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1.
Life Sci ; 248: 117468, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105705

RESUMO

AIMS: Treatment with 5-fluorouracil (5-FU) can cause impairment to adult hippocampal neurogenesis, resulting in cognitive deficits. As melatonin has been shown to enhance memory and hippocampal neurogenesis in animal models, this research investigated the neuroprotective effects of melatonin against spatial memory and hippocampal neurogenesis impairment in 5-fluorouracil (5-FU)-treated rats. MATERIALS AND METHODS: Four-Five weeks old male Spraque-Dawley rats weighing between 180 and 200 g were used. Animals were maintained under standard laboratory conditions with 25 °C and 12 h light/dark cycle. Animal were administered intravenous (i.v.) injections of 5-FU (25 mg/kg) 5 times every 3 days starting on day 9 of the experiment. The rats were divided into preventive, recovery, and throughout groups and co-treated with melatonin (8 mg/kg, i.p.) once daily (at 7.00 pm) for 21 days prior to, after, and throughout 5-FU treatment, respectively. Spatial memory was assessed using a novel object location (NOL) test. Hippocampal neurogenesis was then examined using Ki67, bromodeoxyuridine (BrdU), and doublecortin (DCX) immunohistochemistry staining. KEY FINDINGS: Melatonin administration was able to both protect the subjects from and reverse spatial memory deficits. 5-FU was also found to reduce the generation of hippocampal newborn neurons. However, co-treatment with melatonin ameliorated the reductions in neurogenesis caused by 5-FU. SIGNIFICANCE: These findings suggest that melatonin administration was able to ameliorate the 5-FU-induced spatial memory deficits associated with neurogenesis. The present work will be valuable for patients who suffer memory deficits from 5-FU chemotherapy.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Fluoruracila/antagonistas & inibidores , Melatonina/farmacologia , Transtornos da Memória/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Memória Espacial/efeitos dos fármacos , Animais , Antimetabólitos/efeitos adversos , Biomarcadores/metabolismo , Proliferação de Células/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/patologia , Esquema de Medicação , Fluoruracila/efeitos adversos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Injeções Intravenosas , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Neurogênese/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Memória Espacial/fisiologia
2.
Cell Prolif ; 53(1): e12730, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31746040

RESUMO

OBJECTIVES: In peripheral neuropathy, the underlying mechanisms of nerve and muscle degeneration include chronic inflammation and oxidative stress in fibrotic tissues. (-)-Epigallocatechin gallate (EGCG) is a major, active component in green tea and may scavenge free radical oxygen and attenuate inflammation. Conservative treatments such as steroid injection only deal with early, asymptomatic, peripheral neuropathy. In contrast, neurolysis and nerve conduit implantation work effectively for treating advanced stages. MATERIALS AND METHODS: An EGCG-loaded polycaprolactone (PCL) porous scaffold was fabricated using an integrated moulding method. We evaluated proliferative, oxidative and inflammatory activity of rat Schwann cells (RSCs) and rat skeletal muscle cells (RSMCs) cultured on different scaffolds in vitro. In a rat radiation injury model, we assessed the morphological, electrophysiological and functional performance of regenerated sciatic nerves and gastrocnemius muscles, as well as oxidative stress and inflammation state. RESULTS: RSCs and RSMCs exhibited higher proliferative, anti-oxidant and anti-inflammatory states in an EGCG/PCL scaffold. In vivo studies showed improved nerve and muscle recovery in the EGCG/PCL group, with increased nerve myelination and muscle fibre proliferation and reduced macrophage infiltration, lipid peroxidation, inflammation and oxidative stress indicators. CONCLUSIONS: The EGCG-modified PCL porous nerve scaffold alleviates cellular oxidative stress and repairs peripheral nerve and muscle structure in rats. It attenuates oxidative stress and inflammation in vivo and may provide further insights into peripheral nerve repair in the future.


Assuntos
Catequina/análogos & derivados , Regeneração Nervosa/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Estresse Oxidativo , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Poliésteres , Lesões Experimentais por Radiação/tratamento farmacológico , Células de Schwann/metabolismo , Nervo Isquiático/fisiologia , Tecidos Suporte/química , Animais , Catequina/química , Catequina/farmacologia , Linhagem Celular , Músculo Esquelético/inervação , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Poliésteres/química , Poliésteres/farmacologia , Porosidade , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Ratos , Células de Schwann/patologia , Nervo Isquiático/lesões , Nervo Isquiático/patologia
3.
PLoS Biol ; 17(10): e3000081, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31634368

RESUMO

In vitro models of postimplantation human development are valuable to the fields of regenerative medicine and developmental biology. Here, we report characterization of a robust in vitro platform that enabled high-content screening of multiple human pluripotent stem cell (hPSC) lines for their ability to undergo peri-gastrulation-like fate patterning upon bone morphogenetic protein 4 (BMP4) treatment of geometrically confined colonies and observed significant heterogeneity in their differentiation propensities along a gastrulation associable and neuralization associable axis. This cell line-associated heterogeneity was found to be attributable to endogenous Nodal expression, with up-regulation of Nodal correlated with expression of a gastrulation-associated gene profile, and Nodal down-regulation correlated with a preneurulation-associated gene profile expression. We harness this knowledge to establish a platform of preneurulation-like fate patterning in geometrically confined hPSC colonies in which fates arise because of a BMPs signalling gradient conveying positional information. Our work identifies a Nodal signalling-dependent switch in peri-gastrulation versus preneurulation-associated fate patterning in hPSC cells, provides a technology to robustly assay hPSC differentiation outcomes, and suggests conserved mechanisms of organized fate specification in differentiating epiblast and ectodermal tissues.


Assuntos
Proteína Morfogenética Óssea 4/farmacologia , Linhagem da Célula/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento , Proteína Nodal/genética , Células-Tronco Pluripotentes/efeitos dos fármacos , Fenômenos Biomecânicos , Padronização Corporal/genética , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 4/metabolismo , Técnicas de Cultura de Células , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Linhagem da Célula/genética , Gastrulação/efeitos dos fármacos , Gastrulação/genética , Perfilação da Expressão Gênica , Heterogeneidade Genética , Ensaios de Triagem em Larga Escala , Humanos , Modelos Biológicos , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Proteína Nodal/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Transdução de Sinais , Propriedades de Superfície
4.
Tissue Cell ; 60: 14-20, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31582013

RESUMO

A number of studies have indicated the benefits of coffee consumption on physical and mental health; however, scientific evidence on these effects, in particular of the benefits to brain function, has not been determined. In the present study, we aimed to determine the benefits of caffeic acid in the nervous system. For this purpose, we administered doses of 0 or 300 mg/kg for 30 days to mice that were not otherwise affected. We analyzed survival of newly born cells, oxidative stress, inflammatory marker expression, and microglial activation in the hippocampus. We found that caffeic acid had no effect on the expression levels of neurotrophic factors and inflammatory or anti-inflammatory cytokines. However, caffeic acid-treated mice exhibited significantly lower levels of 4-hydroxynonenal, an oxidative stress marker, in the hippocampus, as well as significantly fewer activated microglia. Abnormally high oxidative stress, as well as activated microglia accumulation are both considered to relate to the pathophysiology of neurological and psychiatric disorders. The present study demonstrates the physiological effects of caffeic acid and may explain the suggested benefits of coffee consumption on brain health.


Assuntos
Antioxidantes/farmacologia , Ácidos Cafeicos/farmacologia , Hipocampo/efeitos dos fármacos , Microglia/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Neurogênese/efeitos dos fármacos
5.
Acta Neurobiol Exp (Wars) ; 79(3): 302-308, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31587022

RESUMO

Preclinical studies have suggested that increased adult neurogenesis in the hippocampus might have potential therapeutic effects for Alzheimer's disease and depression; therefore, it is a target for the treatment of some brain diseases. In this technical communication, we propose a cell-based fluorescence assay to study the neurogenesis of adult hippocampal progenitor cells that can be used for high-throughput screening of drugs promoting neurogenesis. Three fluorescent dyes (DAPI, Alexa Fluor 488, and Alexa Fluor 594) and a fluorescence spectrophotometry reader were used, which confirmed that the mutual interference of the three fluorescent dyes is very low. We used this cell-based fluorescence assay to evaluate the effects of three neurotrophic factors, ciliary neurotrophic factor (CNTF), insulin-like growth factor 1 (IGF-1), and IGF-2 on the promotion of neurogenesis in adult hippocampal neural progenitor cells. The fluorescence intensity ratio of the neuronal marker, class III ß-tubulin, to the housekeeping protein, glyceraldehyde 3-phosphate dehydrogenase, or nuclear staining dye, DAPI, in CNTF-treated cells was significantly higher than in control cells. The ratios in IGF-1 and IGF-2-treated cells were slightly higher under higher cell density conditions. These results are consistent with those in previous reports; therefore, this report proved the efficacy of this method. Taken together, the results showed that this simple, rapid, and economical cell-based immunofluorescence assay could be a powerful tool for the rapid screening of drugs that promote adult neurogenesis.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Hipocampo/patologia , Células-Tronco Neurais/citologia , Neurogênese/efeitos dos fármacos , Neurônios/citologia , Animais , Contagem de Células/métodos , Diferenciação Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Imunofluorescência , Hipocampo/efeitos dos fármacos , Humanos , Fatores de Crescimento Neural/farmacologia , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/fisiologia , Neurônios/efeitos dos fármacos
6.
Int J Mol Sci ; 20(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509934

RESUMO

In addition to its role as an endocrine messenger, growth hormone (GH) also acts as a neurotrophic factor in the central nervous system (CNS), whose effects are involved in neuroprotection, axonal growth, and synaptogenic modulation. An increasing amount of clinical evidence shows a beneficial effect of GH treatment in patients with brain trauma, stroke, spinal cord injury, impaired cognitive function, and neurodegenerative processes. In response to injury, Müller cells transdifferentiate into neural progenitors and proliferate, which constitutes an early regenerative process in the chicken retina. In this work, we studied the long-term protective effect of GH after causing severe excitotoxic damage in the retina. Thus, an acute neural injury was induced via the intravitreal injection of kainic acid (KA, 20 µg), which was followed by chronic administration of GH (10 injections [300 ng] over 21 days). Damage provoked a severe disruption of several retinal layers. However, in KA-damaged retinas treated with GH, we observed a significant restoration of the inner plexiform layer (IPL, 2.4-fold) and inner nuclear layer (INL, 1.5-fold) thickness and a general improvement of the retinal structure. In addition, we also observed an increase in the expression of several genes involved in important regenerative pathways, including: synaptogenic markers (DLG1, NRXN1, GAP43); glutamate receptor subunits (NR1 and GRIK4); pro-survival factors (BDNF, Bcl-2 and TNF-R2); and Notch signaling proteins (Notch1 and Hes5). Interestingly, Müller cell transdifferentiation markers (Sox2 and FGF2) were upregulated by this long-term chronic GH treatment. These results are consistent with a significant increase in the number of BrdU-positive cells observed in the KA-damaged retina, which was induced by GH administration. Our data suggest that GH is able to facilitate the early proliferative response of the injured retina and enhance the regeneration of neurite interconnections.


Assuntos
Hormônio do Crescimento/farmacologia , Ácido Caínico/toxicidade , Regeneração/efeitos dos fármacos , Retina/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Fator Neurotrófico Derivado do Encéfalo/genética , Embrião de Galinha , Galinhas , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Neurogênese/fisiologia , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Receptor Notch1/genética , Regeneração/genética , Regeneração/fisiologia , Retina/metabolismo , Retina/fisiopatologia , Fatores de Transcrição SOXB1/genética
7.
Int J Mol Sci ; 20(18)2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31540019

RESUMO

Evidence has been accumulated demonstrating that heavy metals may accumulate in various organs, leading to tissue damage and toxic effects in mammals. In particular, the Central Nervous System (CNS) seems to be particularly vulnerable to cumulative concentrations of heavy metals, though the pathophysiological mechanisms is still to be clarified. In particular, the potential role of oligodendrocyte dysfunction and myelin production after exposure to subtoxic concentration I confirmed. It is ok of heavy metals is to be better assessed. Here we investigated on the effect of sub-toxic concentration of several essential (Cu2 +, Cr3 +, Ni2 +, Co2+) and non-essential (Pb2 +, Cd2+, Al3+) heavy metals on human oligodendrocyte MO3.13 and human neuronal SHSY5Y cell lines (grown individually or in co-culture). MO3.13 cells are an immortal human-human hybrid cell line with the phenotypic characteristics of primary oligodendrocytes but following the differentiation assume the morphological and biochemical features of mature oligodendrocytes. For this reason, we decided to use differentiated MO3.13 cell line. In particular, exposure of both cell lines to heavy metals produced a reduced cell viability of co-cultured cell lines compared to cells grown separately. This effect was more pronounced in neurons that were more sensitive to metals than oligodendrocytes when the cells were grown in co-culture. On the other hand, a significant reduction of lipid component in cells occurred after their exposure to heavy metals, an effect accompanied by substantial reduction of the main protein that makes up myelin (MBP) in co-cultured cells. Finally, the effect of heavy metals in oligodendrocytes were associated to imbalanced intracellular calcium ion concentration as measured through the fluorescent Rhod-2 probe, thus confirming that heavy metals, even used at subtoxic concentrations, lead to dysfunctional oligodendrocytes. In conclusion, our data show, for the first time, that sub-toxic concentrations of several heavy metals lead to dysfunctional oligodendrocytes, an effect highlighted when these cells are co-cultured with neurons. The pathophysiological mechanism(s) underlying this effect is to be better clarified. However, imbalanced intracellular calcium ion regulation, altered lipid formation and, finally, imbalanced myelin formation seem to play a major role in early stages of heavy metal-related oligodendrocyte dysfunction.


Assuntos
Metais Pesados/toxicidade , Proteína Básica da Mielina/metabolismo , Neurônios/metabolismo , Oligodendroglia/metabolismo , Cálcio/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular , Sistema Nervoso Central , Humanos , Metais Pesados/química , Bainha de Mielina/metabolismo , Neurogênese/efeitos dos fármacos , Neurônios/química , Neurônios/efeitos dos fármacos , Neurônios/patologia , Oligodendroglia/química , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia
8.
Ecotoxicol Environ Saf ; 185: 109686, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31546205

RESUMO

Gestational exposure to PM2.5 is a worldwide environmental issue associated with long-lasting behavior abnormalities and neurodevelopmental impairments in the hippocampus of offspring. PM2.5 may induce hippocampus injury and lead to autism-like behavior such as social communication deficits and stereotyped repetitive behavior in children through neuroinflammation and neurodegeneration. Here, we investigated the preventive effect of B-vitamin on PM2.5-induced deleterious effects by focusing on anti-inflammation, antioxidant, synaptic remodeling and neurodevelopment. Pregnant mice were randomly divided into three groups including control group (mice subject to PBS only), model group (mice subject to both 30 µL PM2.5 of 3.456 µg/µL and 10 mL/(kg·d) PBS), and intervention group (mice subject to both 30 µL PM2.5 of 3.456 µg/µL and 10 mL/(kg·d) B-vitamin supplementation (folic acid, vitamin B6 and vitamin B12 with concentrations at 0.06, 1.14 and 0.02 mg/mL, respectively)). In the current study B-vitamin significantly alleviated neurobehavioral impairment reflected in reduced social communication disorders, stereotyped repetitive behavior, along with learning and spatial memory impairment in PM2.5-stimulated mice offspring. Next, B-vitamin corrected synaptic loss and reduced mitochondrial damage in hippocampus of mice offspring, demonstrated by normalized synapse quantity, synaptic cleft, postsynaptic density (PSD) thickness and length of synaptic active area. Furthermore, significantly down-regulated expression of pro-inflammatory cytokines including NF-κB, TNF-α and IL-1ß, and lipid peroxidation were found. We observed elevated levels of oxidant-related genes (SOD, GSH and GSH-Px). Moreover, decreased cleaved caspase-3 and TUNEL-positive cells suggested inhibited PM2.5-induced apoptosis by B-vitamin. Furthermore, B-vitamin increased neurogenesis by increasing EdU-positive cells in the subgranular zone (SGZ) of offspring. Collectively, our results suggest that B-vitamin supplementation exerts preventive effect on autism-like behavior and neurodevelopmental impairment in hippocampus of mice offspring gestationally exposed to PM2.5, to which alleviated mitochondrial damage, increased anti-inflammatory and antioxidant capacity and synaptic efficiency, reduced neuronal apoptosis and improved hippocampal neurogenesis may contribute.


Assuntos
Poluentes Atmosféricos/toxicidade , Transtorno Autístico/prevenção & controle , Hipocampo/efeitos dos fármacos , Material Particulado/toxicidade , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Complexo Vitamínico B/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Transtorno Autístico/induzido quimicamente , Citocinas/metabolismo , Suplementos Nutricionais , Feminino , Hipocampo/crescimento & desenvolvimento , Hipocampo/imunologia , Aprendizagem/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Neurogênese/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Sinapses/efeitos dos fármacos , Complexo Vitamínico B/administração & dosagem
9.
Mater Sci Eng C Mater Biol Appl ; 105: 110029, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546373

RESUMO

The cytocompatibility of cardiomyocytes derived from embryonic stem cells and neural progenitors, which were seeded on the surface of composite films made of graphene oxide (GO) and polypyrrole (PPy-GO) or poly(3,4-ethylenedioxythiophene) (PEDOT-GO) are reported. The GO incorporated in the composite matrix contributes to the patterning of the composite surface, while the electrically conducting PPy and PEDOT serve as ion-to-electron transducers facilitating electrical stimulation/sensing. The films were fabricated by a simple one-step electropolymerization procedure on electrically conducting indium tin oxide (ITO) and graphene paper (GP) substrates. Factors affecting the cell behaviour, i.e. the surface topography, wettability, and electrical surface conductivity, were studied. The PPy-GO and PEDOT-GO prepared on ITO exhibited high surface conductivity, especially in the case of the ITO/PPy-GO composite. We found that for cardiomyocytes, the PPy-GO and PEDOT-GO composites counteracted the negative effect of the GP substrate that inhibited their growth. Both the PPy-GO and PEDOT-GO composites prepared on ITO and GP significantly decreased the cytocompatibility of neural progenitors. The presented results enhance the knowledge about the biological properties of electroactive materials, which are critical for tissue engineering, especially in context stimuli-responsive scaffolds.


Assuntos
Condutividade Elétrica , Eletroquímica , Grafite/farmacologia , Miócitos Cardíacos/citologia , Células-Tronco Neurais/citologia , Polímeros/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/química , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Polímeros/química , Pirróis/química , Água/química
10.
Life Sci ; 235: 116844, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31499069

RESUMO

AIMS: 10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H), a new derivative of ginkgolide B, has drawn great attention for its potent bioactivities against ischemia-induced injury. The purpose of this study was to further investigate the effect of XQ-1H against acute ischemic stroke by inducing middle cerebral artery occlusion/reperfusion (MCAO/R) injuries in mice. MAIN METHODS: Treatment of XQ-1H (78 or 39 mg/kg, i.g., bid) 2 h after MCAO improved motor skills and ameliorated the severity of brain infarction and apoptosis seen in the mice by diminishing pathological changes and the activation of a pro-apoptotic protein Cleaved-Caspase-3, which in turn induced anti-apoptotic Bcl-xL. Through introducing Wnt/ß-catenin signaling inhibitor XAV-939, XQ-1H was proven to intensively promoted neurogenesis in the peri-infarct cortex, subventricular area (SVZ) and the dentate gyrus (DG) subgranular area (SGZ) in a Wnt signal dependent way by compromising the activation of GSK3ß, which in turn upregulated Wnt1, ß-catenin, Neuro D1 and Cyclin D1, most possibly through the activation of PI3K/Akt signaling via the upregulation of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). KEY FINDINGS: We conclude that XQ-1H preserved the motor functions, limited apoptosis, and concomitantly promoted neurogenesis-related protein expression by Wnt signaling-dependently compromising GSK3ß/Caspase-3 activity and enhancing the expression of Wnt1/ß-catenin/Neuro D1/Cyclin D1 and Bcl-xL. SIGNIFICANCE: This research may benefit the development of stroke therapeutics targeting neurogenesis through Wnt upregulation by XQ-1H.


Assuntos
Apoptose/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Ginkgolídeos/farmacologia , Ginkgolídeos/uso terapêutico , Lactonas/farmacologia , Lactonas/uso terapêutico , Neurogênese/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Caspase 3/metabolismo , Ciclina D1/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacologia , Infarto da Artéria Cerebral Média , Masculino , Camundongos , Fator de Crescimento Neural/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/patologia , Regulação para Cima/efeitos dos fármacos , Proteína bcl-X/metabolismo
11.
Mater Sci Eng C Mater Biol Appl ; 104: 109904, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499954

RESUMO

Brain extracellular matrix (ECM) is complex, heterogeneous and often poorly replicated in traditional 2D cell culture systems. The development of more physiologically relevant 3D cell models capable of emulating the native ECM is of paramount importance for the study of human induced pluripotent stem cell (iPSC)-derived neurons. Due to its structural similarity with hyaluronic acid, a primary component of brain ECM, alginate is a potential biomaterial for 3D cell culture systems. However, a lack of cell adhesion motifs within the chemical structure of alginate has limited its application in neural culture systems. This study presents a simple and accessible method of incorporating collagen fibrils into an alginate hydrogel by physical mixing and controlled gelation under physiological conditions and tests the hypothesis that such a substrate could influence the behaviour of human neurons in 3D culture. Regulation of the gelation process enabled the penetration of collagen fibrils throughout the hydrogel structure as demonstrated by transmission electron microscopy. Encapsulated human iPSC-derived neurons adhered to the blended hydrogel as evidenced by the increased expression of α1, α2 and ß1 integrins. Furthermore, immunofluorescence microscopy revealed that encapsulated neurons formed complex neural networks and matured into branched neurons expressing synaptophysin, a key protein involved in neurotransmission, along the neurites. Mechanical tuning of the hydrogel stiffness by modulation of the alginate ionic crosslinker concentration also influenced neuron-specific gene expression. In conclusion, we have shown that by tuning the physicochemical properties of the alginate/collagen blend it is possible to create different ECM-like microenvironments where complex mechanisms underpinning the growth and development of human neurons can be simulated and systematically investigated.


Assuntos
Alginatos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Colágeno/farmacologia , Hidrogéis/farmacologia , Neurogênese/efeitos dos fármacos , Neurônios/citologia , Adesão Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Junções Célula-Matriz/efeitos dos fármacos , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fenótipo , Reologia
12.
Int J Mol Sci ; 20(17)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31480215

RESUMO

The mammalian brain is enriched with lipids that serve as energy catalyzers or secondary messengers of essential signaling pathways. Docosahexaenoic acid (DHA) is an omega-3 fatty acid synthesized de novo at low levels in humans, an endogenous supply from its precursors, and is mainly incorporated from nutrition, an exogeneous supply. Decreased levels of DHA have been reported in the brains of patients with neurodegenerative diseases. Preventing this decrease or supplementing the brain with DHA has been considered as a therapy for the DHA brain deficiency that could be linked with neuronal death or neurodegeneration. The mammalian brain has, however, a mechanism of compensation for loss of neurons in the brain: neurogenesis, the birth of neurons from neural stem cells. In adulthood, neurogenesis is still present, although at a slower rate and with low efficiency, where most of the newly born neurons die. Neural stem/progenitor cells (NSPCs) have been shown to require lipids for proper metabolism for proliferation maintenance and neurogenesis induction. Recent studies have focused on the effects of these essential lipids on the neurobiology of NSPCs. This review aimed to introduce the possible use of DHA to impact NSPC fate-decision as a therapy for neurodegenerative diseases.


Assuntos
Células-Tronco Adultas/citologia , Linhagem da Célula/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/farmacologia , Células-Tronco Neurais/citologia , Células-Tronco Adultas/efeitos dos fármacos , Células-Tronco Adultas/metabolismo , Animais , Humanos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia
13.
Biomed Pharmacother ; 118: 109263, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31369988

RESUMO

It is well known that chamomile is one of the oldest known medicinal herbs and has been used to treat various disorders, but it is mainly German chamomile. The effects of Roman chamomile on depression still unclear. In this study, we used chronically stressed mice to investigate whether inhalation of Roman chamomile essential oil affects depression-like behavior. We previously reported that restraint and water immersion stress produce depression-like behavior and a blunted response to the tricyclic antidepressant clomipramine. Each mouse was exposed to restraint and water immersion stress for 15 days, and resistance to the effect of clomipramine was induced in a behavioral despair paradigm. In the present study, we found that cotreatment with clomipramine and inhalation of Roman chamomile attenuated depression-like behavior in a forced swim test. Next, we examined the hippocampal mRNA levels of two cytokines, tumor necrosis factor (TNF) alpha and interleukin-6 (IL-6); a neurotrophic factor, brain derived-neurotrophic factor (BDNF); and nerve growth factor (NGF). TNF alpha, IL-6 and BDNF mRNA levels did not change in the hippocampus of stressed mice. However, the NGF mRNA level was significantly decreased, and this decrease was not attenuated by treatment with clomipramine or inhalation of Roman chamomile alone. We also examined whether Roman chamomile combined with clomipramine treatment affects hippocampal neurogenesis and serum corticosterone levels. Stressed mice had fewer doublecortin (DCX)-positive cells in the subgranular zone of the dentate gyrus, but this was significantly attenuated by Roman chamomile and clomipramine treatment. In addition, the serum corticosterone level was also significantly decreased by treatment with Roman chamomile and clomipramine. These results suggest that Roman chamomile inhalation may enhance the antidepressant effect of clomipramine by increasing hippocampal neurogenesis and modulating corticosterone levels in patients with treatment-resistant depression.


Assuntos
Comportamento Animal , Chamaemelum/química , Clomipramina/uso terapêutico , Depressão/tratamento farmacológico , Exposição por Inalação , Extratos Vegetais/uso terapêutico , Animais , Proliferação de Células/efeitos dos fármacos , Clomipramina/farmacologia , Corticosterona/sangue , Citocinas/genética , Citocinas/metabolismo , Depressão/sangue , Quimioterapia Combinada , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Neurogênese/efeitos dos fármacos , Extratos Vegetais/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estresse Psicológico/sangue , Estresse Psicológico/tratamento farmacológico
14.
Ecotoxicol Environ Saf ; 183: 109498, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31377521

RESUMO

2',2',4,4'-tetrabromo diphenyl ether (BDE-47), one of the most abundant congeners of commercial pentaBDE utilized as flame retardants, has been phased out of production due to its potential neural toxicity and endocrine disrupting activities, and yet still present in the environment. Several alternatives to BDE-47, including tetrabromobisphenol A (TBBPA), tetrabromobisphenol S (TBBPS), tetrachlorobisphenol A (TCBPA) and decabromodiphenyl ether (BDE-209), are presently employed without restrictions and their potential toxic effects on human neural development are still unclear. In this study, we utilized a human neural stem cell (hNSC)-based system to evaluate the potential developmental neurotoxic effects of the above-mentioned five chemicals, at environment and human exposure relevant concentrations. We found that those compounds slightly altered the expression of hNSC identity markers (SOX2, SOX3 and NES), without impairing cell viability or proliferation, in part by either modulating glycogen synthase kinase 3 beta (GSK3ß) signaling (TBBPS, TCBPA and BDE-47), and slightly disturbing the NOTCH pathway (TBBPA, TBBPS and TCBPA). Moreover, the five chemicals seemed to alter hNSC differentiation by perturbing triiodothyronine (T3) cellular signaling. Thus, our findings suggest that the five compounds, especially TBBPS, TCBPA, and BDE-47, may affect hNSC self-renewal and differentiation abilities and potentially elicit neural developmental toxicity.


Assuntos
Retardadores de Chama/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tri-Iodotironina/metabolismo , Humanos , Hidrocarbonetos Halogenados/toxicidade , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Neurogênese/efeitos dos fármacos , Neurogênese/genética
15.
PLoS Biol ; 17(8): e3000086, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31433818

RESUMO

Lengthy use of general anesthetics (GAs) causes neurobehavioral deficits in the developing brain, which has raised significant clinical concerns such that the United States Food and Drug Administration (FDA) is warning on the use of GAs in children younger than 3 years. However, the molecular and cellular mechanisms for GAs-induced neurotoxicity remain largely unknown. Here, we report that sevoflurane (Sevo), a commonly used GA in pediatrics, caused compromised astrocyte morphogenesis spatiotemporally correlated to synaptic overgrowth, with reduced synaptic function in developing cortex in a regional-, exposure-length-, and age-specific manner. Sevo disrupted astrocyte Ca2+ homeostasis both acutely and chronically, which led to the down-regulation of Ezrin, an actin-binding membrane-bound protein, which we found was critically involved in astrocyte morphogenesis in vivo. Importantly, overexpression of astrocyte Ezrin rescued astrocytic and neuronal dysfunctions and fully corrected deficits in social behaviors in developing mice with lengthy Sevo exposure. Our data uncover that, in addition to neurons, astrocytes may represent important targets for GAs to exert toxic effects and that astrocyte morphological integrity is crucial for synaptogenesis and neurological behaviors.


Assuntos
Astrócitos/efeitos dos fármacos , Sevoflurano/efeitos adversos , Sinapses/efeitos dos fármacos , Anestesia Geral/efeitos adversos , Anestésicos Inalatórios/efeitos adversos , Animais , Animais Recém-Nascidos , Comportamento Animal , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Proteínas do Citoesqueleto/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Comportamento Social
16.
Nat Commun ; 10(1): 3768, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434877

RESUMO

The etiology of major depressive disorder (MDD), the leading cause of worldwide disability, is unknown. The neurogenic hypothesis proposes that MDD is linked to impairments of adult neurogenesis in the hippocampal dentate gyrus (DG), while the effects of antidepressants are mediated by increased neurogenesis. However, alterations in neurogenesis and endophenotypes are not always causally linked, and the relationship between increased neurogenesis and altered behavior is controversial. To address causality, we used chemogenetics in transgenic mice to selectively manipulate activity of newborn DG neurons. Suppressing excitability of newborn neurons without altering neurogenesis abolish the antidepressant effects of fluoxetine. Remarkably, activating these neurons is sufficient to alleviate depression-like behavior and reverse the adverse effects of unpredictable chronic mild stress. Our results demonstrate a direct causal relationship between newborn neuronal activity and affective behavior. Thus, strategies that target not only neurogenesis but also activity of newborn neurons may lead to more effective antidepressants.


Assuntos
Antidepressivos/farmacologia , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
17.
Neurochem Res ; 44(9): 2170-2181, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31420834

RESUMO

Acute inhalation of combustion smoke produces long-term neurologic deficits in survivors. To study the mechanisms that contribute to the development of neurologic deficits and identify targets for prevention, we developed a mouse model of acute inhalation of combustion smoke, which supports longitudinal investigation of mechanisms that underlie the smoke induced inimical sequelae in the brain. Using a transgenic mouse engineered to overexpress neuroglobin, a neuroprotective oxygen-binding globin protein, we previously demonstrated that elevated neuroglobin preserves mitochondrial respiration and attenuates formation of oxidative DNA damage in the mouse brain after smoke exposure. In the current study, we show that elevated neuronal neuroglobin attenuates the persistent inflammatory changes induced by smoke exposure in the mouse brain and mitigates concordant smoke-induced long-term neurobehavioral deficits. Specifically, we found that increases in hippocampal density of GFAP and Iba-1 positive cells that are detected post-smoke in wild-type mice are absent in the neuroglobin overexpressing transgenic (Ngb-tg) mice. Similarly, the smoke induced hippocampal myelin depletion is not observed in the Ngb-tg mice. Importantly, elevated neuroglobin alleviates behavioral and memory deficits that develop after acute smoke inhalation in the wild-type mice. Taken together, our findings suggest that the protective effects exerted by neuroglobin in the brains of smoke exposed mice afford protection from long-term neurologic sequelae of acute inhalation of combustion smoke. Our transgenic mouse provides a tool for assessing the potential of elevated neuroglobin as possible strategy for management of smoke inhalation injury.


Assuntos
Hipocampo/metabolismo , Inflamação/metabolismo , Neuroglobina/metabolismo , Animais , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/metabolismo , Expressão Gênica/efeitos dos fármacos , Hipocampo/patologia , Inflamação/induzido quimicamente , Aprendizagem/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/efeitos dos fármacos , Neuroglobina/genética , RNA Mensageiro/metabolismo , Fumaça
18.
Biol Pharm Bull ; 42(7): 1146-1154, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257291

RESUMO

Helicid (4-formylphenyl-O-ß-D-allopyranoside), an active component found in seeds from the Chinese herb Helicia nilagirica, has been reported to exert sedative, analgesic, hypnotic and antidepressant effects. The present study was designed to evaluate the antidepressant, learning and cognitive improvement effects of helicid in a chronic unpredictable mild stress (CUMS) model of depression in rats and to explore cAMP/protein kinase A (PKA)/cAMP response element-binding (CREB) signaling pathway. Sprague-Dawley rats were randomly assigned to six groups (n = 10): control; CUMS; CUMS + fluoxetine (5 mg/kg) and CUMS + helicid at 8, 16 and 32 mg/kg. All rats were subjected to 12 weeks of CUMS protocols and drug administration during the last 6 weeks of CUMS. Our results showed that helicid, at a dose of 32 mg/kg, significantly reversed decreases in body weight and sucrose consumption, increased the distance and number of crossings in the open-field test (OFT), reduced immobility times in the forced swimming test (FST) and improved spatial memory in the Morris water maze (MWM); all of these effects had been induced by CUMS paradigm. Immunohistochemistry showed that administration of helicid could promoted the proliferation of neurons in the hippocampal CA1 and dentate gyrus (DG) regions. CUMS rats treated with helicid had dramatically decreased protein levels of serotonin transporters (SERTs). In addition, CUMS resulted in a significant reduction in the expression of cAMP, PKA C-α and p-CREB, each of which were partially attenuated by helicid administration. These results indicated that helicid could improve depressive behaviors, learning and cognitive deficits and increase hippocampal neurogenesis, which may be mediated by the regulation of SERTs, activation of the cAMP/PKA/CREB signaling pathway and upregulation of p-CREB levels in hippocampal.


Assuntos
Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Benzaldeídos/farmacologia , Benzaldeídos/uso terapêutico , Depressão/tratamento farmacológico , Estresse Psicológico/tratamento farmacológico , Animais , Cognição/efeitos dos fármacos , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Depressão/metabolismo , Depressão/psicologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiologia , Aprendizagem/efeitos dos fármacos , Masculino , Neurogênese/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia
19.
Biol Aujourdhui ; 213(1-2): 7-16, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31274098

RESUMO

Thyroid hormones (THs) are vital for vertebrate brain function throughout life, from early development to ageing. Epidemiological studies show an adequate supply of maternal TH during pregnancy to be necessary for normal brain development, and this from the first trimester of onwards. Maternal TH deficiency irreversibly affects fetal brain development, increasing the risk of offspring cognitive disorders and IQ loss. Mammalian and non-mammalian (zebrafish, xenopus, chicken) models are useful to dissect TH-dependent cellular and molecular mechanisms governing embryonic and fetal brain development: a complex process including cell proliferation, survival, determination, migration, differentiation and maturation of neural stem cells (NSCs). Notably, rodent models have strongly contributed to understand the key neurogenic roles of TH still at work in adult life. Neurogenesis continues in two main areas, the sub-ventricular zone lining the lateral ventricles (essential for olfaction) and the sub-granular zone in the dentate gyrus of the hippocampus (involved in memory, learning and mood control). In both niches, THs tightly regulate the balance between neurogenesis and oligodendrogenesis under physiological and pathological contexts. Understanding how THs modulate NSCs determination toward a neuronal or a glial fate throughout life is a crucial question in neural stem cell biology. Providing answers to this question can offer therapeutic strategies for brain repair, notably in neurodegenerative diseases, demyelinating diseases or stroke where new neurons and/or oligodendrocytes are required. The review focuses on TH regulation of NSC fate in mammals and humans both during development and in the adult.


Assuntos
Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Hormônios Tireóideos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Gravidez , Hormônios Tireóideos/fisiologia
20.
J Ethnopharmacol ; 243: 112079, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31302206

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Zhi-Zi-Hou-Po decoction (ZZHPD), a classical Chinese prescription, has been reported to improve depressive behaviors in clinic. However, definite pharmacological effects and mechanisms of ZZHPD on monoaminergic system and hippocampal neurogenesis are ambiguous. It need to be further illuminated. AIM OF THE STUDY: Our study is designed to reveal pharmacological mechanisms of ZZHPD on depression through pharmacokinetics, monoamine neurotransmitters and neurogenesis. MATERIALS AND METHODS: Chronic unpredictable mild stress (CUMS) is used to establish rats model of depression. Then, the antidepressant effects of ZZHPD are evaluated by detecting body weight, sucrose preference and forced swimming test. The regulatory functions of ZZHPD on monoaminergic system are assessed by measuring monoamine neurotransmitters, neurotransmitter precursor substances, synthesized rate-limiting enzymes and transporters. Finally, potential molecular mechanism of ZZHPD on hippocampal neurogenesis is evaluated by investigating newborn immature neuron and newborn mature neuron. RESULTS: Our results show that ZZHPD remarkably normalizes CUMS-induced decline in weight gain, decrease of sucrose consumption rate in sucrose preference test and increase of immobility time in forced swimming test. Moreover, ZZHPD significantly reverses CUMS-induced reduction of 5-hydroxytryptamine (5-HT), dopamine (DA), tryptophan (Trp), tyrosine (Tyr), tryptophan hydroxylase2 (TPH2) and tyrosine hydroxylase (TH), whereas decreases level of serotonin transporter (SERT) in CUMS-induced rats. Finally, ZZHPD obviously improves CUMS-induced decrease of newborn immature neuron and newborn mature neuron in dentate gyrus of hippocampus. CONCLUSION: This study demonstrates that ZZHPD can alleviate CUMS-induced depression-like behaviors. It is probably attributed to the fact that ZZHPD could enhance monoaminergic system and hippocampal neurogenesis. Our findings provide the new perspectives on molecular targets of ZZHPD, and it will facilitate its clinical application.


Assuntos
Antidepressivos/farmacologia , Depressão/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Iridoides/farmacologia , Estresse Psicológico/metabolismo , Animais , Antidepressivos/uso terapêutico , Monoaminas Biogênicas/metabolismo , Doença Crônica , Depressão/tratamento farmacológico , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/uso terapêutico , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Iridoides/farmacocinética , Iridoides/uso terapêutico , Masculino , Neurogênese/efeitos dos fármacos , Ratos Sprague-Dawley , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Estresse Psicológico/tratamento farmacológico , Triptofano Hidroxilase/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
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