis. Although physical training (PT) was reported to cause further increase in neurogenesis after SE, how PT affect their integration pattern is still elusive, whether they integrate into normal circuits or increase aberrant integrations is yet to be determined. To understand this basic mechanism by which PT effects SE and to elaborate the possible role of neuronal integrations in prognosis of SE, we evaluated the effect of 4 weeks of treadmill PT in adult male mice after pilocarpine-induced SE on behavioral and aberrant integrations' parameters. Changes in BDNF gene methylation and its protein level in hippocampus was also measured at latent stage (2-weeks) to explore underlying pathways involved in increasing neurogenesis. Our results demonstrated that although PT increased proliferation and maturation of neurons in dentate gyrus, they showed reduced aberrant integrations into hippocampal circuitry assessed through a decrease in the number of ectopic granular cells, hilar basal dendrites and mossy fiber sprouting as compared to non-exercised SE mice. While SE decreased the percentage methylation of specific CpGs of BDNF gene's promoter, PT did not yield any significant difference in methylation of BDNF CpGs as compared to non-exercised SE mice. In conclusion, PT increases hippocampal neurogenesis through increasing BDNF levels by some pathways other than demethylating BDNF CpGs and causes post SE newly-born neurons to integrate into normal circuits thus resulting in decreased spontaneous recurrent seizures and enhanced spatial memory.


Assuntos
Giro Denteado/metabolismo , Hipocampo/metabolismo , Neurogênese/fisiologia , Condicionamento Físico Animal , Estado Epiléptico/terapia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proliferação de Células/fisiologia , Ilhas de CpG , DNA/metabolismo , Metilação de DNA , Giro Denteado/patologia , Hipocampo/patologia , Masculino , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Pilocarpina , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo , Regulação para Cima
10.
J Microbiol Biotechnol ; 29(9): 1369-1374, 2019 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-31564078

RESUMO

We isolated Lactobacillus mucosae NK41 and Bifidobacterium longum NK46 from human feces, which induced BDNF expression in corticosterone-stimulated SH-SY5Y cells, and examined their anti-depressive effects in mice. NK41, NK46, and their (1:1) mixture significantly mitigated immobilization stress (IS)-induced anxiety-like/depressive behaviors, hippocampal NF-κB activation, BDNF expression, Iba1+ cell population, and blood corticosterone, TNF-α, IL- 6, and lipopolysaccharide levels. Furthermore, they inhibited colitis marker NF-κB activation, and TNF-α expression in mice with IS-induced anxiety/depression. They additionally suppressed gut Proteobacteria and Bacteroidetes populations and bacterial lipopolysaccharide production. These findings suggest that NK41 and NK46 may alleviate anxiety/depression and colitis by suppressing gut dysbiosis.


Assuntos
Ansiedade/dietoterapia , Bifidobacterium longum , Depressão/dietoterapia , Microbioma Gastrointestinal/efeitos dos fármacos , Lactobacillus , Probióticos/farmacologia , Probióticos/uso terapêutico , Animais , Antidepressivos/administração & dosagem , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Ansiedade/sangue , Ansiedade/microbiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Colite/microbiologia , Colite/patologia , Corticosterona/sangue , Depressão/sangue , Depressão/microbiologia , Modelos Animais de Doenças , Disbiose/microbiologia , Disbiose/patologia , Fezes/microbiologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Interleucina-6/sangue , Lipopolissacarídeos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , NF-kappa B/metabolismo , Probióticos/administração & dosagem , Estresse Psicológico/sangue , Estresse Psicológico/microbiologia , Estresse Psicológico/psicologia , Fator de Necrose Tumoral alfa/sangue
11.
Oral Dis ; 25(8): 1925-1936, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31498938

RESUMO

OBJECTIVES: To evaluate the expression of brain-derived neurotrophic factor (BDNF), its tyrosine kinase receptor B (TrkB), and two downstream targets of this pathway, Akt and ribosomal protein S6 (RPS6), in normal oral mucosa (NOM), oral leukoplakia (OL), and oral squamous cell carcinoma (OSCC) and correlate this expression with OSCC patients' outcomes, cell senescence, and "stemness" profile. MATERIALS AND METHODS: Ten cases of NOM, 32 OL, and 72 primary OSCC were included. Immunohistochemical analysis for BDNF, TrkB, p-TrkB, p-Akt, and p-RPS6 was performed. Cell senescence and stemness profile of OSCC were evaluated through p16 and BMI-1 immunohistochemical expression, respectively. The slides were scanned into high-resolution images and quantified through digital analysis. RESULTS: Oral squamous cell carcinoma presented increased expression of BDNF/TrkB/Akt pathway compared to NOM and OL. OSCC diagnosed in advanced clinical stages presented an upregulation of BDNF and p-TrkB. BDNF and p-Akt were identified as predictors of poor disease-specific survival. The increase in stemness profile was correlated with a decrease in p-TrkB and p-Akt expression. CONCLUSIONS: BDNF/TrkB/Akt pathway is significantly increased in malignant cells from OSCC. Moreover, BDNF and Akt represent biomarkers capable to predict a poor prognosis of OSCC patients.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/patologia , Receptor trkB/metabolismo , Carcinoma de Células Escamosas/metabolismo , Humanos , Neoplasias Bucais/mortalidade , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas c-akt , Receptor trkB/genética
12.
Psychiatr Danub ; 31(Suppl 3): 549-553, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31488789

RESUMO

Depression affects over 121 million people annually worldwide. Relatively low remission rates among depressive patients enforce the search for new therapeutic solutions and an urgent need to develop faster-acting antidepressants with a different mechanism of action occurs. The pathomechanism of depression postulated by the monoamine hypothesis is limited. The results of abnormalities in glutamate and γ-aminobutyric acid (GABA) systems in the brains of people with mood disorders allowed to develop new theories regarding pathophysiology of these disorders. Glutamatergic transmission is influenced by magnesium and ketamine through glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonistic effects. Magnesium and ketamine have a common mechanism of action in the treatment of depression: an increase in GluN2B (NMDAR subunit) expression is related to the administration of both of the agents, as well as inhibition of phosphorylation of eEF2 (eukaryotic elongation factor 2) in cell culture and increase of the expression of BDNF in the hippocampus. Combination of ketamine and magnesium in a normal magnesium level presents a superadditive effect in depression treatment. Analysed substances affect the GABAergic system and have anti-inflammatory effects, which is correlated with their antidepressant effect. The synergistic interaction between the pharmacodynamic activity of magnesium and ketamine may be of particular importance for patients with mood disorders. Further research is needed to determine the relationship between magnesium levels and ketamine treatment response mainly in the attempt to establish if the magnesium supplementation can change ketamine treatment response time or present superadditive effect.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Ketamina/uso terapêutico , Magnésio/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Humanos , Fator 2 de Elongação de Peptídeos/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
13.
Int J Mol Sci ; 20(17)2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484392

RESUMO

Brain-derived neurotrophic factor (BDNF) has previously been shown to play an important role in glutamatergic synaptic plasticity in the amygdala, correlating with cued fear learning. While glutamatergic neurotransmission is facilitated by BDNF signaling in the amygdala, its mechanism of action at inhibitory synapses in this nucleus is far less understood. We therefore analyzed the impact of chronic BDNF depletion on GABAA-mediated synaptic transmission in BDNF heterozygous knockout mice (BDNF+/-). Analysis of miniature and evoked inhibitory postsynaptic currents (IPSCs) in the lateral amygdala (LA) revealed neither pre- nor postsynaptic differences in BDNF+/- mice compared to wild-type littermates. In addition, long-term potentiation (LTP) of IPSCs was similar in both genotypes. In contrast, facilitation of spontaneous IPSCs (sIPSCs) by norepinephrine (NE) was significantly reduced in BDNF+/- mice. These results argue against a generally impaired efficacy and plasticity at GABAergic synapses due to a chronic BDNF deficit. Importantly, the increase in GABAergic tone mediated by NE is reduced in BDNF+/- mice. As release of NE is elevated during aversive behavioral states in the amygdala, effects of a chronic BDNF deficit on GABAergic inhibition may become evident in response to states of high arousal, leading to amygdala hyper-excitability and impaired amygdala function.


Assuntos
Tonsila do Cerebelo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Potenciação de Longa Duração/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Feminino , Potenciação de Longa Duração/genética , Camundongos , Camundongos Knockout , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Técnicas de Patch-Clamp , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo
14.
EBioMedicine ; 46: 431-443, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31401195

RESUMO

BACKGROUND: Pain due to pancreatic cancer/PCa or chronic pancreatitis/CP, is notoriously resistant to the strongest pain medications. Here, we aimed at deciphering the specific molecular mediators of pain at surgical-stage pancreatic disease and to discover novel translational targets. METHODS: We performed a systematic, quantitative analysis of the neurotransmitter/neuroenzmye profile within intrapancreatic nerves of CP and PCa patients. Ex vivo neuronal cultures treated with human pancreatic extracts, conditional genetically engineered knockout mouse models of PCa and CP, and the cerulein-induced CP model were employed to explore the therapeutic potential of the identified targets. FINDINGS: We identified a unique enrichment of neuronal nitric-oxide-synthase (nNOS) in the pancreatic nerves of CP patients with increasing pain severity. Employment of ex vivo neuronal cultures treated with pancreatic tissue extracts of CP patients, and brain-derived-neurotrophic-factor-deficient (BDNF+/-) mice revealed neuronal enrichment of nNOS to be a consequence of BDNF loss in the progressively destroyed pancreatic tissue. Mechanistically, nNOS upregulation in sensory neurons was induced by tryptase secreted from perineural mast cells. In a head-to-head comparison of several genetically induced, painless mouse models of PCa (KPC, KC mice) or CP (Ptf1a-Cre;Atg5fl/fl) against the hypersecretion/cerulein-induced, painful CP mouse model, we show that a similar nNOS enrichment is present in the painful cerulein-CP model, but absent in painless genetic models. Consequently, mice afflicted with painful cerulein-induced CP could be significantly relieved upon treatment with the specific nNOS inhibitor NPLA. INTERPRETATION: We propose nNOS inhibition as a novel strategy to treat the unbearable pain in CP. FUND: Deutsche Forschungsgemeinschaft/DFG (DE2428/3-1 and 3-2).


Assuntos
Neuralgia/diagnóstico , Neuralgia/etiologia , Óxido Nítrico Sintase Tipo I/metabolismo , Pancreatite Crônica/complicações , Pancreatite Crônica/metabolismo , Adulto , Animais , Biomarcadores , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Neuralgia/tratamento farmacológico , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/cirurgia , Pancreatite Crônica/cirurgia
15.
J Stroke Cerebrovasc Dis ; 28(11): 104288, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31395423

RESUMO

PURPOSE: The present study was to observe the therapeutic efficiency of Clematichinenoside (AR) on cerebral ischemic injury in rats, especially on neurological and motor function recovery and to explore the underlying mechanism. METHODS: Following middle cerebral artery occlusion/reperfusion (MCAO/R) surgery, rats were treated orally with 32, 16, and 8 mg/kg AR respectively for 14 days during which cerebral injury was evaluated and proinflammatory factors tumor necrosis factor-α and interleukin-6 as well as neurotrophic factors brain-derived neurotrophic factor and Neurotrophin-3 levels were determined with ELISA kits. Immunohistochemical analysis on number of neurons and reactive astrocytes in the hippocampus was to demonstrate the effect of AR on neuronal survival. Motor, learning, and memory recovery were assessed by Morris water maze, passive avoidance experiment, and rotatory rod test. Neuroprotection and anti-inflammation-related Notch and nuclear factor-κB (NF-κB) signaling pathways were analyzed by PCR and Western blot techniques on mammalian achaete-scute homologs1, Notch-1, intracellular Notch receptor domain, Jagged-1, transcription factor hairy, enhancer of split1 (Hes1), as well as the nuclear import of NF-κB in hippocampus. RESULTS: AR administration reduced cerebral injury in rats exposed to MCAO/R and after treatment of AR for 14 days, proinflammatory reaction was inhibited, with neuronal survival rate raised and motor function recovery facilitated. PCR and WB analysis of Notch/NF-κB signaling pathway revealed the inhibitory effect of AR on pathway related components. CONCLUSIONS: AR is beneficial to recovery of neurological and motor function in rats after cerebral ischemic injury via inhibiting Notch/NF-κB pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Comportamento Animal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Receptor Notch1/metabolismo , Saponinas/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/psicologia , Masculino , Memória/efeitos dos fármacos , Neurotrofina 3/metabolismo , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Transdução de Sinais
16.
Elife ; 82019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429825

RESUMO

Brain-derived neurotrophic factor (BDNF) is a potent modulator of brain synaptic plasticity. Signaling defects caused by dysregulation of its Ntrk2 (TrkB) kinase (TrkB.FL) and truncated receptors (TrkB.T1) have been linked to the pathophysiology of several neurological and neurodegenerative disorders. We found that upregulation of Rbfox1, an RNA binding protein associated with intellectual disability, epilepsy and autism, increases selectively hippocampal TrkB.T1 isoform expression. Physiologically, increased Rbfox1 impairs BDNF-dependent LTP which can be rescued by genetically restoring TrkB.T1 levels. RNA-seq analysis of hippocampi with upregulation of Rbfox1 in conjunction with the specific increase of TrkB.T1 isoform expression also shows that the genes affected by Rbfox1 gain of function are surprisingly different from those influenced by Rbfox1 deletion. These findings not only identify TrkB as a major target of Rbfox1 pathophysiology but also suggest that gain or loss of function of Rbfox1 regulate different genetic landscapes.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/fisiologia , Potenciação de Longa Duração , Glicoproteínas de Membrana/biossíntese , Proteínas Tirosina Quinases/biossíntese , Fatores de Processamento de RNA/biossíntese , Regulação para Cima , Animais , Perfilação da Expressão Gênica , Camundongos , Isoformas de Proteínas/biossíntese , Análise de Sequência de RNA
17.
Sheng Li Xue Bao ; 71(4): 537-546, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31440750

RESUMO

Intermittent hypoxia (IH) has preventive and therapeutic effects on hypertension, myocardial infarction, cerebral ischemia and depression, but its effect on post-traumatic stress disorder (PTSD) has not been known. In this study, we used inescapable electric foot shock combined with context recapture to build PTSD mouse model. The levels of fear and anxiety were valued by the open field, the elevated plus maze (EPM) and the fear conditioning tests; the level of spatial memory was valued by Y maze test; the number of Fos positive neurons in hippocampus, amygdala and medial prefrontal cortex was valued by immunohistochemical staining; and the protein expressions of hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and brain derived neurotrophic factor (BDNF) in these brain area were valued by Western blot. The results showed that IH and model (foot shock) had an interaction on percentage of entering open arms (OE%) in EPM and freezing time and the number of fecal pellets in fear conditioning test. IH increased OE% in EPM and reduced the freezing time and the number of fecal pellets in fear conditioning test in PTSD model mice. At the same time, IH reduced the number of Fos positive neurons in the hippocampus, amygdala and medial prefrontal cortex of PTSD model mice, and increased the protein expression levels of HIF-1α, VEGF and BDNF in these brain tissues. In conclusion, IH pretreatment can relieve fear and anxiety behavior in post-traumatic stress model mice, suggesting that IH may be an effective means of preventing PTSD.


Assuntos
Ansiedade/terapia , Medo , Hipóxia , Transtornos de Estresse Pós-Traumáticos/terapia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
Biomed Environ Sci ; 32(7): 496-507, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31331434

RESUMO

OBJECTIVE: To explore the dynamic impacts of simulated microgravity (SM) on different vital brain regions of rats. METHODS: Microgravity was simulated for 7 and 21 days, respectively, using the tail-suspension rat model. Histomorphology, oxidative stress, inflammatory cytokines and the expression of some key proteins were determined in hippocampus, cerebral cortex and striatum. RESULTS: 21-day SM decreased brain derived neurotrophic factor and induced neuron atrophy in the cerebral cortex. Strong oxidative stress was triggered at day 7 and the oxidative status returned to physiological level at day 21. Inflammatory cytokines were gradually suppressed and in striatum, the suppression was regulated partially through c-Jun/c-Fos. CONCLUSION: The results revealed that the significant impacts of SM on rat brain tissue depended on durations and regions, which might help to understand the health risk and to prevent brain damage for astronauts in space travel.


Assuntos
Encéfalo/metabolismo , Citocinas/metabolismo , Simulação de Ausência de Peso , Animais , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Masculino , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Distribuição Aleatória , Ratos
19.
Medicine (Baltimore) ; 98(28): e16445, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305474

RESUMO

BACKOGROUND: Evidence available in the literature suggests that physical exercise increases the release of brain-derived neurotrophic factor (BDNF) in humans and may possibly be related to improvements in executive function. However, studies of this phenomenon in adolescents are still scarce. The objective of this work is to describe the protocol for a systematic review (SR) and meta-analysis of interventional studies aiming to determine the effect of physical exercise on BDNF levels and executive function in adolescents. METHODS: This protocol is guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) and by the Cochrane Handbook of Systematic Reviews of Interventions. The databases to be searched are PubMed, EMBASE, Scopus, ScienceDirect, Web of Science, SPORTDiscus, the Cochrane Central Register of Controlled Trials (CENTRAL), and CINAHL. Interventional studies conducted on adolescents with different exercise protocols and evaluations of BDNF levels and executive function in pre- and post-intervention periods will be included in the systematic review. The characteristics of the studies, participants, and main results will be described, then the evaluation of the risk of biases and the level of evidence obtained by the protocol will be assessed. The selection of studies, data extraction, and evaluation of the methodological quality will be performed by 2 experienced reviewers independently. CONCLUSION: The systematic review will present the effects of the practice of physical exercises on the BDNF and executive function levels. The results will strengthen the interventions with the focus on the brain health of adolescents through general orientations and the evidences described shall direct future research. PROSPERO REGISTRATION NUMBER: CRD42018110683.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Função Executiva/fisiologia , Exercício/fisiologia , Exercício/psicologia , Metanálise como Assunto , Revisão Sistemática como Assunto , Adolescente , Humanos
20.
Phytomedicine ; 63: 153007, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31301537

RESUMO

BACKGROUND: Aerial parts of Peganum harmala Linn is used as a traditional medical herb for treatment of amnesia in Uighur medicine in China. Deoxyvasicine (DVAS) is one of the chief active ingredients in P. harmala, it possesses strong acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities in vitro, but the therapeutic effect and mechanisms on amnesia in vivo are unclear. PURPOSE: The objective of this study was to investigate the improvement effect of DVAS from P. harmala in learning and memory deficits of scopolamine-induced mice and elucidate the underlying mechanisms involved. METHODS: Mice were pretreated with DVAS (5, 15 and 45 mg/kg) and huperzine-A (0.2 mg/kg) by gavage for 7 days, and subsequently were daily intraperitoneally injected with scopolamine (1 mg/kg) to induce learning and memory deficits and behavioral performance was assessed by Morris water maze. To further evaluate the potential mechanisms of DVAS in improving learning and memory capabilities, pathological change, levels of various biochemical markers and protein expressions related to cholinergic system, oxidative stress, and neuroinflammation were examined. RESULTS: The results showed that DVAS could alleviate learning and memory deficits in scopolamine-treated mice. DVAS could regulate cholinergic function by inhibiting AChE and activating choline acetyltransferase (ChAT) activities and protein expressions. DVAS could induce brain-derived neurotrophic factor and protect hippocampal pyramidal cells against neuronal damage. DVAS also enhanced antioxidant defense via increasing the antioxidant enzyme level and activity of glutathione peroxidase, and anti-inflammatory function through suppressing tumor necrosis factor-α. Additionally, DVAS could regulate the neurotransmitters by elevating acetylcholine, 5-hydroxytryptamine, γ-aminobutyric acid and reducing 5-hydroxyindole-3-acetic acid and glutamic acid. CONCLUSION: Results illustrated that DVAS may be a promising candidate compound against amnesia via restoration of cholinergic function, regulating neurotransmitters, attenuating neuroinflammation and oxidative stress.


Assuntos
Alcaloides/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Quinazolinas/farmacologia , Acetilcolina/metabolismo , Amnésia/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Inibidores da Colinesterase/farmacologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Masculino , Memória/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Camundongos Endogâmicos C57BL , Neurotransmissores/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peganum/química , Escopolamina/toxicidade , Sesquiterpenos/farmacologia
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