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1.
Neurology ; 94(4): e397-e406, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31888974

RESUMO

OBJECTIVE: To determine the temporal sequence of objectively defined subtle cognitive difficulties (Obj-SCD) in relation to amyloidosis and neurodegeneration, the current study examined the trajectories of amyloid PET and medial temporal neurodegeneration in participants with Obj-SCD relative to cognitively normal (CN) and mild cognitive impairment (MCI) groups. METHOD: A total of 747 Alzheimer's Disease Neuroimaging Initiative participants (305 CN, 153 Obj-SCD, 289 MCI) underwent neuropsychological testing and serial amyloid PET and structural MRI examinations. Linear mixed effects models examined 4-year rate of change in cortical 18F-florbetapir PET, entorhinal cortex thickness, and hippocampal volume in those classified as Obj-SCD and MCI relative to CN. RESULT: Amyloid accumulation was faster in the Obj-SCD group than in the CN group; the MCI and CN groups did not significantly differ from each other. The Obj-SCD and MCI groups both demonstrated faster entorhinal cortical thinning relative to the CN group; only the MCI group exhibited faster hippocampal atrophy than CN participants. CONCLUSION: Relative to CN participants, Obj-SCD was associated with faster amyloid accumulation and selective vulnerability of entorhinal cortical thinning, whereas MCI was associated with faster entorhinal and hippocampal atrophy. Findings suggest that Obj-SCD, operationally defined using sensitive neuropsychological measures, can be identified prior to or during the preclinical stage of amyloid deposition. Further, consistent with the Braak neurofibrillary staging scheme, Obj-SCD status may track with early entorhinal pathologic changes, whereas MCI may track with more widespread medial temporal change. Thus, Obj-SCD may be a sensitive and noninvasive predictor of encroaching amyloidosis and neurodegeneration, prior to frank cognitive impairment associated with MCI.


Assuntos
Peptídeos beta-Amiloides/análise , Encéfalo/patologia , Disfunção Cognitiva/etiologia , Diagnóstico Precoce , Degeneração Neural/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/diagnóstico , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Degeneração Neural/patologia , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons
2.
J Ethnopharmacol ; 247: 112299, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31606537

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Hua-Feng-Dan (HFD) is a traditional Chinese medicine used for neurological disorders. HFD contains cinnabar (HgS) and realgar (As4S4). The ethnopharmacological basis of cinnabar and realgar in HFD is not known. AIM OF THE STUDY: To address the role of cinnabar and realgar in HFD-produced neuroprotection against neurodegenerative diseases and disturbance of gut microbiota. MATERIALS AND METHODS: Lipopolysaccharide (LPS) plus rotenone (ROT)-elicited rat dopaminergic (DA) neuronal damage loss was performed as a Parkinson's disease animal model. Rats were given a single injection of LPS. Four months later, rats were challenged with the threshold dose of ROT. The clinical dose of HFD was administered via feed, starting from ROT administration for 46 days. Behavioral dysfunction was detected by rotarod and Y-maze tests. DA neuron loss and microglial activation were assessed via immunohistochemical staining and western bolt analysis. The colon content was collected to extract bacterial DNA followed by real-time PCR analysis with 16S rRNA primers. RESULTS: LPS plus ROT induced neurotoxicity, as evidenced by DA neuron loss in substantia nigra, impaired behavioral functions and increased microglial activation. HFD-original (containing 10% cinnabar and 10% realgar) rescued loss of DA neurons, improved behavioral dysfunction and attenuated microglial activation. Compared with HFD-original, HFD-reduced (3% cinnabar and 3% realgar) was also effective, but to be a less extent, while HFD-removed (without cinnabar and realgar) was ineffective. In analysis of gut microbiome, the increased Verrucomicrobiaceae and Lactobacteriaceae, and the decreased Enterobacteeriaceae by LPS plus ROT were ameliorated by HFD-original, and to be the less extent by HFD-reduced. CONCLUSION: Cinnabar and realgar are active ingredients in HFD to exert beneficial effects in a neurodegenerative model and gut microbiota.


Assuntos
Arsenicais/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Compostos de Mercúrio/farmacologia , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/tratamento farmacológico , Sulfetos/farmacologia , Animais , Arsenicais/química , Arsenicais/uso terapêutico , DNA Bacteriano/isolamento & purificação , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/genética , Enterobacteriaceae/isolamento & purificação , Etnofarmacologia , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/imunologia , Humanos , Mediadores da Inflamação/metabolismo , Lactobacillaceae/efeitos dos fármacos , Lactobacillaceae/genética , Lactobacillaceae/isolamento & purificação , Lipopolissacarídeos/toxicidade , Masculino , Compostos de Mercúrio/química , Compostos de Mercúrio/uso terapêutico , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/patologia , Degeneração Neural , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/imunologia , Síndromes Neurotóxicas/patologia , RNA Ribossômico 16S/genética , Ratos , Rotenona/toxicidade , Sulfetos/química , Sulfetos/uso terapêutico , Verrucomicrobia/efeitos dos fármacos , Verrucomicrobia/genética , Verrucomicrobia/isolamento & purificação
3.
Invest Ophthalmol Vis Sci ; 60(14): 4606-4618, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31756254

RESUMO

Purpose: To investigate the neuroprotective effects of Lycium barbarum polysaccharides (LBP) against chronic ocular hypertension (OHT) in rats and to consider if effects differed when treatment was applied before (pretreatment) or during (posttreatment) chronic IOP elevation. Methods: Sprague-Dawley rats (10-weeks old) underwent suture implantation around the limbus for 15 weeks (OHT) or 1 day (sham). Four experimental groups were studied, three OHT groups (n = 8 each) treated either with vehicle (PBS), LBP pretreatment or posttreatment, and a sham control (n = 5) received no treatment. LBP (1 mg/kg) pre- and posttreatment were commenced at 1 week before and 4 weeks after OHT induction, respectively. Treatments continued up through week 15. IOP was monitored twice weekly for 15 weeks. Optical coherence tomography and ERG were measured at baseline, week 4, 8, 12, and 15. Eyes were collected for ganglion cell layer (GCL) histologic analysis at week 15. Results: Suture implantation successfully induced approximately 50% IOP elevation and the cumulative IOP was similar between the three OHT groups. When compared with vehicle control (week 4: -23 ± 5%, P = 0.03), LBP pretreatment delayed the onset of retinal nerve fiber layer (RNFL) thinning (week 4, 8: -2 ± 7%, -11 ± 3%, P > 0.05) and arrested further reduction up through week 15 (-10 ± 4%, P > 0.05). LBP posttreatment intervention showed no significant change in rate of loss (week 4, 15: -25 ± 4.1%, -28 ± 3%). However, both LBP treatments preserved the retinal ganglion cells (RGC) and retinal functions up to week 15, which were significantly reduced in vehicle control. Conclusions: LBP posttreatment arrested the subsequent neuronal degeneration after treatment commencement and preserved RGC density and retinal functions in a chronic OHT model, which was comparable with pretreatment outcomes.


Assuntos
Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Degeneração Neural/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Hipertensão Ocular/tratamento farmacológico , Animais , Doença Crônica , Eletrorretinografia , Feminino , Pressão Intraocular/fisiologia , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Fibras Nervosas/patologia , Hipertensão Ocular/metabolismo , Hipertensão Ocular/fisiopatologia , Ratos , Ratos Sprague-Dawley , Retina/fisiopatologia , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica
4.
Nat Neurosci ; 22(11): 1793-1805, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31591561

RESUMO

Neuromuscular junction (NMJ) disruption is an early pathogenic event in amyotrophic lateral sclerosis (ALS). Yet, direct links between NMJ pathways and ALS-associated genes such as FUS, whose heterozygous mutations cause aggressive forms of ALS, remain elusive. In a knock-in Fus-ALS mouse model, we identified postsynaptic NMJ defects in newborn homozygous mutants that were attributable to mutant FUS toxicity in skeletal muscle. Adult heterozygous knock-in mice displayed smaller neuromuscular endplates that denervated before motor neuron loss, which is consistent with 'dying-back' neuronopathy. FUS was enriched in subsynaptic myonuclei, and this innervation-dependent enrichment was distorted in FUS-ALS. Mechanistically, FUS collaborates with the ETS transcription factor ERM to stimulate transcription of acetylcholine receptor genes. Co-cultures of induced pluripotent stem cell-derived motor neurons and myotubes from patients with FUS-ALS revealed endplate maturation defects due to intrinsic FUS toxicity in both motor neurons and myotubes. Thus, FUS regulates acetylcholine receptor gene expression in subsynaptic myonuclei, and muscle-intrinsic toxicity of ALS mutant FUS may contribute to dying-back motor neuronopathy.


Assuntos
Esclerose Amiotrófica Lateral/fisiopatologia , Regulação da Expressão Gênica/fisiologia , Degeneração Neural/fisiopatologia , Junção Neuromuscular/metabolismo , Proteína FUS de Ligação a RNA/fisiologia , Adulto , Esclerose Amiotrófica Lateral/patologia , Animais , Células Cultivadas , Feminino , Técnicas de Introdução de Genes , Humanos , Masculino , Camundongos , Camundongos Knockout , Neurônios Motores/patologia , Fibras Musculares Esqueléticas/patologia , Junção Neuromuscular/patologia , Proteína FUS de Ligação a RNA/genética , Proteína FUS de Ligação a RNA/metabolismo , Receptores Colinérgicos/metabolismo , Adulto Jovem
5.
Neurology ; 93(17): e1635-e1646, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31597710

RESUMO

OBJECTIVE: To apply the ATN scheme to memory clinic patients, to assess whether it discriminates patient populations with specific features. METHODS: We included 305 memory clinic patients (33% subjective cognitive decline [SCD]: 60 ± 9 years, 61% M; 19% mild cognitive impairment [MCI]: 68 ± 9 years, 68% M; 48% dementia: 66 ± 10 years, 58% M) classified for positivity (±) of amyloid (A) ([18F]Florbetaben PET), tau (T) (CSF p-tau), and neurodegeneration (N) (medial temporal lobe atrophy). We assessed ATN profiles' demographic, clinical, and cognitive features at baseline, and cognitive decline over time. RESULTS: The proportion of A+T+N+ patients increased with syndrome severity (from 1% in SCD to 14% in MCI and 35% in dementia), while the opposite was true for A-T-N- (from 48% to 19% and 6%). Compared to A-T-N-, patients with the Alzheimer disease profiles (A+T+N- and A+T+N+) were older (both p < 0.05) and had a higher prevalence of APOE ε4 (both p < 0.05) and lower Mini-Mental State Examination (MMSE) (both p < 0.05), memory (both p < 0.05), and visuospatial abilities (both p < 0.05) at baseline. Non-Alzheimer profiles A-T-N+ and A-T+N+ showed more severe white matter hyperintensities (both p < 0.05) and worse language performance (both p < 0.05) than A-T-N-. A linear mixed model showed faster decline on MMSE over time in A+T+N- and A+T+N+ (p = 0.059 and p < 0.001 vs A-T-N-), attributable mainly to patients without dementia. CONCLUSIONS: The ATN scheme identified different biomarker profiles with overlapping baseline features and patterns of cognitive decline. The large number of profiles, which may have different implications in patients with vs without dementia, poses a challenge to the application of the ATN scheme.


Assuntos
Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Demência/diagnóstico por imagem , Idoso , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquidiano , Encéfalo/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Demência/genética , Demência/metabolismo , Diagnóstico Diferencial , Feminino , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Degeneração Neural/diagnóstico por imagem , Degeneração Neural/metabolismo , Tomografia por Emissão de Pósitrons , Estudos Prospectivos , Proteínas tau/metabolismo
6.
J Hum Genet ; 64(11): 1145-1151, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31515523

RESUMO

More than 80 known or suspected genes/loci have been reported to be involved in hereditary spastic paraplegia (HSP). Genetic and clinical overlap have been reported between HSP and other neurological condition, yet about 50% of HSP patients remain genetically undiagnosed. To identify novel genes involved in HSP, we performed a genetic analysis of 383 HSP patients from 289 families with HSP. Two patients with biallelic SPTAN1 variants were identified; one carried the c.2572G>T p.(Ala858Ser) and c.4283C>G p.(Ala1428Gly) variants, and the second also carried the c.2572G>T p.(Ala858Ser) variant, and an additional variant, c.6990G>C p.(Met2330Ile). In silico predictive and structural analyses suggested that these variants are likely to be deleterious. SPTAN1 was highly intolerant for functional variants (in the top 0.31% of intolerant genes) with much lower observed vs. expected number of loss-of-function variants (8 vs. 142.7, p < 5 × 10-15). Using public databases of animal models and previously published data, we have found previously described zebrafish, mouse, and rat animal models of SPTAN1 deficiency, all consistently showing axonal degeneration, fitting the pathological features of HSP in humans. This study expands the phenotype of SPTAN1 mutations, which at the heterozygous state, when occurred de novo, may cause early infantile epileptic encephalopathy-5 (EIEE5). Our results further suggest that SPTAN1 may cause autosomal recessive HSP, and that it should be included in genetic screening panels for genetically undiagnosed HSP patients.


Assuntos
Proteínas de Transporte/genética , Proteínas dos Microfilamentos/genética , Degeneração Neural/genética , Paraplegia Espástica Hereditária/genética , Animais , Axônios/patologia , Proteínas de Transporte/química , Simulação por Computador , Feminino , Heterozigoto , Humanos , Masculino , Camundongos , Proteínas dos Microfilamentos/química , Modelos Animais , Mutação/genética , Degeneração Neural/fisiopatologia , Fenótipo , Conformação Proteica , Paraplegia Espástica Hereditária/epidemiologia , Peixe-Zebra/genética
7.
Neurochirurgie ; 65(6): 402-416, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31518578

RESUMO

Differential diagnosis of isolated single neurocysticercosis can be difficult, and management is controversial. We report here an original surgical strategy, and review previous studies reporting misdiagnosis, using the PRISMA guidelines. A 24-year-old man was admitted to our hospital for recent memory impairment, hypoesthesia of the right hand, and recurrent focal seizures without loss of consciousness. Brain MRI revealed a single ring-enhancing parenchymal lesion in the left superior postcentral gyrus, with large perilesional edema. Since exhaustive systemic exploration was negative, surgical resection of the lesion was decided on in a multidisciplinary team meeting. To preserve eloquent brain areas, surgery was performed in awake condition. It allowed complete resolution of clinical manifestations. The diagnosis of neurocysticercosis was confirmed on pathology. This case illustrates the utility of awake surgery in degenerating neurocysticercosis in functional areas, and emphasizes the importance of including it in differential diagnosis of cystic ring-enhancing brain lesions.


Assuntos
Encefalopatias/diagnóstico , Encefalopatias/cirurgia , Erros de Diagnóstico , Neurocisticercose/diagnóstico , Neurocisticercose/cirurgia , Procedimentos Neurocirúrgicos/métodos , Encefalopatias/diagnóstico por imagem , Diagnóstico Diferencial , Humanos , Imagem por Ressonância Magnética , Masculino , Degeneração Neural , Neurocisticercose/diagnóstico por imagem , Resultado do Tratamento , Vigília , Adulto Jovem
8.
Nat Neurosci ; 22(10): 1635-1648, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31551592

RESUMO

In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activation of naive astrocytes to the A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria into the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glial cells. The propagation of the inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration-one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria.


Assuntos
Astrócitos/patologia , Inflamação/patologia , Microglia/patologia , Mitocôndrias/patologia , Degeneração Neural/patologia , Animais , Morte Celular , Dinaminas/genética , Espaço Extracelular , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/genética , Neurônios/patologia , Ratos , Ratos Sprague-Dawley
9.
Nat Commun ; 10(1): 3945, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477726

RESUMO

Neuroinflammation is one of the hallmarks of Parkinson's disease (PD) and may contribute to midbrain dopamine (DA) neuron degeneration. Recent studies link chronic inflammation with failure to resolve early inflammation, a process operated by specialized pro-resolving mediators, including resolvins. However, the effects of stimulating the resolution of inflammation in PD - to modulate disease progression - still remain unexplored. Here we show that rats overexpressing human α-synuclein (Syn) display altered DA neuron properties, reduced striatal DA outflow and motor deficits prior to nigral degeneration. These early alterations are coupled with microglia activation and perturbations of inflammatory and pro-resolving mediators, namely IFN-γ and resolvin D1 (RvD1). Chronic and early RvD1 administration in Syn rats prevents central and peripheral inflammation, as well as neuronal dysfunction and motor deficits. We also show that endogenous RvD1 is decreased in human patients with early-PD. Our results suggest there is an imbalance between neuroinflammatory and pro-resolving processes in PD.


Assuntos
Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/administração & dosagem , Inflamação/prevenção & controle , Degeneração Neural/prevenção & controle , Doença de Parkinson/prevenção & controle , Animais , Ácidos Docosa-Hexaenoicos/genética , Ácidos Docosa-Hexaenoicos/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Humanos , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
10.
Int. arch. otorhinolaryngol. (Impr.) ; 23(3): 267-275, July-Sept. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1040018

RESUMO

Abstract Introduction Riluzole (2-amino-6-trifluoromethoxy benzothiazole) is known as a neuroprotective, antioxidant, antiapoptotic agent. It may have beneficial effects on neuronal cell death due to cisplatin-induced ototoxicity. Objective To evaluate the effect of riluzole on cisplatin-induced ototoxicity in guinea pigs. Methods Twenty-four guinea pigs, studied in three groups, underwent auditory brainstem response evaluation using click and 8 kHz tone burst stimuli. Subsequently, 5 mg/kg of cisplatin were administered to all animals for 3 days intraperitoneally (i.p.) to induce ototoxicity. Half an hour prior to cisplatin, groups 1, 2 and 3 received 2 ml of saline i.p., 6 mg/kg of riluzole hydrochloride i.p., and 8 mg/kg of riluzole hydrochloride i.p., respectively, for 3 days. The auditory brainstem responses were repeated 24 hours after the last drug administration. The cochleae were analyzed by transmission electron microscopy (TEM). Results After drug administiration, for 8,000 Hz stimulus, group 1 had significantly higher threshold shifts when compared with groups 2 (p < 0.05) and 3 (p < 0.05), and there was no significant difference in threshold shifts between groups 2 and 3 (p > 0.05). Transmission electron microscopy findings demonstrated the protective effect of riluzole on the hair cells and the stria vascularis, especially in the group treated with 8 mg/kg of riluzole hydrochloride. Conclusion We can say that riluzolemay have a protective effect on cisplatin- induced ototoxicity. However, additional studies are needed to confirm these results and the mechanisms of action of riluzole.


Assuntos
Animais , Masculino , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Cisplatino/efeitos adversos , Riluzol/farmacologia , Perda Auditiva Neurossensorial/induzido quimicamente , Limiar Auditivo/efeitos dos fármacos , Estria Vascular/efeitos dos fármacos , Estria Vascular/patologia , Nervo Coclear/efeitos dos fármacos , Nervo Coclear/patologia , Riluzol/uso terapêutico , Modelos Animais , Microscopia Eletrônica de Transmissão , Cobaias , Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Auditivas/patologia , Degeneração Neural/induzido quimicamente
11.
Nutrients ; 11(8)2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31387244

RESUMO

Resveratrol is the best-known chemical for extending the lifespan of various organisms. Extensive recent research has shown that resveratrol can extend the lifespan of single-celled organisms, but its effects on the extension of animal lifespans are marginal. Despite the limited efficacy of pure resveratrol, resveratrol with the endogenous property of the DJ rice in the resveratrol rice DJ526 previously showed profound health benefits. Here, we report that the resveratrol rice DJ526 markedly extended the lifespan of the fruit fly Drosophila melanogaster by as much as 41.4% compared to that of the control. The resveratrol rice DJ526 also improved age-related symptoms such as locomotive deterioration, body weight gain, eye degeneration and neurodegeneration in D. melanogaster upon aging. This result shows the most significantly improved lifespan in animal experiments to date, meaning that the resveratrol rice DJ526 will assist in the development of a therapeutic agent for longevity or addressing age-related degeneration.


Assuntos
Drosophila melanogaster/efeitos dos fármacos , Alimentos Fortificados , Longevidade/efeitos dos fármacos , Oryza , Resveratrol/administração & dosagem , Animais , Olho/efeitos dos fármacos , Olho/patologia , Feminino , Locomoção/efeitos dos fármacos , Masculino , Degeneração Neural , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/patologia , Valor Nutritivo , Fatores de Tempo , Ganho de Peso/efeitos dos fármacos
12.
Pathologica ; 111(2): 67-69, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31388198

RESUMO

Peripheral nerve mucoid degeneration (PNMD) is a rare non-neoplastic degenerative condition characterized by endoneural deposit of mucoid matrix. Herein, we report a case of PNMD involving the sciatic nerve with preoperative features, surgical treatment and pathological findings.


Assuntos
Degeneração Neural/diagnóstico por imagem , Degeneração Neural/cirurgia , Doenças do Sistema Nervoso Periférico/diagnóstico por imagem , Doenças do Sistema Nervoso Periférico/cirurgia , Nervo Isquiático/diagnóstico por imagem , Nervo Isquiático/cirurgia , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Nervo Isquiático/patologia
13.
Acta Diabetol ; 56(12): 1275-1282, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401734

RESUMO

AIMS: To investigate the association between progressive macular ganglion cell/inner plexiform layer (mGCIPL) thinning and change of optical coherence tomography angiography (OCTA)-derived microvascular parameters in early-stage diabetic retinopathy (DR). METHODS: A retrospective cohort study involved 40 eyes presenting with no DR or mild non-proliferative DR at baseline, and 30 healthy controls were included. All participants underwent spectral-domain OCT and OCTA at baseline and at 6, 12, 18, and 24 months. Change of mGCIPL thickness and OCTA metrics including foveal avascular zone (FAZ) area and FAZ circularity, vessel density (VD), and perfusion index (PI) was measured. Correlations between mGCIPL thickness and OCTA metrics were explored using regression models. RESULTS: Average progressive mGCIPL loss was 0.45 µm per year. Three microvascular parameters were significantly impaired at 24 months compared to baseline (FAZ area: 0.34-0.36 mm2, VD: 18.9-18.5/mm, PI: 0.35-0.34). A strong positive correlation was found between loss of mGCIPL and VD from baseline to 24 months (r = 0.817, p < 0.001). Multivariable regression analysis showed that thinner baseline mGCIPL and greater loss of mGCIPL thickness (B = 0.658, p < 0.001) were significantly associated with change of VD. CONCLUSIONS: In the early stage of DR, progressive structural retinal neurodegeneration and parafoveal microvascular change seem to be highly linked. Advanced mGCIPL thinning might precede microvascular impairment in early DR.


Assuntos
Angiopatias Diabéticas/patologia , Neuropatias Diabéticas/patologia , Retinopatia Diabética/patologia , Degeneração Neural/patologia , Neurônios Retinianos/patologia , Vasos Retinianos/diagnóstico por imagem , Idoso , Estudos de Casos e Controles , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/patologia , Angiopatias Diabéticas/diagnóstico , Neuropatias Diabéticas/diagnóstico , Retinopatia Diabética/complicações , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/fisiopatologia , Progressão da Doença , Feminino , Angiofluoresceinografia , Humanos , Estudos Longitudinais , Macula Lutea/diagnóstico por imagem , Macula Lutea/patologia , Masculino , Pessoa de Meia-Idade , Degeneração Neural/diagnóstico , Degeneração Neural/etiologia , Retina/diagnóstico por imagem , Retina/patologia , Neurônios Retinianos/ultraestrutura , Vasos Retinianos/patologia , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos
14.
Cells ; 8(8)2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31426448

RESUMO

: Accumulative evidence indicated that the pathologically accumulated metal ions (iron species and Mn3+) and abnormally up-regulated monoamine oxidase B (MAOB) activity induced oxidation of endogenous dopamine (DA) can lead to mitochondria impairment, lysosome dysfunction, proteasome inhibition, and selective DA neuron vulnerability, which is implicated in the pathogenesis of Parkinson's disease (PD). The DA oxidation can generate deleterious reactive oxygen species (ROS) and highly reactive DA quinones (DAQ) to induce DA-related toxicity, which can be alleviated by DA oxidation suppressors, ROS scavengers, DAQ quenchers, and MAOB inhibitors. On the other hand, the nuclear factor erythroid 2-related factor 2 (Nrf2)-Keap1 and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) anti-oxidative and proliferative signaling pathways play roles in anti-oxidative cell defense and mitochondria biogenesis, which is implicated in DA neuron protections. Therefore, agents with capabilities to suppress DA-related toxicity including inhibition of DA oxidation, scavenge of ROS, detoxification of DAQ, inhibition of MAOB, and modulations of anti-oxidative signaling pathways can be protective to DA neurons. Accumulative evidence shows that tea or coffee consumptions and smoking are related to deceased PD prevalence with unknown mechanisms. In this study, we investigate the protective capabilities of tea polyphenols and other PD relevant agents to inhibit DA-related toxicity and protect against environmental or genetic factors induced DA neuron degeneration in vitro and in vivo. We find that tea polyphenols can significantly suppress DA-related toxicity to protect DA neurons. The tea polyphenols can protect DA neurons via inhibition of DA oxidation, conjugation with DAQ, scavenge of ROS, inhibition of MAOB, and modulations of Nrf2-Keap1 and PGC-1α anti-oxidative signaling pathways. The tea polyphenols with more phenolic hydroxyl groups and ring structures have stronger protective functions. The protective capabilities of tea polyphenols is further strengthened by evidence that phenolic hydroxyl groups can directly conjugate with DAQ. However, GSH and other sulfhydyl groups containing agents have weaker capabilities to abrogate DA oxidation, detoxify ROS and DAQ and inhibit MAOB; whereas nicotine (NICO) and caffeine (CAF) can only modulate Nrf2-Keap1 and PGC-1α pathways to protect DA neurons weakly. The tea polyphenols are identified to protect against overexpression of mutant A30P α-synuclein (α-syn) induced DA neuron degeneration and PD-like symptoms in transgenic Drosophila. Based on achievements from current studies, the excellent and versatile protective capabilities of tea polyphenols are highlighted, which will contribute and benefit to future anti-PD therapy.


Assuntos
Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Degeneração Neural/tratamento farmacológico , Doença de Parkinson , Polifenóis/farmacologia , Animais , Dopamina/análogos & derivados , Dopamina/toxicidade , Drosophila , Células HEK293 , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Extratos Vegetais , Chá
15.
Adv Exp Med Biol ; 1173: 145-152, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456209

RESUMO

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of motor neurons in the motor cortex, brainstem, and spinal cord. The etiology and pathogenesis of this devastating disease remain largely unknown. Increasing evidence suggests that iron accumulation is involved in the onset and progression of ALS. In this review, we discuss the regulation of iron homoeostasis in the brain, the misregulation of iron homeostasis in ALS, and its possible roles in the mechanism of the disease. Finally, we summarize the recent progress and problems with respect to iron chelator therapies on ALS, aiming to propose a new therapeutic strategy to ameliorate the progression of the disease.


Assuntos
Esclerose Amiotrófica Lateral/fisiopatologia , Encéfalo/metabolismo , Ferro/metabolismo , Homeostase , Humanos , Neurônios Motores/patologia , Degeneração Neural
16.
J Trace Elem Med Biol ; 56: 146-155, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31470248

RESUMO

BACKGROUND: Calcium is an essential macronutrient that is involved in many cellular processes. Homeostatic control of intracellular levels of calcium ions [Ca2+] is vital to maintaining cellular structure and function. Several signaling molecules are involved in regulating Ca2+ levels in cells and perturbation of calcium signaling processes is implicated in several neurodegenerative and neurologic conditions. Manganese [Mn] is a metal which is essential for basic physiological functions. However, overexposure to Mn from environmental contamination and workplace hazards is a global concern. Mn overexposure leads to its accumulation in several human organs particularly the brain. Mn accumulation in the brain results in a manganism, a Parkinsonian-like syndrome. Additionally, Mn is a risk factor for several neurodegenerative diseases including Parkinson's disease and Alzheimer's disease. Mn neurotoxicity also affects several neurotransmitter systems including dopaminergic, cholinergic and GABAergic. The mechanisms of Mn neurotoxicity are still being elucidated. AIM: The review will highlight a potential role for calcium signaling molecules in the mechanisms of Mn neurotoxicity. CONCLUSION: Ca2+ regulation influences the neurodegenerative process and there is possible role for perturbed calcium signaling in Mn neurotoxicity. Mechanisms implicated in Mn-induced neurodegeneration include oxidative stress, generation of free radicals, and apoptosis. These are influenced by mitochondrial integrity which can be dependent on intracellular Ca2+ homeostasis. Nevertheless, further elucidation of the direct effects of calcium signaling dysfunction and calcium-binding proteins activities in Mn neurotoxicity is required.


Assuntos
Sinalização do Cálcio , Manganês/toxicidade , Neurotoxinas/toxicidade , Animais , Sinalização do Cálcio/efeitos dos fármacos , Humanos , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Espécies Reativas de Oxigênio/metabolismo
17.
EMBO J ; 38(18): e100811, 2019 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-31436334

RESUMO

The retina is a specialized neural tissue that senses light and initiates image processing. Although the functional organization of specific retina cells has been well studied, the molecular profile of many cell types remains unclear in humans. To comprehensively profile the human retina, we performed single-cell RNA sequencing on 20,009 cells from three donors and compiled a reference transcriptome atlas. Using unsupervised clustering analysis, we identified 18 transcriptionally distinct cell populations representing all known neural retinal cells: rod photoreceptors, cone photoreceptors, Müller glia, bipolar cells, amacrine cells, retinal ganglion cells, horizontal cells, astrocytes, and microglia. Our data captured molecular profiles for healthy and putative early degenerating rod photoreceptors, and revealed the loss of MALAT1 expression with longer post-mortem time, which potentially suggested a novel role of MALAT1 in rod photoreceptor degeneration. We have demonstrated the use of this retina transcriptome atlas to benchmark pluripotent stem cell-derived cone photoreceptors and an adult Müller glia cell line. This work provides an important reference with unprecedented insights into the transcriptional landscape of human retinal cells, which is fundamental to understanding retinal biology and disease.


Assuntos
Degeneração Neural/genética , RNA Longo não Codificante/genética , Retina/química , Análise de Célula Única/métodos , Transcriptoma , Autopsia , Análise por Conglomerados , Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Humanos , Especificidade de Órgãos , Células Fotorreceptoras Retinianas Bastonetes/química , Análise de Sequência de RNA , Aprendizado de Máquina não Supervisionado
18.
Nat Commun ; 10(1): 3784, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439839

RESUMO

Disruption in membrane excitability contributes to malfunction and differential vulnerability of specific neuronal subpopulations in a number of neurological diseases. The adaptor protein p11, and background potassium channel TASK1, have overlapping distributions in the CNS. Here, we report that the transcription factor Sp1 controls p11 expression, which impacts on excitability by hampering functional expression of TASK1. In the SOD1-G93A mouse model of ALS, Sp1-p11-TASK1 dysregulation contributes to increased excitability and vulnerability of motor neurons. Interference with either Sp1 or p11 is neuroprotective, delaying neuron loss and prolonging lifespan in this model. Nitrosative stress, a potential factor in human neurodegeneration, stimulated Sp1 expression and human p11 promoter activity, at least in part, through a Sp1-binding site. Disruption of Sp1 or p11 also has neuroprotective effects in a traumatic model of motor neuron degeneration. Together our work suggests the Sp1-p11-TASK1 pathway is a potential target for treatment of degeneration of motor neurons.


Assuntos
Esclerose Amiotrófica Lateral/patologia , Anexina A2/metabolismo , Neurônios Motores/patologia , Degeneração Neural/patologia , Proteínas do Tecido Nervoso/genética , Canais de Potássio de Domínios Poros em Tandem/genética , Proteínas S100/metabolismo , Fator de Transcrição Sp1/metabolismo , Esclerose Amiotrófica Lateral/etiologia , Animais , Membrana Celular/patologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Masculino , Potenciais da Membrana , Camundongos , Camundongos Transgênicos , Neurônios Motores/citologia , Degeneração Neural/etiologia , Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Cultura Primária de Células , Regiões Promotoras Genéticas , Ratos , Fator de Transcrição Sp1/genética , Medula Espinal/citologia , Medula Espinal/patologia
19.
Invest Ophthalmol Vis Sci ; 60(10): 3283-3296, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31369031

RESUMO

Purpose: Glaucoma is a complex disease with major risk factors including advancing age and increased intraocular pressure (IOP). Dissecting these earliest events will likely identify new avenues for therapeutics. Previously, we performed transcriptional profiling in DBA/2J (D2) mice, a widely used mouse model relevant to glaucoma. Here, we use these data to identify and test regulators of early gene expression changes in DBA/2J glaucoma. Methods: Upstream regulator analysis (URA) in Ingenuity Pathway Analysis was performed to identify potential master regulators of differentially expressed genes. The function of one putative regulator, mesenchyme homeobox 2 (Meox2), was tested using a combination of genetic, biochemical, and immunofluorescence approaches. Results: URA identified Meox2 as a potential regulator of early gene expression changes in the optic nerve head (ONH) of DBA/2J mice. Meox2 haploinsufficiency did not affect the characteristic diseases of the iris or IOP elevation seen in DBA/2J mice but did cause a significant increase in the numbers of eyes with axon damage compared to controls. While young mice appeared normal, aged Meox2 haploinsufficient DBA/2J mice showed a 44% reduction in MEOX2 protein levels. This correlated with modulation of age- and disease-specific vascular and myeloid alterations. Conclusions: Our data support a model whereby Meox2 controls IOP-dependent vascular remodeling and neuroinflammation to promote axon survival. Promoting these earliest responses prior to IOP elevation may be a viable neuroprotective strategy to delay or prevent human glaucoma.


Assuntos
Axônios/patologia , Glaucoma/genética , Haploinsuficiência/genética , Proteínas de Homeodomínio/genética , Degeneração Neural/genética , Disco Óptico/patologia , Células Ganglionares da Retina/patologia , Animais , Pressão Sanguínea/fisiologia , Western Blotting , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/fisiologia , Glaucoma/patologia , Pressão Intraocular/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Degeneração Neural/patologia , Microscopia com Lâmpada de Fenda
20.
Acta Neurol Taiwan ; 28(1): 1-11, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31321759

RESUMO

OBJECTIVE: Vagal nerves and their thermoreceptors could regulate temperature of brain. Cerebrospinal fluid (CSF) is increased in the early phases of subarachnoid hemorrhage (SAH). We hypothesised that choroid plexuses probably innervated by vagal nerves may play a role on the regulation of brain temperature and studied this subject. METHODS: This study was conducted on 32 rabbits, divided into four groups, with five rabbits in the control group (group I), five rabbits in the sham group (Group II), and 22 rabbits in the SAH group. In the SAH group, 7 of the animals were decapitated after 7 days of cisternal blood injections (Group III), and the other 15 animals were decapitated after 21 days of injections (Group IV). Brain temperature via laser thermometer 5 times a day during the experiment was measured. Normal and degenerated neuron density of nodose ganglia, water vesicles numbers of choroid plexuses were stereologicallyanalyzed. Statistical analysis was performed. RESULTS: At histopathologic analysis of present study, thermo regulator like structure was noted and the mean number of this structure was estimated.The mean number of water-filled vesicles, thermo regulator like structure, in SAH-induced animals,brain temperature and degenerated neuron density of nodose ganglia was statistically different between the early decapitated group (group III) and the late decapitated group (group IV) (P less then 0.05). CONCLUSIONS: We introduce a thermo regulator like structure, describe a new syndrome. In addition, it was noted thatwater-filled vesicles of CP are increased, brain temperature in nearly normal in the early phase of SAH due to likely irritation of vagal nerves. However in the late phase, mean number of water-filled vesicles numbers decreased in accordance with increased brain temperature with degenerative changes of the nodose ganglion.


Assuntos
Hemorragia Subaracnóidea , Animais , Encéfalo , Corioide , Febre , Degeneração Neural , Coelhos
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