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1.
Nihon Yakurigaku Zasshi ; 155(2): 87-92, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32115484

RESUMO

Glaucoma, progressive optic neuropathy, is the first cause of blindness in Japan. Blindness in this disease is induced by damages or degeneration of retinal ganglion cells (RGCs), retinal neurons transmit visual information to brain. An elevated intraocular pressure (IOP) is widely recognized as one of the most important risk factors and that IOP directly damages RGCs by mechanical stress, however, accumulating evidences have shown that a majority of Japanese patients for primary open angle glaucoma shows normal level of IOP. Thus, new target for glaucoma pathology is emerged. In this issue, we introduce potential roles of glial cells for pathogenesis of glaucoma. In the CNS, reactive gliosis has been recognized in a variety of neurodegenerative diseases. Such glial activation is also found in retinae of human glaucoma patients and animal models. Importantly, glial activation precedes RGS degeneration, indicating the possibility that reactive glial cells actively contribute to pathogenesis of glaucoma. In this issue, we will focus on macroglial cells such as Muller cells and astrocytes, and discuss their roles in glaucoma.


Assuntos
Glaucoma/patologia , Neuroglia/patologia , Retina/patologia , Células Ganglionares da Retina/patologia , Animais , Astrócitos/patologia , Modelos Animais de Doenças , Células Ependimogliais/patologia , Humanos , Pressão Intraocular , Retina/citologia
2.
Adv Exp Med Biol ; 1190: 65-83, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760639

RESUMO

Propagation of action potentials along axons is optimized through interactions between neurons and myelinating glial cells. Myelination drives division of the axons into distinct molecular domains including nodes of Ranvier. The high density of voltage-gated sodium channels at nodes generates action potentials allowing for rapid and efficient saltatory nerve conduction. At paranodes flanking both sides of the nodes, myelinating glial cells interact with axons, forming junctions that are essential for node formation and maintenance. Recent studies indicate that the disruption of these specialized axonal domains is involved in the pathophysiology of various neurological diseases. Loss of paranodal axoglial junctions due to genetic mutations or autoimmune attack against the paranodal proteins leads to nerve conduction failure and neurological symptoms. Breakdown of nodal and paranodal proteins by calpains, the calcium-dependent cysteine proteases, may be a common mechanism involved in various nervous system diseases and injuries. This chapter reviews recent progress in neurobiology and pathophysiology of specialized axonal domains along myelinated nerve fibers.


Assuntos
Axônios/fisiologia , Fibras Nervosas Mielinizadas/fisiologia , Condução Nervosa , Axônios/patologia , Humanos , Fibras Nervosas Mielinizadas/patologia , Neuroglia/patologia , Neuroglia/fisiologia
3.
Nature ; 574(7779): 543-548, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645720

RESUMO

Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota1. In mammals, changes in the composition of the microbiota can influence many physiologic processes (including development, metabolism and immune cell function) and are associated with susceptibility to multiple diseases2. Alterations in the microbiota can also modulate host behaviours-such as social activity, stress, and anxiety-related responses-that are linked to diverse neuropsychiatric disorders3. However, the mechanisms by which the microbiota influence neuronal activity and host behaviour remain poorly defined. Here we show that manipulation of the microbiota in antibiotic-treated or germ-free adult mice results in significant deficits in fear extinction learning. Single-nucleus RNA sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in excitatory neurons, glia and other cell types. Transcranial two-photon imaging showed that deficits in extinction learning after manipulation of the microbiota in adult mice were associated with defective learning-related remodelling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Finally, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and have been reported to be related to neuropsychiatric disorders in humans and mouse models, suggesting that microbiota-derived compounds may directly affect brain function and behaviour. Together, these data indicate that fear extinction learning requires microbiota-derived signals both during early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders.


Assuntos
Extinção Psicológica/fisiologia , Medo/fisiologia , Metabolômica , Microbiota/fisiologia , Neurônios/fisiologia , Animais , Antibacterianos/farmacologia , Transtorno Autístico/metabolismo , Sangue/metabolismo , Cálcio/metabolismo , Líquido Cefalorraquidiano/química , Líquido Cefalorraquidiano/metabolismo , Sinais (Psicologia) , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/patologia , Espinhas Dendríticas/fisiologia , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Fezes/química , Vida Livre de Germes , Indicã/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microbiota/efeitos dos fármacos , Microbiota/imunologia , Inibição Neural , Neuroglia/patologia , Neuroglia/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios/patologia , Fenilpropionatos/metabolismo , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/imunologia , Córtex Pré-Frontal/fisiologia , Esquizofrenia/metabolismo , Transcriptoma , Nervo Vago/fisiologia
4.
Int J Mol Sci ; 20(17)2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31480448

RESUMO

Aging causes many changes in the human body, and is a high risk for various diseases. Dementia, a common age-related disease, is a clinical disorder triggered by neurodegeneration. Brain damage caused by neuronal death leads to cognitive decline, memory loss, learning inabilities and mood changes. Numerous disease conditions may cause dementia; however, the most common one is Alzheimer's disease (AD), a futile and yet untreatable illness. Adult neurogenesis carries the potential of brain self-repair by an endogenous formation of newly-born neurons in the adult brain; however it also declines with age. Strategies to improve the symptoms of aging and age-related diseases have included different means to stimulate neurogenesis, both pharmacologically and naturally. Finally, the regulatory mechanisms of stem cells neurogenesis or a functional integration of newborn neurons have been explored to provide the basis for grafted stem cell therapy. This review aims to provide an overview of AD pathology of different neural and glial cell types and summarizes current strategies of experimental stem cell treatments and their putative future use in clinical settings.


Assuntos
Doença de Alzheimer/terapia , Neurogênese , Transplante de Células-Tronco , Doença de Alzheimer/patologia , Animais , Humanos , Neuroglia/patologia , Neurônios/patologia , Transplante de Células-Tronco/métodos
5.
Exp Neurol ; 322: 113056, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31494101

RESUMO

Inflammatory response triggered by nerve injury plays important roles in the development of neurological disorders, such as neuropathic pain. The signaling events leading to inflammation in the nervous system remain poorly understood. Here, by deleting Dlk in sensory neurons driven by Wnt1a-Cre, we show that dual leucine zipper kinase (DLK) is required for the neuronal intrinsic immune response to induce cytokines and chemokines such as Ccl2, Ccl7, and Ccl12 upon nerve injury. The DLK-controlled injury response in sensory neurons could regulate CD11b+ immune cell infiltration in the dorsal root ganglia, as well as microgliosis and astrogliosis in the spinal dorsal horn but not the ventral horn. Deficiency of Dlk drastically alleviates the neuropathic pain elicited by chronic constriction injury of the sciatic nerve. Thus, DLK is an essential component that mediates the neuronal intrinsic immune response to nerve injury in sensory neurons and regulates inflammation in the spinal cord.


Assuntos
Inflamação/enzimologia , MAP Quinase Quinase Quinases/imunologia , Neuralgia/enzimologia , Neuralgia/imunologia , Células Receptoras Sensoriais/enzimologia , Animais , Inflamação/imunologia , Inflamação/patologia , MAP Quinase Quinase Quinases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/patologia , Neuroglia/patologia , Células Receptoras Sensoriais/imunologia , Células Receptoras Sensoriais/patologia
6.
J. optom. (Internet) ; 12(3): 198-207, jul.-sept. 2019.
Artigo em Espanhol | IBECS | ID: ibc-185371

RESUMO

Alzheimer's disease (AD) is a neurodegenerative dementia characterized by the deposition of extracellular β-amyloid (Aβ) plaques and the presence of neurofibrillary tangles. Until now, the techniques used to analyze these deposits have been difficult to access, invasive, and expensive. This leads us to consider new access routes to the central nervous system (CNS), allowing us to diagnose the disease before the first symptoms appear. Recent studies have shown that microglial and macroglial cell activation could play a role in the development of this disease. Glial cells in the CNS can respond to various damages, such as neurodegenerative pathologies, with morphological and functional changes. These changes are a common feature in neurodegenerative diseases, including AD. The retina is considered an extension of the CNS and has a population of glial cells similar to that of the CNS. When glial cells are activated, various molecules are released and changes in glial cell expression occur, which can be indicators of neuronal damage. The objective of this review is to compile the most relevant findings in the last 10 years relating to alterations in the eye in AD, and the role that glial cells play in the degenerative process in the retina in the context of neurodegeneration


La enfermedad de Alzheimer (EA) es una demencia neurodegenerativa que se caracteriza por la deposición de placas beta-amiloides (βA) extracelulares, y la presencia de ovillos neurofibrilares. Hasta ahora, las técnicas utilizadas para analizar estos depósitos han sido poco accesibles, invasivas y costosas. Esto nos lleva a considerar nuevas vías de acceso al sistema nervioso central (SNC) que nos permitan diagnosticar la enfermedad antes de la aparición de sus primeros síntomas. Los estudios recientes han reflejado que la activación de las células microgliales y macrogliales podría desempeñar un papel en el desarrollo de esta enfermedad. Las células gliales del SNC pueden responder a diversos daños, tales como patologías neurodegenerativas, con cambios morfológicos y funcionales. Dichos cambios son una característica común en las enfermedades neurodegenerativas, incluyendo la EA. La retina se considera una extensión del SNC, y cuenta con una población de células gliales similar a la de dicho sistema. Cuando las células gliales se activan, se liberan diversas moléculas, y se producen diversos cambios en la expresión de las células gliales, que pueden ser indicadores de daño neuronal. El objetivo de esta revisión es recopilar los hallazgos más relevantes de los últimos diez años, con relación a las alteraciones oculares en la EA, y el papel que juegan las células gliales en el proceso degenerativo de la retina en el contexto de la neurodegeneración


Assuntos
Humanos , Doença de Alzheimer/patologia , Neuroglia/patologia , Retina/patologia , Emaranhados Neurofibrilares/patologia
7.
Nat Commun ; 10(1): 3879, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462640

RESUMO

Traumatic spinal cord injury results in severe and irreversible loss of function. The injury triggers a complex cascade of inflammatory and pathological processes, culminating in formation of a scar. While traditionally referred to as a glial scar, the spinal injury scar in fact comprises multiple cellular and extracellular components. This multidimensional nature should be considered when aiming to understand the role of scarring in limiting tissue repair and recovery. In this Review we discuss recent advances in understanding the composition and phenotypic characteristics of the spinal injury scar, the oversimplification of defining the scar in binary terms as good or bad, and the development of therapeutic approaches to target scar components to enable improved functional outcome after spinal cord injury.


Assuntos
Cicatriz/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Animais , Astrócitos/patologia , Humanos , Inflamação , Neuroglia/patologia , Traumatismos da Medula Espinal/patologia , Regeneração da Medula Espinal , Cicatrização
8.
Int J Mol Sci ; 20(15)2019 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-31382568

RESUMO

(1) Background: Amyotrophic lateral sclerosis (ALS) is a multifactorial non-cell autonomous disease where activation of microglia and astrocytes largely contributes to motor neurons death. Heat shock proteins have been demonstrated to promote neuronal survival and exert a strong anti-inflammatory action in glia. Having previously shown that the pharmacological increase of the histamine content in the central nervous system (CNS) of SOD1-G93A mice decreases neuroinflammation, reduces motor neuron death, and increases mice life span, here we examined whether this effect could be mediated by an enhancement of the heat shock response. (2) Methods: Heat shock protein expression was analyzed in vitro and in vivo. Histamine was provided to primary microglia and NSC-34 motor neurons expressing the SOD1-G93A mutation. The brain permeable histamine precursor histidine was chronically administered to symptomatic SOD1-G93A mice. Spine density was measured by Golgi-staining in motor cortex of histidine-treated SOD1-G93A mice. (3) Results: We demonstrate that histamine activates the heat shock response in cultured SOD1-G93A microglia and motor neurons. In SOD1-G93A mice, histidine augments the protein content of GRP78 and Hsp70 in spinal cord and cortex, where the treatment also rescues type I motor neuron dendritic spine loss. (4) Conclusion: Besides the established histaminergic neuroprotective and anti-inflammatory effects, the induction of the heat shock response in the SOD1-G93A model by histamine confirms the importance of this pathway in the search for successful therapeutic solutions to treat ALS.


Assuntos
Resposta ao Choque Térmico/efeitos dos fármacos , Histamina/farmacologia , Neurônios Motores/efeitos dos fármacos , Superóxido Dismutase-1/genética , Esclerose Amiotrófica Lateral , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Morte Celular/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/genética , Modelos Animais de Doenças , Resposta ao Choque Térmico/genética , Humanos , Camundongos , Microglia/metabolismo , Microglia/patologia , Neurônios Motores/patologia , Mutação , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia
9.
Arch. Soc. Esp. Oftalmol ; 94(8): 405-408, ago. 2019. ilus
Artigo em Espanhol | IBECS | ID: ibc-185628

RESUMO

Paciente de 13 años de edad que presenta un escotoma del campo visual superior de 48 horas de evolución. Mejor agudeza visual corregida de 20/20 en ambos ojos. La exploración del fondo de ojo derecho reveló un asa vascular prepapilar torsionada asociada a un área de blanqueamiento retiniano y atenuación vascular tanto en el sector nasal como temporal, la cual no afectaba fóvea. Durante el seguimiento el asa vascular desaparece y es reemplazada por tejido glial sobre el disco óptico. La mejor agudeza visual corregida permaneció en 20/20. Este caso muestra el comportamiento del asa vascular posterior a la oclusión de la misma. La ausencia de flujo sanguíneo produce un colapso de las paredes arteriales, que con el tiempo llevan a la formación de tejido glial


We report the case of a 13-year-old patient who complains of an acute superior visual field scotoma in the last 48hours. Best corrected visual acuity (BCVA) was 20/20 in both eyes. The right eye fundus examination revealed torsion of a prepapillary loop in the inferior branch of the retinal artery, associated with a arterial vascular attenuation and whitenning of the inferior retina that involved both nasal and temporal branches but spared the foveal region. During the follow-up the vascular loop dissapeared and only glial tissue was seen in front of the optic nerve head. BCVA remained 20/20 in both eyes. This report shows the evolution of the vascular loop after an occlusion. The absence of blood flow produces a collapse of the arterial walls, in time the vascular loop is replaced by glial tissue


Assuntos
Humanos , Masculino , Adolescente , Anormalidades do Olho/complicações , Oclusão da Artéria Retiniana/etiologia , Vasos Retinianos/anormalidades , Malformações Vasculares/complicações , Velocidade do Fluxo Sanguíneo , Anormalidades do Olho/diagnóstico por imagem , Fundo de Olho , Neuroglia/patologia , Disco Óptico/diagnóstico por imagem , Disco Óptico/patologia , Artéria Retiniana/diagnóstico por imagem , Oclusão da Artéria Retiniana/diagnóstico por imagem , Vasos Retinianos/diagnóstico por imagem , Escotoma/complicações , Anormalidade Torcional/diagnóstico por imagem , Malformações Vasculares/diagnóstico por imagem , Acuidade Visual
10.
Nat Commun ; 10(1): 2966, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31273213

RESUMO

Mutations in genes encoding components of BAF (BRG1/BRM-associated factor) chromatin remodeling complexes cause neurodevelopmental disorders and tumors. The mechanisms leading to the development of these two disease entities alone or in combination remain unclear. We generated mice with a heterozygous nervous system-specific partial loss-of-function mutation in a BAF core component gene, Smarcb1. These Smarcb1 mutant mice show various brain midline abnormalities that are also found in individuals with Coffin-Siris syndrome (CSS) caused by SMARCB1, SMARCE1, and ARID1B mutations and in SMARCB1-related intellectual disability (ID) with choroid plexus hyperplasia (CPH). Analyses of the Smarcb1 mutant animals indicate that one prominent midline abnormality, corpus callosum agenesis, is due to midline glia aberrations. Our results establish a novel role of Smarcb1 in the development of the brain midline and have important clinical implications for BAF complex-related ID/neurodevelopmental disorders.


Assuntos
Anormalidades Múltiplas/genética , Agenesia do Corpo Caloso/genética , Corpo Caloso/crescimento & desenvolvimento , Face/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Proteína SMARCB1/genética , Anormalidades Múltiplas/diagnóstico por imagem , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/patologia , Alelos , Animais , Criança , Pré-Escolar , Corpo Caloso/citologia , Corpo Caloso/diagnóstico por imagem , Modelos Animais de Doenças , Embrião de Mamíferos , Face/diagnóstico por imagem , Feminino , Deformidades Congênitas da Mão/diagnóstico por imagem , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Mutação com Perda de Função , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Transgênicos , Micrognatismo/diagnóstico por imagem , Pescoço/diagnóstico por imagem , Neuroglia/patologia , Cultura Primária de Células
11.
Colloids Surf B Biointerfaces ; 182: 110355, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31306828

RESUMO

Inspired by the excellent membrane affinity of antimicrobial polymers, we synthesized a novel biodegradable poly(amino amine) polymer with pendent side chains that mimic the widely used biocide polyhexamethylene biguanide (PHMB) for gene delivery. Michael addition polymerization was utilized to form the polymer scaffold between N,N'-cystaminebisacrylamide (CBA) and N-Boc-1,6-diaminohexane (Boc-DAH) followed by N-Boc deprotection. Then the exposed primary amino groups were partly (about 75%) transformed into biguanide by an addition reaction with dicyandiamide to obtain the final product CBA-DAH-biguanide (CBA-DAH-BG). The polymer CBA-DAH-BG was able to condense plasmid DNA (pDNA) into nano-sized (<200 nm), positively-charged (>35 mV) polyplexes that were well resistant to heparin and DNase I. Rapid DNA release was observed in the presence of dithiothreitol (DTT), indicating that CBA-DAH-BG was equipped with biodegradability by the cleavage of disulfide bonds, which was helpful for unpacking DNA and decreasing cytotoxicity. CBA-DAH-BG/pDNA polyplexes were characterized by efficient cellular uptake efficacy, extremely low cytotoxicity, and high transfection efficiency in two cell lines (i.e., NIH/3T3 and U87 MG), compared to 25 kDa polyethyleneimine (PEI) and the intermediate product CBA-DAH that were both devoid of biguanide groups. Of note, clathrin-mediated endocytosis and lipid rafts played an important role in the internalization of the polyplexes. Taken together, this strategy described herein may represent an innovative avenue for the design of more advanced nonviral gene vectors with high transfection efficiency and biocompatibility.


Assuntos
Anti-Infecciosos/síntese química , Biguanidas/síntese química , Técnicas de Transferência de Genes , Plasmídeos/metabolismo , Polietilenoimina/química , Acrilamidas/química , Animais , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Biguanidas/metabolismo , Biguanidas/farmacologia , Linhagem Celular Tumoral , Desoxirribonuclease I/química , Diaminas/química , Ditiotreitol/química , Endocitose , Genes Reporter , Heparina/química , Hexanos/química , Humanos , Hidrólise , Luciferases/genética , Luciferases/metabolismo , Camundongos , Células NIH 3T3 , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Plasmídeos/química , Polietilenoimina/toxicidade
12.
Artigo em Inglês | MEDLINE | ID: mdl-31280243

RESUMO

Neurons have been considered the major functional entities of the nervous system that are responsible for most of the functions even though glial cells largely outnumber them. However, recent reports have proved that glial cells do not function just like glue in the nervous system but also substantially affect neuronal function and activities, and are significantly involved in the underlying pathobiology of various psychiatric disorders. Dysfunctional astrocytes and degeneration of glial cells are postulated to be critical factors contributing to the aggravation of depressive-like symptoms in humans, which was proved using animal models. Alteration in glial cell function predominantly targets three main brain regions - the prefrontal cortex, limbic areas including the hippocampus, and the amygdala, which have been extensively studied by various researchers across the globe. These studies have postulated that failure in adopting to the changing neurophysiology due to stress will lead to regressive plasticity in the hippocampus and prefrontal cortex, but to progressive plasticity in the amygdala. In this present review, an effort has been made to understand the different alterations in chronic stress models in correlation with clinical conditions, providing evidence on the defective maintenance of glial function and its potential role in the precipitation of neuropsychiatric disorders.


Assuntos
Depressão/patologia , Neuroglia/patologia , Animais , Astrócitos/patologia , Hipocampo/patologia , Humanos , Neurônios/patologia , Córtex Pré-Frontal/patologia
13.
Eur J Pharmacol ; 858: 172475, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31228456

RESUMO

The development of effective therapeutics for cancer-induced bone pain (CIBP) remains a tremendous challenge owing to its unclear mechanisms. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). Emerging studies have shown that disinhibition in the spinal cord dorsal horn may account for the development of chronic pain. However, the role of GABA in the development of CIBP remains elusive. In addition, accumulating evidence has shown that neuroglial cells in the peripheral nervous system, especially astrocytes and microglial cells, played an important role in the maintenance of CIBP. In this study, we investigated the expression of GABA and Gamma-aminobutyric acid transporter-1 (GAT-1), a transporter of GABA. Our results demonstrate that GABA was decreased in CIBP rats as expected. However, the expression of glutamic acid decarboxylase (GAD) 65 was up-regulated on day 21 after surgery, while the expression of GAD 67 remained unchanged after surgery. We also found that the expression of GAT-1 was up-regulated mainly in the astrocytes of the spinal cord. Moreover, we evaluated the analgesic effect of exogenous GABA and the GAT-1 inhibitor. Intrathecal administration of exogenous GABA and NO-711 (a GAT-1 selective inhibitor) significantly reversed CIBP-induced mechanical allodynia in a dose-dependent manner. These results firstly show that neuron-glia interactions, especially on the GABAergic pathway, contribute to the development of CIBP. In conclusion, exogenous GABA and GAT-1 inhibitor might be alternative therapeutic strategies for the treatment of CIBP.


Assuntos
Neoplasias Ósseas/complicações , Dor do Câncer/tratamento farmacológico , Dor do Câncer/patologia , Comunicação Celular/efeitos dos fármacos , Neuroglia/patologia , Neurônios/patologia , Ácido gama-Aminobutírico/farmacologia , Animais , Neoplasias Ósseas/secundário , Dor do Câncer/etiologia , Linhagem Celular Tumoral , Feminino , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glutamato Descarboxilase/metabolismo , Hiperalgesia/tratamento farmacológico , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/uso terapêutico
14.
Redox Biol ; 26: 101220, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31176262

RESUMO

Glioblastoma (GBM) has a poor prognosis despite intensive treatment with surgery and chemoradiotherapy. Previous studies using dose-escalated radiotherapy have demonstrated improved survival; however, increased rates of radionecrosis have limited its use. Development of radiosensitizers could improve patient outcome. In the present study, we report the use of sodium sulfide (Na2S), a hydrogen sulfide (H2S) donor, to selectively kill GBM cells (T98G and U87) while sparing normal human cerebral microvascular endothelial cells (hCMEC/D3). Na2S also decreased mitochondrial respiration, increased oxidative stress and induced γH2AX foci and oxidative base damage in GBM cells. Since Na2S did not significantly alter T98G capacity to perform non-homologous end-joining or base excision repair, it is possible that GBM cell killing could be attributed to increased damage induction due to enhanced reactive oxygen species production. Interestingly, Na2S enhanced mitochondrial respiration, produced a more reducing environment and did not induce high levels of DNA damage in hCMEC/D3. Taken together, this data suggests involvement of mitochondrial respiration in Na2S toxicity in GBM cells. The fact that survival of LN-18 GBM cells lacking mitochondrial DNA (ρ0) was not altered by Na2S whereas the survival of LN-18 ρ+ cells was compromised supports this conclusion. When cells were treated with Na2S and photon or proton radiation, GBM cell killing was enhanced, which opens the possibility of H2S being a radiosensitizer. Therefore, this study provides the first evidence that H2S donors could be used in GBM therapy to potentiate radiation-induced killing.


Assuntos
Reparo do DNA/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Mitocôndrias/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Sulfetos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular , Linhagem Celular Tumoral , Dano ao DNA , Reparo do DNA/efeitos da radiação , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/efeitos da radiação , Humanos , Sulfeto de Hidrogênio/química , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação , Neuroglia/patologia , Neuroglia/efeitos da radiação , Especificidade de Órgãos , Fosforilação Oxidativa/efeitos dos fármacos , Fosforilação Oxidativa/efeitos da radiação , Estresse Oxidativo , Fótons , Terapia com Prótons , Radiossensibilizantes/química , Espécies Reativas de Oxigênio/metabolismo , Sulfetos/química
15.
J Neurol ; 266(10): 2396-2405, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31190169

RESUMO

OBJECTIVE: To describe the clinical, biochemical, and neuropathological findings of an autosomal dominant globular glial tauopathy caused by the P301T mutation at the MAPT gene. METHODS: Five patients from two unrelated pedigrees underwent clinical evaluation. Genetic analysis, brain pathological examination, and biochemical analysis of tau were performed. RESULTS: The patients studied were 3 men and 2 women with a mean age at onset of 52.2 years and mean disease duration of 5.2 years. Three patients presented a corticobasal syndrome, one patient an asymmetric pyramidal syndrome compatible with primary lateral sclerosis, and one patient a frontotemporal dementia. In both pedigrees (4 patients) Sanger sequencing showed the p.P301T mutation in exon 10 of the MAPT gene. Neuropathological findings consisted of atrophy of frontal and temporal lobes with marked spongiosis and astrogliosis, and abundant phosphorylated tau protein deposits in the frontal and temporal cortex, limbic area, basal ganglia, and brain stem. The most striking finding was the presence of oligodendroglial 4R phospho-tau globular positive inclusions in the white matter and cortex. Globose-type neurofibrillary neuronal tangles, and in particular astrocytic globular inclusions and coarse tufts, were present in the grey matter. Biochemical analysis of sarkosyl-insoluble fractions revealed two tau bands of 64 and 68 kDa and case-dependent bands of lower molecular weight. CONCLUSION: This is the first pathological and biochemical study of the MAPT p.P301T mutation showing variable clinical manifestation and neuropathological phenotype of globular glial tauopathy not only among different families but also within families.


Assuntos
Substância Cinzenta , Neuroglia , Tauopatias , Substância Branca , Proteínas tau/metabolismo , Idoso , Feminino , Substância Cinzenta/metabolismo , Substância Cinzenta/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Neuroglia/metabolismo , Neuroglia/patologia , Linhagem , Espanha , Tauopatias/genética , Tauopatias/metabolismo , Tauopatias/patologia , Tauopatias/fisiopatologia , Substância Branca/metabolismo , Substância Branca/patologia , Proteínas tau/genética
16.
Cell Physiol Biochem ; 53(1): 76-86, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31192545

RESUMO

BACKGROUND/AIMS: Diabetes causes damage to the enteric nervous system. The enteric nervous system consists of neurons and enteric glial cells (EGCs). The present study evaluated the effects of an ethyl-acetate fraction (EAF) from Trichilia catigua (T. catigua; 200 mg/kg) on the total population of enteric neurons (HuC/D-immunoreactive [IR]) and EGCs (S100-IR and glial fibrillary acidic protein [GFAP]-IR) in the total preparation and jejunal mucosa in diabetic rats. METHODS: The animals were distributed into four groups: normoglycemic rats (N), diabetic rats (D), normoglycemic rats that received the EAF (NC), and diabetic rats that received the EAF (DC). The jejunum was processed for immunohistochemistry to evaluate HuC/D, S100, and GFAP immunoreactivity. The expression of S100 and GFAP proteins was also quantified by Western blot. RESULTS: The D group exhibited a decrease in the number of neurons and EGCs, an increase in the area of cell bodies, an increase in S100 protein expression, a decrease in GFAP protein expression, and a decrease in S100-IR and GFAP-IR EGCs in the jejunal mucosa. The DC group exhibited a decrease in the number of neurons and EGCs, a decrease in the area of cell bodies, a decrease in S100 and GFAP protein expression, and a decrease in S100-IR and GFAP-IR EGCs in the jejunal mucosa. The NC group exhibited maintenance of the number of neurons and EGCs, an increase in the area of cell bodies, and a decrease in S100 and GFAP protein expression. CONCLUSION: The EAF from T. catigua partially conferred protection against diabetic neuropathy in the enteric nervous system.


Assuntos
Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/prevenção & controle , Jejuno/inervação , Meliaceae/química , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Acetatos/química , Animais , Diabetes Mellitus Experimental/patologia , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/patologia , Sistema Nervoso Entérico/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/análise , Jejuno/efeitos dos fármacos , Jejuno/patologia , Masculino , Neuroglia/patologia , Neurônios/patologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Proteínas S100/análise
17.
Nat Commun ; 10(1): 2612, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197141

RESUMO

Primary microcephaly is caused by mutations in genes encoding centrosomal proteins including WDR62 and KIF2A. However, mechanisms underlying human microcephaly remain elusive. By creating mutant mice and human cerebral organoids, here we found that WDR62 deletion resulted in a reduction in the size of mouse brains and organoids due to the disruption of neural progenitor cells (NPCs), including outer radial glia (oRG). WDR62 ablation led to retarded cilium disassembly, long cilium, and delayed cell cycle progression leading to decreased proliferation and premature differentiation of NPCs. Mechanistically, WDR62 interacts with and promotes CEP170's localization to the basal body of primary cilium, where CEP170 recruits microtubule-depolymerizing factor KIF2A to disassemble cilium. WDR62 depletion reduced KIF2A's basal body localization, and enhanced KIF2A expression partially rescued deficits in cilium length and NPC proliferation. Thus, modeling microcephaly with cerebral organoids and mice reveals a WDR62-CEP170-KIF2A pathway promoting cilium disassembly, disruption of which contributes to microcephaly.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Cinesina/metabolismo , Microcefalia/patologia , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fosfoproteínas/metabolismo , Proteínas Repressoras/metabolismo , Animais , Técnicas de Cultura de Células , Proteínas de Ciclo Celular/genética , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Cílios/metabolismo , Modelos Animais de Doenças , Feminino , Técnicas de Inativação de Genes , Humanos , Masculino , Camundongos , Camundongos Knockout , Microcefalia/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas do Tecido Nervoso/genética , Células-Tronco Neurais/citologia , Células-Tronco Neurais/patologia , Neuroglia/citologia , Neuroglia/patologia , Organoides/patologia , Fosfoproteínas/genética , RNA Interferente Pequeno/metabolismo
18.
J Clin Neurosci ; 66: 196-201, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31147232

RESUMO

Alterations in the BRAF gene have been reported to play a key role in the tumorigenesis of various tumors. Recent studies have shown the existence of BRAF alterations in ganglioglioma (GG), pilocytic astrocytoma (PA), pleomorphic xanthoastrocytomas (PXA), and epithelioid glioblastoma (eGBM). The focus of this review was the association between the clinical characteristics and BRAF status in these glial and glioneuronal tumors. The BRAF abnormalities, KIAA1549-BRAF fusion and BRAF mutation, were detected in approximately 50% of the analyzed tumors regardless of the tumor location, and there were site-specific BRAF abnormalities that became more remarkable on analysis by each tumor subtype. The median age of patients with KIAA1549-BRAF fusion was much lesser than that of those with BRAF mutations. Histological analysis indicates that the existence of KIAA1549-BRAF fusion is related to pilocytic morphology. The review of imaging features indicated that cyst formation is associated with the existence of KIAA1549-BRAF fusion in PA and GG and the lack of BRAF mutation in GG. Hemorrhage was significantly present in cases of GG with KIAA1549-BRAF fusion, but no relevance was shown in cases with BRAF mutations. No significant relevance was detected between the presence of calcification and BRAF alterations. Our clinical and genetic review of BRAF-related tumors indicated that the KIAA1549-BRAF fusion was strongly associated with PA, but not with other glial and glioneuronal tumors.


Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Ganglioglioma/genética , Glioblastoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Astrocitoma/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Ganglioglioma/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Humanos , Mutação/genética , Neuroglia/patologia
19.
Mol Med Rep ; 20(2): 887-894, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173255

RESUMO

The purpose of the present study was to determine the effects of metformin on the inhibition of proliferation, apoptosis, invasion and migration of A172 human glioma cells in vitro and determine the underlying mechanism. The effects of metformin at different concentrations (0, 0.1, 1 and 10 mmol/l) on the inhibition of A172 cell proliferation were detected using a 3­(4,5­dimethylthiazol­2­yl)­2,5­diphenyltetrazolium bromide assay. Cell apoptosis was detected by flow cytometry. Caspase­3 activity was analyzed by spectrophotometry. The invasion and migration of cells were detected by Transwell assays. The levels of Bcl­2­associated X protein (Bax), B­cell lymphoma 2 (Bcl­2), AMP­activated protein kinase (AMPK), phosphorylated­(p)AMPK and mechanistic target of rapamycin (mTOR) protein expression were detected by western blot analysis, and changes in the malondialdehyde (MDA) content and activity of superoxide dismutase (SOD) were determined. Compared with the control group, metformin significantly increased the inhibition of proliferation and apoptosis, and significantly reduced the invasion and migration of A172 cells in dose­ and time­dependent manners (P<0.05). In addition, compared with the control group, metformin significantly enhanced the activity of caspase­3, increased the expression of AMPK/pAMPK/Bax proteins and reduced the expression of mTOR/Bcl­2 proteins (P<0.05). Metformin increased the MDA content and reduced the activity of SOD in a dose­dependent manner (P<0.05). Metformin may inhibit glioma cell proliferation, migration and invasion, and promote its apoptosis; the effects may be associated with the AMPK/mTOR signaling pathway and oxidative stress.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Neuroglia/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/genética , Caspase 3/genética , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Malondialdeído/agonistas , Malondialdeído/metabolismo , Neuroglia/metabolismo , Neuroglia/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
20.
Arch Soc Esp Oftalmol ; 94(8): 405-408, 2019 Aug.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31153658

RESUMO

We report the case of a 13-year-old patient who complains of an acute superior visual field scotoma in the last 48hours. Best corrected visual acuity (BCVA) was 20/20 in both eyes. The right eye fundus examination revealed torsion of a prepapillary loop in the inferior branch of the retinal artery, associated with a arterial vascular attenuation and whitenning of the inferior retina that involved both nasal and temporal branches but spared the foveal region. During the follow-up the vascular loop dissapeared and only glial tissue was seen in front of the optic nerve head. BCVA remained 20/20 in both eyes. This report shows the evolution of the vascular loop after an occlusion. The absence of blood flow produces a collapse of the arterial walls, in time the vascular loop is replaced by glial tissue.


Assuntos
Anormalidades do Olho/complicações , Oclusão da Artéria Retiniana/etiologia , Vasos Retinianos/anormalidades , Malformações Vasculares/complicações , Adolescente , Velocidade do Fluxo Sanguíneo , Anormalidades do Olho/diagnóstico por imagem , Fundo de Olho , Humanos , Masculino , Neuroglia/patologia , Disco Óptico/diagnóstico por imagem , Disco Óptico/patologia , Artéria Retiniana/diagnóstico por imagem , Oclusão da Artéria Retiniana/diagnóstico por imagem , Vasos Retinianos/diagnóstico por imagem , Escotoma/complicações , Anormalidade Torcional/diagnóstico por imagem , Malformações Vasculares/diagnóstico por imagem , Acuidade Visual
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