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  1 / 21697 MEDLINE  
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[PMID]:29217196
[Au] Autor:Kim M; Subramanian M; Cho YH; Kim GH; Lee E; Park JJ
[Ad] Endereço:Department of Preventive Medicine, College of Medicine, Korea University, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
[Ti] Título:Short-term exposure to dim light at night disrupts rhythmic behaviors and causes neurodegeneration in fly models of tauopathy and Alzheimer's disease.
[So] Source:Biochem Biophys Res Commun;495(2):1722-1729, 2018 01 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The accumulation and aggregation of phosphorylated tau proteins in the brain are the hallmarks for the onset of Alzheimer's disease (AD). In addition, disruptions in circadian rhythms (CRs) with altered sleep-wake cycles, dysregulation of locomotion, and increased memory defects have been reported in patients with AD. Drosophila flies that have an overexpression of human tau protein in neurons exhibit most of the symptoms of human patients with AD, including locomotion defects and neurodegeneration. Using the fly model for tauopathy/AD, we investigated the effects of an exposure to dim light at night on AD symptoms. We used a light intensity of 10 lux, which is considered the lower limit of light pollution in many countries. After the tauopathy flies were exposed to the dim light at night for 3 days, the flies showed disrupted CRs, altered sleep-wake cycles due to increased pTau proteins and neurodegeneration, in the brains of the AD flies. The results indicate that the nighttime exposure of tauopathy/AD model Drosophila flies to dim light disrupted CR and sleep-wake behavior and promoted neurodegeneration.
[Mh] Termos MeSH primário: Doença de Alzheimer/etiologia
Ritmo Circadiano/efeitos da radiação
Degeneração Neural/etiologia
Tauopatias/etiologia
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Encéfalo/metabolismo
Encéfalo/patologia
Ritmo Circadiano/fisiologia
Modelos Animais de Doenças
Drosophila melanogaster/fisiologia
Drosophila melanogaster/efeitos da radiação
Seres Humanos
Luz
Longevidade/genética
Longevidade/fisiologia
Masculino
Proteínas Mutantes/genética
Proteínas Mutantes/metabolismo
Degeneração Neural/metabolismo
Degeneração Neural/patologia
Fotoperíodo
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Transtornos do Sono-Vigília/etiologia
Proteínas tau/genética
Proteínas tau/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (MAPT protein, human); 0 (Mutant Proteins); 0 (Recombinant Proteins); 0 (tau Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE


  2 / 21697 MEDLINE  
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[PMID]:29338042
[Au] Autor:Rimkus SA; Wassarman DA
[Ad] Endereço:Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI.
[Ti] Título:A pharmacological screen for compounds that rescue the developmental lethality of a Drosophila ATM mutant.
[So] Source:PLoS One;13(1):e0190821, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ataxia-telangiectasia (A-T) is a neurodegenerative disease caused by mutation of the A-T mutated (ATM) gene. ATM encodes a protein kinase that is activated by DNA damage and phosphorylates many proteins, including those involved in DNA repair, cell cycle control, and apoptosis. Characteristic biological and molecular functions of ATM observed in mammals are conserved in Drosophila melanogaster. As an example, conditional loss-of-function ATM alleles in flies cause progressive neurodegeneration through activation of the innate immune response. However, unlike in mammals, null alleles of ATM in flies cause lethality during development. With the goals of understanding biological and molecular roles of ATM in a whole animal and identifying candidate therapeutics for A-T, we performed a screen of 2400 compounds, including FDA-approved drugs, natural products, and bioactive compounds, for modifiers of the developmental lethality caused by a temperature-sensitive ATM allele (ATM8) that has reduced kinase activity at non-permissive temperatures. Ten compounds reproducibly suppressed the developmental lethality of ATM8 flies, including Ronnel, which is an organophosphate. Ronnel and other suppressor compounds are known to cause mitochondrial dysfunction or to inhibit the enzyme acetylcholinesterase, which controls the levels of the neurotransmitter acetylcholine, suggesting that detrimental consequences of reduced ATM kinase activity can be rescued by inhibiting the function of mitochondria or increasing acetylcholine levels. We carried out further studies of Ronnel because, unlike the other compounds that suppressed the developmental lethality of homozygous ATM8 flies, Ronnel was toxic to the development of heterozygous ATM8 flies. Ronnel did not affect the innate immune response of ATM8 flies, and it further increased the already high levels of DNA damage in brains of ATM8 flies, but its effects were not harmful to the lifespan of rescued ATM8 flies. These results provide new leads for understanding the biological and molecular roles of ATM and for the treatment of A-T.
[Mh] Termos MeSH primário: Proteínas Mutadas de Ataxia Telangiectasia/genética
Drosophila melanogaster/efeitos dos fármacos
Drosophila melanogaster/genética
[Mh] Termos MeSH secundário: Alelos
Animais
Dano ao DNA
Proteínas de Drosophila/genética
Drosophila melanogaster/crescimento & desenvolvimento
Avaliação Pré-Clínica de Medicamentos/métodos
Feminino
Genes de Insetos/efeitos dos fármacos
Genes Letais/efeitos dos fármacos
Imunidade Inata/efeitos dos fármacos
Imunidade Inata/genética
Masculino
Mutação
Degeneração Neural/genética
Compostos Organotiofosforados/farmacologia
Fenótipo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Drosophila Proteins); 0 (Organothiophosphorus Compounds); 89RAG7SB3B (ronnel); EC 2.7.11.1 (ATM protein, Drosophila); EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180210
[Lr] Data última revisão:
180210
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180117
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190821


  3 / 21697 MEDLINE  
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[PMID]:28460881
[Au] Autor:Düsterhöft S; Künzel U; Freeman M
[Ad] Endereço:Dunn School of Pathology, University of Oxford, OX1 3RE, United Kingdom.
[Ti] Título:Rhomboid proteases in human disease: Mechanisms and future prospects.
[So] Source:Biochim Biophys Acta;1864(11 Pt B):2200-2209, 2017 11.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Rhomboids are intramembrane serine proteases that cleave the transmembrane helices of substrate proteins, typically releasing luminal/extracellular domains from the membrane. They are conserved in all branches of life and there is a growing recognition of their association with a wide range of human diseases. Human rhomboids, for example, have been implicated in cancer, metabolic disease and neurodegeneration, while rhomboids in apicomplexan parasites appear to contribute to their invasion of host cells. Recent advances in our knowledge of the structure and the enzyme function of rhomboids, and increasing efforts to identify specific inhibitors, are beginning to provide important insight into the prospect of rhomboids becoming future therapeutic targets. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.
[Mh] Termos MeSH primário: Filogenia
Proteólise
Serina Proteases/genética
[Mh] Termos MeSH secundário: Seres Humanos
Doenças Metabólicas/genética
Terapia de Alvo Molecular
Neoplasias/genética
Degeneração Neural/genética
Serina Proteases/uso terapêutico
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
EC 3.4.- (Serine Proteases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


  4 / 21697 MEDLINE  
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[PMID]:29261743
[Au] Autor:Bharani KL; Derex R; Granholm AC; Ledreux A
[Ad] Endereço:Department of Neurosciences, Medical University of South Carolina, BSB, Charleston, SC, United States of America.
[Ti] Título:A noradrenergic lesion aggravates the effects of systemic inflammation on the hippocampus of aged rats.
[So] Source:PLoS One;12(12):e0189821, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neuroinflammation is potentiated by early degeneration of the locus coeruleus noradrenergic pathway (LC-NE) commonly seen in aging-related neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In animal models, lipopolysaccharide (LPS) induces strong peripheral immune responses that can cause cognitive changes secondary to neuroinflammation. The influence of the peripheral immune response on cognition might be exacerbated by LC-NE degeneration, but this has not been well characterized previously. In this study, we investigated how systemic inflammation affects neuroinflammation and cognition in aged rats that have had either normal or damaged LC-NE transmitter systems. Rats were first exposed to the selective noradrenergic (NE) neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) to induce degeneration of central NE pathways. Two weeks later, the rats received a low dose of LPS. This resulted in 3 treatment groups (Control, LPS-, and DSP4+LPS-treated rats) studied at 4 hours (short-term subgroup) and 7 days (long-term subgroup) following the LPS injection. DSP4+LPS-treated rats exhibited increased serum levels of several pro-inflammatory cytokines, increased astroglial and microglial activation in the hippocampus, and poorer performance in the novel object recognition task (NORT) compared to controls and LPS-treated rats. Additionally, serum and brain tissue levels of brain-derived neurotrophic factor (BDNF) were modulated over time in the DSP4+LPS group compared to the other two groups. Specifically, DSP4+LPS-treated rats in the short-term subgroup had lower hippocampal BDNF levels (~25%) than controls and LPS-treated rats, which negatively correlated with hippocampal astrogliosis and positively correlated with hippocampal IL-1ß levels. Serum and hippocampal BDNF levels in the DSP4+LPS-treated rats in the long-term subgroup returned to levels similar to the control group. These results show that systemic inflammation in LC-NE-lesioned aged rats promotes an exacerbated systemic and central inflammatory response compared to LC-NE-intact rats and alters BDNF levels, indicating the important role of this neurotransmitter system in response to neuroinflammation.
[Mh] Termos MeSH primário: Envelhecimento/patologia
Hipocampo/patologia
Inflamação/patologia
Norepinefrina/metabolismo
[Mh] Termos MeSH secundário: Análise de Variância
Animais
Astrócitos/patologia
Benzilaminas
Fator Neurotrófico Derivado do Encéfalo/sangue
Fator Neurotrófico Derivado do Encéfalo/metabolismo
Proteínas de Ligação ao Cálcio/metabolismo
Quimiocinas/sangue
Discriminação (Psicologia)
Imunofluorescência
Proteína Glial Fibrilar Ácida/metabolismo
Hipocampo/fisiopatologia
Inflamação/sangue
Interleucina-1beta/metabolismo
Lipopolissacarídeos
Locomoção
Masculino
Proteínas dos Microfilamentos/metabolismo
Microglia/patologia
Degeneração Neural/patologia
Ratos Endogâmicos F344
Análise e Desempenho de Tarefas
Tirosina 3-Mono-Oxigenase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aif1 protein, rat); 0 (Benzylamines); 0 (Brain-Derived Neurotrophic Factor); 0 (Calcium-Binding Proteins); 0 (Chemokines); 0 (Glial Fibrillary Acidic Protein); 0 (Interleukin-1beta); 0 (Lipopolysaccharides); 0 (Microfilament Proteins); EC 1.14.16.2 (Tyrosine 3-Monooxygenase); PQ1P7JP5C1 (DSP 4); X4W3ENH1CV (Norepinephrine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189821


  5 / 21697 MEDLINE  
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[PMID]:28681915
[Au] Autor:Lu H; Ma K; Jin L; Zhu H; Cao R
[Ad] Endereço:Intensive Care Unit of Department of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
[Ti] Título:17ß-estradiol rescues damages following traumatic brain injury from molecule to behavior in mice.
[So] Source:J Cell Physiol;233(2):1712-1722, 2018 Feb.
[Is] ISSN:1097-4652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Traumatic brain injury (TBI) is a public health concern, and causes cognitive dysfunction, emotional disorders, and neurodegeration, as well. The currently available treatments are all symptom-oriented with unsatifying efficacy. It is highly demanded to understand its underlying mechanisms. Controlled cortical impact (CCI) was used to induce TBI in aged female mice subjected to ovariectomy. Brain damages were assessed with neurological severity score, brain infarction and edema. Morris water maze and elevated plus maze were applied to evaluate the levels of anxiety. Apoptosis in the hippocampus was assayed with Fluoro-Jade B staining and TUNEL staining. Western blot was employed to measure the expression of NMDA receptor subunits and phosphorylation of ERK1/2, and biochemical assays were used to estimate oxidative stress. 17beta-Estradiol (E2) was intraperitoneally administered at 10-80 µg/kg once per day for 7 consecutive days before or after CCI. Chronic administration of E2 both before and immediately after CCI conferred neuroprotection, reducing neurological severity score, brain infarction, and edema in TBI mice. Additionally, E2 improved many aspects of deleterious effects of TBI on the hippocampus, including neuronal apoptosis, dysfunction in spatial memory, reduction in NR2B, enhancement of oxidative stress, and activation of ERK1/2 pathway. The present study provides clue for the notion that E2 has therapeutic potential for both prevention and intervention of TBI-induced brain damages.
[Mh] Termos MeSH primário: Comportamento Animal/efeitos dos fármacos
Edema Encefálico/tratamento farmacológico
Infarto Encefálico/tratamento farmacológico
Lesões Encefálicas Traumáticas/tratamento farmacológico
Estradiol/farmacologia
Hipocampo/efeitos dos fármacos
Fármacos Neuroprotetores/farmacologia
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Edema Encefálico/metabolismo
Edema Encefálico/fisiopatologia
Edema Encefálico/psicologia
Infarto Encefálico/metabolismo
Infarto Encefálico/fisiopatologia
Infarto Encefálico/psicologia
Lesões Encefálicas Traumáticas/metabolismo
Lesões Encefálicas Traumáticas/fisiopatologia
Lesões Encefálicas Traumáticas/psicologia
Cognição/efeitos dos fármacos
Citoproteção
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Feminino
Hipocampo/metabolismo
Hipocampo/patologia
Hipocampo/fisiopatologia
Aprendizagem em Labirinto/efeitos dos fármacos
Memória/efeitos dos fármacos
Camundongos Endogâmicos C57BL
Degeneração Neural
Ovariectomia
Estresse Oxidativo/efeitos dos fármacos
Fosforilação
Receptores de N-Metil-D-Aspartato/metabolismo
Índice de Gravidade de Doença
Transdução de Sinais/efeitos dos fármacos
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NR2B NMDA receptor); 0 (Neuroprotective Agents); 0 (Receptors, N-Methyl-D-Aspartate); 4TI98Z838E (Estradiol); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE
[do] DOI:10.1002/jcp.26083


  6 / 21697 MEDLINE  
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[PMID]:28457579
[Au] Autor:Jacquemont T; De Vico Fallani F; Bertrand A; Epelbaum S; Routier A; Dubois B; Hampel H; Durrleman S; Colliot O; Alzheimer's Disease Neuroimaging Initiative
[Ad] Endereço:Inserm, U1127, Paris, France; CNRS, UMR 7225 ICM, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, Paris, France; Inria, Aramis project-team, Centre de Recherche de Paris, France; Département de Biologie, Ecole nor
[Ti] Título:Amyloidosis and neurodegeneration result in distinct structural connectivity patterns in mild cognitive impairment.
[So] Source:Neurobiol Aging;55:177-189, 2017 Jul.
[Is] ISSN:1558-1497
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Alzheimer's disease (AD) is increasingly considered as a disconnection syndrome. Previous studies of the structural connectome in early AD stages have focused on mild cognitive impaired subjects (MCI), considering them as a homogeneous group. We studied 168 subjects from the Alzheimer's Disease Neuroimaging Initiative database (116 MCI and 52 cognitively normal subjects). Biomarker-based stratification using amyloid biomarkers (AV45 PET) and neurodegeneration biomarkers (MRI and FDG PET) led to 4 subgroups based on amyloid positivity (A+/-) and neurodegeneration positivity (N+/-): A-N-, A+N-, A-N+, and A+N+. Using diffusion MRI, we showed that both MCI A-N+ and MCI A+N+ subjects displayed an alteration of the white matter in the fornix and a significant bihemispheric network of decreased connections. These network alterations in MCI A+N+ are stronger and more focal than those of MCI A-N+. Only MCI A+N+ subjects exhibited specific changes in hippocampal connectivity and an AD-like alteration pattern. Our results indicate that the connectome disintegration pattern of MCI subgroups differ with respect to brain amyloid and neurodegeneration. Each of these 2 AD biomarkers induces a connectome alteration that is maximal when they coexist.
[Mh] Termos MeSH primário: Doença de Alzheimer/complicações
Angiopatia Amiloide Cerebral/complicações
Cognição/fisiologia
Disfunção Cognitiva/etiologia
Disfunção Cognitiva/psicologia
Degeneração Neural/complicações
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Doença de Alzheimer/diagnóstico por imagem
Biomarcadores
Angiopatia Amiloide Cerebral/diagnóstico por imagem
Disfunção Cognitiva/diagnóstico por imagem
Disfunção Cognitiva/patologia
Conectoma
Imagem de Difusão por Ressonância Magnética
Feminino
Hipocampo/diagnóstico por imagem
Hipocampo/fisiopatologia
Seres Humanos
Masculino
Meia-Idade
Degeneração Neural/diagnóstico por imagem
Tomografia por Emissão de Pósitrons
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


  7 / 21697 MEDLINE  
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[PMID]:29050386
[Au] Autor:Tong J; Rathitharan G; Meyer JH; Furukawa Y; Ang LC; Boileau I; Guttman M; Hornykiewicz O; Kish SJ
[Ad] Endereço:Preclinical Imaging Unit, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
[Ti] Título:Brain monoamine oxidase B and A in human parkinsonian dopamine deficiency disorders.
[So] Source:Brain;140(9):2460-2474, 2017 Sep 01.
[Is] ISSN:1460-2156
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:See Jellinger (doi:10.1093/awx190) for a scientific commentary on this article. The enzyme monoamine oxidases (B and A subtypes, encoded by MAOB and MAOA, respectively) are drug targets in the treatment of Parkinson's disease. Inhibitors of MAOB are used clinically in Parkinson's disease for symptomatic purposes whereas the potential disease-modifying effect of monoamine oxidase inhibitors is debated. As astroglial cells express high levels of MAOB, the enzyme has been proposed as a brain imaging marker of astrogliosis, a cellular process possibly involved in Parkinson's disease pathogenesis as elevation of MAOB in astrocytes might be harmful. Since brain monoamine oxidase status in Parkinson's disease is uncertain, our objective was to measure, by quantitative immunoblotting in autopsied brain homogenates, protein levels of both monoamine oxidases in three different degenerative parkinsonian disorders: Parkinson's disease (n = 11), multiple system atrophy (n = 11), and progressive supranuclear palsy (n = 16) and in matched controls (n = 16). We hypothesized that if MAOB is 'substantially' localized to astroglial cells, MAOB levels should be generally associated with standard astroglial protein measures (e.g. glial fibrillary acidic protein). MAOB levels were increased in degenerating putamen (+83%) and substantia nigra (+10%, non-significant) in multiple system atrophy; in caudate (+26%), putamen (+27%), frontal cortex (+31%) and substantia nigra (+23%) of progressive supranuclear palsy; and in frontal cortex (+33%), but not in substantia nigra of Parkinson's disease, a region we previously reported no increase in astrocyte protein markers. Although the magnitude of MAOB increase was less than those of standard astrocytic markers, significant positive correlations were observed amongst the astrocyte proteins and MAOB. Despite suggestions that MAOA (versus MAOB) is primarily responsible for metabolism of dopamine in dopamine neurons, there was no loss of the enzyme in the parkinsonian substantia nigra; instead, increased nigral levels of a MAOA fragment and 'turnover' of the enzyme were observed in the conditions. Our findings provide support that MAOB might serve as a biochemical imaging marker, albeit not entirely specific, for astrocyte activation in human brain. The observation that MAOB protein concentration is generally increased in degenerating brain areas in multiple system atrophy (especially putamen) and in progressive supranuclear palsy, but not in the nigra in Parkinson's disease, also distinguishes astrocyte behaviour in Parkinson's disease from that in the two 'Parkinson-plus' conditions. The question remains whether suppression of either MAOB in astrocytes or MAOA in dopamine neurons might influence progression of the parkinsonian disorders.
[Mh] Termos MeSH primário: Encéfalo/enzimologia
Dopamina/deficiência
Monoaminoxidase/metabolismo
Atrofia de Múltiplos Sistemas/metabolismo
Doença de Parkinson/metabolismo
Paralisia Supranuclear Progressiva/metabolismo
[Mh] Termos MeSH secundário: Adolescente
Adulto
Estudos de Casos e Controles
Núcleo Caudado/metabolismo
Feminino
Lobo Frontal/metabolismo
Proteína Glial Fibrilar Ácida/metabolismo
Seres Humanos
Isoenzimas/metabolismo
Masculino
Meia-Idade
Atrofia de Múltiplos Sistemas/patologia
Degeneração Neural/patologia
Doença de Parkinson/patologia
Fragmentos de Peptídeos/metabolismo
Fosfopiruvato Hidratase/metabolismo
Putamen/metabolismo
Substância Negra/metabolismo
Paralisia Supranuclear Progressiva/patologia
Tubulina (Proteína)/metabolismo
Adulto Jovem
alfa-Sinucleína/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glial Fibrillary Acidic Protein); 0 (Isoenzymes); 0 (Peptide Fragments); 0 (Tubulin); 0 (alpha-Synuclein); EC 1.4.3.4 (Monoamine Oxidase); EC 4.2.1.11 (Phosphopyruvate Hydratase); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171021
[St] Status:MEDLINE
[do] DOI:10.1093/brain/awx172


  8 / 21697 MEDLINE  
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[PMID]:29024661
[Au] Autor:Pease-Raissi SE; Pazyra-Murphy MF; Li Y; Wachter F; Fukuda Y; Fenstermacher SJ; Barclay LA; Bird GH; Walensky LD; Segal RA
[Ad] Endereço:Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Departments of Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
[Ti] Título:Paclitaxel Reduces Axonal Bclw to Initiate IP R1-Dependent Axon Degeneration.
[So] Source:Neuron;96(2):373-386.e6, 2017 Oct 11.
[Is] ISSN:1097-4199
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of many cancer treatments. The hallmark of CIPN is degeneration of long axons required for transmission of sensory information; axonal degeneration causes impaired tactile sensation and persistent pain. Currently the molecular mechanisms of CIPN are not understood, and there are no available treatments. Here we show that the chemotherapeutic agent paclitaxel triggers CIPN by altering IP receptor phosphorylation and intracellular calcium flux, and activating calcium-dependent calpain proteases. Concomitantly paclitaxel impairs axonal trafficking of RNA-granules and reduces synthesis of Bclw (bcl2l2), a Bcl2 family member that binds IP R1 and restrains axon degeneration. Surprisingly, Bclw or a stapled peptide corresponding to the Bclw BH4 domain interact with axonal IP R1 and prevent paclitaxel-induced degeneration, while Bcl2 and Bclx cannot do so. Together these data identify a Bclw-IP R1-dependent cascade that causes axon degeneration and suggest that Bclw-mimetics could provide effective therapy to prevent CIPN.
[Mh] Termos MeSH primário: Axônios/metabolismo
Receptores de Inositol 1,4,5-Trifosfato/metabolismo
Degeneração Neural/induzido quimicamente
Degeneração Neural/metabolismo
Paclitaxel/toxicidade
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Antineoplásicos Fitogênicos/toxicidade
Axônios/efeitos dos fármacos
Axônios/patologia
Células Cultivadas
Feminino
Gânglios Espinais/efeitos dos fármacos
Gânglios Espinais/metabolismo
Gânglios Espinais/patologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Degeneração Neural/patologia
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Phytogenic); 0 (Bcl2l2 protein, rat); 0 (Inositol 1,4,5-Trisphosphate Receptors); 0 (Itpr1 protein, rat); 0 (Proto-Oncogene Proteins c-bcl-2); P88XT4IS4D (Paclitaxel)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171111
[Lr] Data última revisão:
171111
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171013
[St] Status:MEDLINE


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[PMID]:28980003
[Au] Autor:Kitaoka Y; Sase K; Tsukahara C; Kojima K; Shiono A; Kogo J; Tokuda N; Takagi H
[Ad] Endereço:Department of Ophthalmology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
[Ti] Título:Axonal Protection by Ripasudil, a Rho Kinase Inhibitor, via Modulating Autophagy in TNF-Induced Optic Nerve Degeneration.
[So] Source:Invest Ophthalmol Vis Sci;58(12):5056-5064, 2017 Oct 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: The Rho kinase inhibitor ripasudil decreases intraocular pressure, although its role in optic nerve axonal damage should be clarified. We therefore investigated whether ripasudil modulates TNF-induced axonal loss and affects autophagy machinery after the induction of optic nerve degeneration. Methods: Rats were given intravitreal injection of TNF, concomitant injection of ripasudil hydrochloride hydrate and TNF, or ripasudil alone. Axon numbers were counted to evaluate the effects of ripasudil against axon loss. Immunoblot analysis was performed to examine p62 as well as LC3-II expression in optic nerves. Electron microscopy was used to determine autophagosome numbers in axons and glia. Immunogold labeling was performed to evaluate autophagosomes in axons. Results: Ripasudil injected intravitreally resulted in significant neuroprotection against TNF-induced axon loss. Intravitreal TNF injection upregulated p62 in the optic nerve, but ripasudil completely inhibited this increment. The ripasudil alone injection diminished p62 and enhanced LC3-II protein levels significantly compared with baseline. Ripasudil-induced upregulation of LC3-II was seen after TNF injection, and immunohistochemical analysis revealed that LC3 colocalized in nerve fibers. Electron microscopic analysis revealed that autophagosomes were present in axons and glia, although autophagosome numbers increased significantly after ripasudil injection only in axons. Conclusions: These results suggest that ripasudil-enhanced intra-axonal autophagy is at least partly involved in axonal protection.
[Mh] Termos MeSH primário: Autofagia/efeitos dos fármacos
Axônios/efeitos dos fármacos
Isoquinolinas/farmacologia
Degeneração Neural/prevenção & controle
Fármacos Neuroprotetores/farmacologia
Doenças do Nervo Óptico/prevenção & controle
Sulfonamidas/farmacologia
Quinases Associadas a rho/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Axônios/patologia
Contagem de Células
Citoproteção
Modelos Animais de Doenças
Immunoblotting
Injeções Intravítreas
Masculino
Proteínas Associadas aos Microtúbulos/metabolismo
Degeneração Neural/metabolismo
Degeneração Neural/patologia
Doenças do Nervo Óptico/metabolismo
Doenças do Nervo Óptico/patologia
Ratos
Ratos Wistar
Proteína Sequestossoma-1/metabolismo
Fator de Necrose Tumoral alfa/toxicidade
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Isoquinolines); 0 (K-115); 0 (LC3 protein, rat); 0 (Microtubule-Associated Proteins); 0 (Neuroprotective Agents); 0 (Sequestosome-1 Protein); 0 (Sqstm1 protein, rat); 0 (Sulfonamides); 0 (Tumor Necrosis Factor-alpha); EC 2.7.11.1 (rho-Associated Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171006
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.17-22000


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[PMID]:28951257
[Au] Autor:Meyer M; Garay LI; Kruse MS; Lara A; Gargiulo-Monachelli G; Schumacher M; Guennoun R; Coirini H; De Nicola AF; Gonzalez Deniselle MC
[Ad] Endereço:Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina.
[Ti] Título:Protective effects of the neurosteroid allopregnanolone in a mouse model of spontaneous motoneuron degeneration.
[So] Source:J Steroid Biochem Mol Biol;174:201-216, 2017 Nov.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by progressive death of motoneurons. The Wobbler (WR) mouse is a preclinical model sharing neuropathological similarities with human ALS. We have shown that progesterone (PROG) prevents the progression of motoneuron degeneration. We now studied if allopregnanolone (ALLO), a reduced metabolite of PROG endowed with gabaergic activity, also prevents WR neuropathology. Sixty-day old WRs remained untreated or received two steroid treatment regimens in order to evaluate the response of several parameters during early or prolonged steroid administration. ALLO was administered s.c. daily for 5days (4mg/kg) or every other day for 32days (3, 3mg/kg), while another group of WRs received a 20mg PROG pellet s.c. for 18 or 60days. ALLO administration to WRs increased ALLO serum levels without changing PROG and 5 alpha dihydroprogesterone (5α-DHP), whereas PROG treatment increased PROG, 5α-DHP and ALLO. Untreated WRs showed higher basal levels of serum 5α-DHP than controls. In the cervical spinal cord we studied markers of oxidative stress or associated to trophic responses. These included nitric oxide synthase (NOS) activity, motoneuron vacuolation, MnSOD immunoreactivity (IR), brain derived neurotrophic factor (BDNF) and TrkB mRNAs, p75 neurotrophin receptor (p75NTR) and, cell survival or death signals such as pAKT and the stress activated kinase JNK. Untreated WRs showed a reduction of MnSOD-IR and BDNF/TrkB mRNAs, associated to high p75NTR in motoneurons, neuronal and glial NOS hyperactivity and neuronal vacuolation. Also, low pAKT, mainly in young WRs, and a high pJNK in the old stage characterized WRs spinal cord. Except for MnSOD and BDNF, these alterations were prevented by an acute ALLO treatment, while short-term PROG elevated MnSOD. Moreover, after chronic administration both steroids enhanced MnSOD-IR and BDNF mRNA, while attenuated pJNK and NOS in glial cells. Long-term PROG also increased pAKT and reduced neuronal NOS, parameters not modulated by chronic ALLO. Clinically, both steroids improved muscle performance. Thus, ALLO was able to reduce neuropathology in this model. Since high oxidative stress activates p75NTR and pJNK in neurodegeneration, steroid reduction of these molecules may provide adequate neuroprotection. These data yield the first evidence that ALLO, a gabaergic neuroactive steroid, brings neuroprotection in a model of motoneuron degeneration.
[Mh] Termos MeSH primário: Degeneração Neural/tratamento farmacológico
Fármacos Neuroprotetores/uso terapêutico
Pregnanolona/uso terapêutico
[Mh] Termos MeSH secundário: Esclerose Amiotrófica Lateral
Animais
Fator Neurotrófico Derivado do Encéfalo/genética
Colina O-Acetiltransferase/metabolismo
Modelos Animais de Doenças
Feminino
Masculino
Camundongos
Neurônios Motores/efeitos dos fármacos
Neurônios Motores/patologia
Degeneração Neural/genética
Degeneração Neural/metabolismo
Fármacos Neuroprotetores/sangue
Fármacos Neuroprotetores/farmacologia
Óxido Nítrico Sintase/metabolismo
Pregnanolona/sangue
Pregnanolona/farmacologia
Progesterona/sangue
Progesterona/farmacologia
Progesterona/uso terapêutico
Receptor trkB/genética
Receptores de Fator de Crescimento Neural/metabolismo
Medula Espinal/metabolismo
Medula Espinal/patologia
Superóxido Dismutase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Brain-Derived Neurotrophic Factor); 0 (Neuroprotective Agents); 0 (Receptors, Nerve Growth Factor); 0 (TNFRSF16 protein, mouse); 4G7DS2Q64Y (Progesterone); BXO86P3XXW (Pregnanolone); EC 1.14.13.39 (Nitric Oxide Synthase); EC 1.15.1.1 (Superoxide Dismutase); EC 2.3.1.6 (Choline O-Acetyltransferase); EC 2.7.10.1 (Receptor, trkB)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170928
[St] Status:MEDLINE



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